Opioids Oxymorphone vs oxycodone bio-availability math problem please help

[c0d3l3g3nd]

Okay so on my drive home from work i was trying to figure this out in my head and I can't seem to come to a satisying conclusion. Maybe I havent been sleeping enough but I greatly appreciate if someone could shed some light on my oxyMorphone to oxyCodone conversion with respect to bio-availability.

%) Please note that for when i refer to the oral doses of oxymorphone and oxycodone I am refering to the IR (instant release) formulations. Not the extended or time release

• Orally Oxymorphone has a bio-availability of around 10% . So by taking a 40mg Opana orally roughly 10% or 4mg would be absorbed.
• Orally oxymorphone is said to be 1.5-2 times as potent as oxycodone. So a 40mg opana is equvilent to roughly 60mg to 80mg of oxycodone orally (lets call it 80mg for the sake of this)
• Orally oxycodone has a bio-availability of 75% - 87% depending on various factors lets call it 80% for the sake of this problem. Meaning an oral dose of oxycodone of 80mg 80% or 64mg is being absorbed.

So you can conclude that orally 4mg of opana absorbed has the same potency as 64mg of the absorbed oxycodone.

Working backwards, say a doctor wants to dose a patient ideally with 4mg of opana per day the only way to dose that would be to A. Intravenously 100% bio-availability so all 4mg would be absorbed. but Because daily intravenous use is inconvient and not very practical they must dose the patient orally with 4mg but due to low oral bio-availability 10% - 40mg must be taken orally to recive the active dose of 4mg of opana. Same goes for oxycodone to recieve a dose of 64mg it must be administred intraveniusoly or 80mg orally because only 80% is absorbed so to recive 64mg of active ingredient an additional 20% is added to the oral dose because it is lost during ingestion.

Here is my problem if bio-availability of opana is increased for example intranasal administration is said to have a bio-availability of 40% meaning that with a 40mg intranasal dose 16mg is being absorbed compared to 4mg orally.

So we know that 4mg of absorbed opana is equal to 64mg absorbed oxycodone. There wouldnt 16mg of absorbed opana be equivalent to 256mg absorbed oxycodone? aka a 16mg IV dose of opana is equal to a 256mg IV oxycodone dose. Or:

a

• 40mg opana dose insufullated would be equal to 320mg of oral oxycodone.
• 40mg opana dose insufflated would be equal to to 545mg of insufflated oxycodone assuming that when insufflated oxcycodone has a bio-availability of 47% so 545mg would need to be snorted to absorb 256mg active oxycodone which is equivalent to the 16mg opana absorbed when insufflated.

Please someone find a flaw in my reasoning or math because I have snorted a 40mg opana and I have snorted 545mg of oxycodone and in my mind 545mg of oxycodone insufflated is WAAAAY stronger than 40mg of opana insufflated. Same goes for 40mg insufflated opana vs 320mg oral oxycodone the oxycodone still wins. Obviously these figures are not exact the range in bio-availability would change some of the numbers but either way the data assuming that oxymorphone is somewhere between 10 and 16 times stronger than oxycodone when it is insufflated of IV'd.

Am I overlooking cross-tolerance or something? Does the fact that oxymorphone half life is approximately 2x that of oxycodone have anything to do with it?

 

[Tommyboy]

Yea you screwed up somewhere if you thought that sniffing 40mg of oxymorphone would be the same as sniffing 545mg of oxycodone. Sniffing an opana 40 would have me high, but sniffing 545mg of oxycodone would have me close to death. For one, the BA of intranasal oxycodone may be higher than you thought since it varies a lot, and can be close to oral in some people.

 

[c0d3l3g3nd]

I don't think 40 mg opana is the same as 545mg of oc. Its apparent there is big difference there im just sayin i cant see anywhere in my math says otherwise. Even if the BA of oxycodone intranasal was 100% it would still be 40mg opana vs 256 mg oxycodone and that still doesnt seem right. I know it cant be right i just want someone to find specially what im doing wrong

 

[Tommyboy]

Well keep in mind that these are for pain killing effects. It doesn't mean that the equivalent doses get you the same high. You only need a very little bit of oxymorphone to give you pain relief, but some people need higher doses to feel the high. On the other hand, most people find oxycodone to be very euphoric, so you may be high at doses just enough for pain relief.

