Opioids Question about Intranasal Bioavailability

[recyclethepandas]

This thread is particularly about generic Morphine Sulphate tablets, 30mg instant release. Those teeny little purple pills with a boxed M on one side and 30 on the other. However, I'm sure this ought to relate to any drug that one might insufflate.

Basically, I'm asking about the bioavailabilities of morphine, specifically the sulphate salt... There are a few discrepancies on the internet, but the most reliable sources I could find, as well as the most generally agreed-upon forum answers, have it that the oral BA is somewhere between 20% and 30%, while the intranasal BA is around 10%. Obviously it is pretty unusual, especially for opiates, that a drug would be absorbed more poorly in the nose than in the stomach, but I'm sure there is a sound chemical explanation, so I have been satisfied with this answer. I have used morphine either orally or intravenously every time because of this, but it dawned on me today that, well, so what if the nasal absorption is worse? Obviously, "nasal bioavailability" and "oral bioavailability" actually describe two more specific, separate processes. Nasal bioavailability is really just a reference to the amount of drug x absorbed into the nasal tissue, rather than the amount of drug x that reaches the brain, since all that is absorbed into the mucous membranes will eventually reach the circulatory system just as it would if parenterally administered. This means that, if 100% of drug x is absorbed by the circulatory system when drug x is injected intravenously, then 10% of drug x is absorbed by the circ. system when drug x is snorted. However, while oral BA describes the same thing, absorption by the circulatory system, it is also a function of metabolism, since drug x must pass through the liver before it can be absorbed by veins. Obvious, I know, but I want to keep the definitions very clear so we can figure this next part out.

We all know that when you sniff drug x, some is going to absorb into your nasal mucous membrane, while some is going to drip down... into your stomach. Now, I suspect that everyone who answered the question of morphine sulphate's intranasal BA found their answer somewhere on google. Going through google will lead one to clinical studies, on sheep, and probably others, that show that 10% of the solution placed in the nasal cavity will eventually pass through the capillaries and into the bloodstream. But how was this measured? Did they simply measure displacement of the solution, to see how much had physically diffused through the membrane? The reason this is relevant is because one would think that all of the morphine that diffuses through the membrane will enter the bloodstream, while all of the morphine that doesn't diffuse through will drip into the stomach, entering the bloodstream after first pass metabolism. I will do a little calculation to show the true results of snorting morphine, if my theory is true, and then I will consider a logical counterargument to the theory.

So, let's say you swallowed 100mg of morphine. Using a fixed average BA of 25%, rather than 20-30%, your bloodstream will obviously only transport 25mg beyond your excretory system.

Now let's say your friend snorted 100mg of morphine instead. Using a fixed average BA of 10%, in my theory, your bloodstream will immediately absorb 10mg. However, assuming the other 90mg didn't just disappear, it's probably a safe bet to say that it dripped down into your stomach. (Now, before criticizing my theory, read the paragraphs under this, because I will go into detail about the other possibility) Once the 90mg has entered your stomach, returning to an oral BA of 25%, after first pass metabolism another 22.5mg has entered your bloodstream. Added together, obviously, your bloodstream now contains 32.5mg, more than your friend got from just swallowing it.

This conclusion assumes that "10% intranasal bioavailability" refers to how much of drug x diffuses through the nasal cavity, and that every molecule that diffuses through the cavity ends up in your bloodstream. One natural counterargument is that "10% intranasal BA" actually refers to how much of drug x diffuses into the bloodstream, not through the nasal cavity. This theory would have it that 100% of drug x actually diffuses through the membrane, but only 10% of the membrane-bound drug x actually makes it into the bloodstream. This would mean, quite literally, that swallowing morphine will get you