Also, comparison charts vary, so perhaps the one you are using is off.

 

[c0d3l3g3nd]

Ya no matter what comparison charts i use, the numbers dont vary enough to make much difference in the end result. I think you hit it right on the head. I was presuming that the strength of opiates is defined by euphoria i feel or how hard i nod. I totally forgot that they are manufactured for another purpose. lol. Im sure the data on opiate comparsion strengths is based on other criteria than euphoria lol. Im sure the data that dictates that opana is 10 times stronger is based off of something like the opiates ability to saturate or bind to opiate receptors or something. If anyone knows how opiate strengths are determined id love to hear it!

 

[Swimmingdancer]

TL;DR: Opioid conversion ratios are unreliable and are merely a rough guide to determine relative analgesia (pain killing effects). Also, nasal BAs for these drugs have not been well-studied.

Long version:
The ratios in conversion charts are for comparative analgesia. But conversions are far from perfect and are only a very rough guide. Most conversion ratios are averages taken from small surveys conducted on opioid-naive patients about how well a particular opioid controls their pain. For example someone might be given enough morphine to alleviate their pain and then the next day be given enough oxymorphone until they said their pain was alleviated or the doctor decided they looked like they were in less pain. That's how imprecise it is. The conversions don't take into account factors like re-dosing, chronic use of the drug, tolerance, incomplete cross-tolerance, individual differences in metabolism (which can be great), etc. Conversion tables/ratios have been criticized as not even accurately reflecting the available evidence, or being based on very old and/or small studies. Most equianalgesic conversion data is derived from old studies not well-designed for practical application in dose-conversion, single dose studies, or studies and case reports that were not even intended to detect relative opioid potencies. Often the conversion recommendations emerged as secondary observations made by clinicians. In addition, if people in acute pain were surveyed, a patient's pain level may be constantly fluctuating, which would make their opinion about how well a particular opioid controlled their pain not very reliable. It is really not a precise science at all. Furthermore, if data only exists on oral administration it is not going to extrapolate very well to other ROAs.

Just to make sure your math was correct, I did the calculations as well just for fun and I did end up with around the same results as you. If you go with the published BAs and dose conversions, then 40mg nasal oxymorphone should = ~480-600mg nasal oxycodone. So, yeah, that seems unrealistic.

So here are my theories to explain the discrepancy:
- Conversions are far from perfect and are only a very rough guide. (see above) The dose equivalence for oxycodone in particular has been disputed.
- There is a lot of variance from person to person.
- We may be measuring strength/efficacy in different areas than they are (say, euphoria vs analgesia).
- The published BAs may not be accurate. There have been very few studies done on the nasal BA of these substances and they definitely leave something to be desired in terms of reliability. Published BAs are also just rough averages from the group they studied (in the case of oxycodone it was like 7 people or something and they did not measure their levels for oral oxycodone to see if they fit the average). And in reality BA varies greatly from person to person.
- There is not complete cross-tolerance between opioids. In reality, cross-tolerance usually ranges from 25%-75%. So if someone were used to using oxymorphone, they may need only around 50% of the "equivalent" dose of oxycodone.
- There may be a problem in measuring the BA of oxycodone if they are just measuring the oxycodone in the blood and not it's other active metabolites. I'm not sure how they measure it.

 

[StretchOutAndWait]

Thanks for the lengthy response. I did not know that conversion studies were so methodologically unreliable, although from my own experience with a a few different opioids administered in a variety of ways I had wondered about this.

- There may be a problem in measuring the BA of oxycodone if they are just measuring the oxycodone in the blood and not it's other active metabolites. I'm not sure how they measure it.

This seems like a really important point and I don't quite understand why this would ever be done. I've been taking a Pharm 101 class and we've been taught that bioavailability is the percentage of a drug which reaches the systemic circulation in an unchanged form. But with drugs like oxy or codeine this seems like a fairly useless definition to me - surely the amount of active metabolites in the systemic circulation is the relevant figure?

Obviously this would be harder to measure because it's not just the area under one curve divided by the area under another, but I mean is measuring the amount of, say, codeine in plasma while ignoring morphine and c6g useful as anything more than an academic exercise?

 

[Swimmingdancer]

I really think the primary issue here is that it's impossible to try to make a remotely accurate dose comparison by using bioavailabities. A BA - even if it were accurate, which I don't believe the nasal BAs in this case are - does not take into account the onset, intensity or duration of effects, which would be different for nasal compared to oral.

Then there's the issue of BAs possibly having no relation to a drug's effects in the case of a pro-drug or partial pro-drug. I'm very curious about this as well. I had previously thought BA was actually supposed to be the percentage of the drug in comparison to IV that reaches systemic circulation in its active form. But do they usually in practice only measure % of unchanged original drug? How do they measure the BAs for pro-drugs and partial pro-drugs? Like some drugs may have their main effects come from a metabolite, and some may get effects from both the original form of the drug and from one or more active metabolites. So if they are not measuring active metabolites, the BAs for pro-drugs or partial pro-drugs are meaningless when it comes to efficacy of the drug.

There are some weird published BAs out there. For example, if you look at the BAs for theophylline, it gives an IV BA of 100% and an oral BA of 111%, which I don't understand. [source]. I could see that happening for a pro-drug if they were measuring the active metabolite, but I didn't think that was the case with theophylline. Strange.

I found one study of a pro-drug's absorption where they measured both - they took the blood levels of the drug itself and compared it with IV, and then they also compared the levels of the active metabolite after oral administration of the pro-drug with IV administration of the active metabolite. I wish I could find the details on how they measure the BA for things like codeine.

 

[Znegative]

I have some personal experience with Oxymorphone along Side Oxycodone, both used IV. From my experienced, IV oxymorphone is approximately 10X more potent than IV Oxycodone. When I was shooting the 10mg IR's, I remember switching to oxycodone IR, and had to shoot 90 mg to feel any semblance of a high (which was weak and short acting, but such is the quality of the IV oxy experience.)

Insufflating the oxymorphone seemed to be 1/2 as potent as intravenous administration, which would lead me to believe that 20mg absorbed (assuming that it's 50 % ) is 10mg absorbed, equal to about 100 mg of oxycodone. If its a 40% BA, then the oxymorphone absorbed would be 8mg, roughly equivalent to 80mg of oxycodone.

Now this is all assuming the Oxycodone is being absorbed 100% so I'll make the calculations for these dosages with the oral Oxycodone BA:

40 mg of Oxymorphone oral: 4 mg of oxymorphone absorbed due to 10% BA equipotent to about 32 mg of oral oxycodone.

40 mg of Oxymorphone insufflated: 20 mg of oxymorphone absorbed absorbed if 50% BA, 16 mg absorbed if 40% BA. 20mg of absorbed oxymorphone would equal about 160 mg of oral oxycodone, whereas 16mg of absorbed oxymorphone should equal about 128 mg of oral oxycodone. Or at least thats the math I got-I'm more of a left brain guy, but I'm pretty sure this takes every thing into account.

 

[StretchOutAndWait]

I really think the primary issue here is that it's impossible to try to make a remotely accurate dose comparison by using bioavailabities. A BA - even if it were accurate, which I don't believe the nasal BAs in this case are - does not take into account the onset, intensity or duration of effects, which would be different for nasal compared to oral.

Yeah, this is it. It has been emphasised in our course that bioavailability is pharmacokinetics (what the body does to the drug). It should not be confused with therapeutic effect which is pharmacodynamics (what the drug does to the body).

But therapeutic effect must at least be a function of bioavailability and as you say the exact methods with which the BA of drugs is calculated do sometimes seem to be rather unclear.

Regarding the theophylline example, it seems to me that you could have an oral BA higher than an IV BA if the drug when taken orally is absorbed into the systemic circulation significantly more slowly than it is metabolised from plasma.

This is the lecture slide on how to calculate BA - looks like they're using the same method with theophylline (comparison of area under curve data (AUC)).

If you had a drug where it was absorbed very slowly but metabolised very quickly, you would (I think!) end up with a graph looking like this:

(Yes I have l33t ms paint skillz.)

So in this theoretical case (which may or may not be the situation with theophylline), the drug is absorbed into plasma so slowly orally that it limits the rate it can be metabolised, so you actually end up with a larger AUC with an oral dose than an IV one. This is total speculation and could be wrong but I think it makes sense. If someone who knows better thinks it is wrong, please tell me!

Edited to add: Yay, not a greenlighter anymore!

 

[DooMMooD]

Considering only X amount would be absorbed, it would be that amount X whatever number. Znegative hit the nail on the head.

So 4mg absorbed? And that 4mg is 1.5-2x stronger than oxy? Your answer right there.

Hence why oral oxymorphone blows to get high. For pain relief its good because its a constantly released low dose.

and STRETCHOUTANDWAIT is right about how to determine differences in the drugs, if you wanna take it that far. AUC differences will give you a better idea of the ENTIRETY of a dose and its effect/absorbtion/etc etc etc. Compare the two AUCs as he says.

 

[Swimmingdancer]

Yeah, this is it. It has been emphasised in our course that bioavailability is pharmacokinetics (what the body does to the drug). It should not be confused with therapeutic effect which is pharmacodynamics (what the drug does to the body).

Yep, for example you could have a drug that is absorbed more slowly have a high BA but less noticeable effects.

Regarding the theophylline example, it seems to me that you could have an oral BA higher than an IV BA if the drug when taken orally is absorbed into the systemic circulation significantly more slowly than it is metabolised from plasma.

Ah, thanks for explaining. I see, so if by IV a drug was flushed out of your system faster or deactivated to an inactive metabolite than it was by mouth, then you could end up with a higher oral BA. It's not really that any less of the drug reaches the bloodstream with IV, it's just that when taken orally the drug stays in the system longer and so some of it is technically being counted twice. Am I understanding correctly? So if that's true, then BA is not actually an accurate measure of how much drug reaches systemic circulation in the bloodstream, it's just the best way we have of estimating it?

You're images didn't show up so I fixed them for you

This is the lecture slide on how to calculate BA:

If you had a drug where it was absorbed very slowly but metabolised very quickly, you would (I think!) end up with a graph looking like this:

Thanks for your helpful and educated post


One thing I wanted to emphasize in the case of oxycodone is that people have brought up some real issues with the published nasal BA.

Considering only X amount would be absorbed, it would be that amount X whatever number.
So 4mg absorbed? And that 4mg is 1.5-2x stronger than oxy? Your answer right there.

That wouldn't work. The published conversion ratio is 1mg of orally administered oxymorphone = ~1.5 to 2mg orally administered oxycodone. That ratio is not describing the amount of each drug that reaches systemic circulation ("absorbed", although that is not technically the correct term), just how many mgs of each drug you swallow.

 

[StretchOutAndWait]

Thanks for fixing the images. Sorry for taking so long to reply. I've been chewing this one over.

Ah, thanks for explaining. I see, so if by IV a drug was flushed out of your system faster or deactivated to an inactive metabolite than it was by mouth, then you could end up with a higher oral BA. It's not really that any less of the drug reaches the bloodstream with IV, it's just that when taken orally the drug stays in the system longer and so some of it is technically being counted twice. Am I understanding correctly? So if that's true, then BA is not actually an accurate measure of how much drug reaches systemic circulation in the bloodstream, it's just the best way we have of estimating it?

When you put it like this, it seemed to me that I must be wrong. But actually, I think that this is the case. Let's say I make a drug called Stretchazalom with the following properties:

1. When taking orally, it is absorbed into the systemic circulation at the rate of 1mg/minute.
2. It is metabolised from plasma at the rate of 100mg per minute.
3. None of it is metabolised through the first pass effect.

So, whether you take this drug IV or orally, the same amount will reach the systemic circulation.

Let's say that you inject 100mg. This will all be metabolised in minute one, leaving you with a "curve" which looks like this:

Whereas if you eat it, 1mg is absorbed into circulation each minute, which is metabolised in that minute just as the next mg is absorbed, leaving you with a constant presence in the blood stream of 1mg until it is all absorbed. So your curve will look this:

(On both of the above graphs, the x axis is time in minutes, and the y axis is mg in systemic circulation.)


Obviously in both cases, 100mg of Stretchazolam is absorbed into the systemic circulation. But if you measure the area under the curves, you get:

IV: This is a right angled triangle so area = 1/2 (length * width) = 1/2 (100 * 1) = 50
Oral: This is (close enough to) a square where area = (length * width) = (100 * 1) = 100

Which would mean that the oral bioavailability of Stretchazolam is 200%.

So yeah, measuring bioavailability in this way (which seems to be the way in the lecture slide I posted above and the way used in the theophylline study) really does not seem to reflect how much of the drug reaches the systemic circulation. I feel like this makes no sense and I must be doing something wrong, but I don't know what. If anyone who knows feels like weighing in on this, that would be much appreciated!

Edit: I actually think this may just be a trick to do with how I've drawn the graphs, and to be consistent the IV graph should also be a square bounded by 0 and 1 on the x axis and 0 and 100 on the y axis. Either that, or the oral graph should really be a series of triangles running from 1mg to 0mg each minute, followed immediately by a straight line from 0 to 1 as soon as the next minute hits, and then a triangle again. Like: l\l\l\l\l\l\l\ etc.

If this was done the BA would be the same (as in the first case it's doubled and in the second it's halved). So, sorry, this doesn't answer your question at all!

 

[Swimmingdancer]

I think you might be on to something. And I think this could have something to do with "non-equivalent clearance" or perhaps a first-pass effect in routes other than oral. I will do more research on this tomorrow, as this subject interests me. If you're right, I think you've latched onto an inherrant flaw in the way BA is measured (at least when it's measured this way, which is the usual way - there's apparently another way involving isotopic labelling which is much less frequently used). So if you add that to the fact that BA can vary greatly from person to person and the fact that BA does not equate to effects or strength of effects (and seems useless when talking about pro-drugs if it in fact only refers to the original drug), then really we should be taking BA as just a rough comparison of ROAs and not gospel

 

[StretchOutAndWait]

I think I'm wrong (see my 12:17 edit)! Gotta go out now I'm afraid, got a train to catch. Have to say, I'm enjoying thinking about this, anyway.

 

[Swimmingdancer]

So I think I found out why some drugs could have a higher BA orally than IV. It's because with different ROAs the drug may be metabolized or cleared differently. So a drug could be deactivated or removed from the body faster when taken IV than when taken orally. So it is correct to say that BA is not truly a measure of how much of a drug reaches systemic circulation. It's just the AUC compared with the AUC.

Theophylline, for example, apparently undergoes first-pass metabolization by the lungs when taken IV, but taking it orally bypasses this first pass. I didn't even think about organs other than the gut and liver enacting extensive first-pass metabolization before. Interesting. Metabolization of theophylline also quickly becomes saturated, so perhaps that might play a role in the BA as well.

 

[StretchOutAndWait]

Sorry, swmmingdancer, this is basically a conversation that has pushed the limits of my (very patchy) knowledge. I've been thinking about this (I even had an ill-advised attempt at explaining it to a friend during day three of a psychedelics bender).

I still feel like I don't understand how theophylline can undergo a first-pass effect in the lungs if IVed. Isn't the point of IV administration that it avoids any first pass effect? I have a lecture slide which says exactly this, which I can upload if you like! The IM and Sub-Q slides don't say this - they just say "bypasses metabolism in the stomach and liver", presumably because the drug can be metabolised in tissue prior to reaching the systemic circulation. But the IV slide is quite explicit.

This is frustrating - feel like I'm going round in circles with quite a basic principle.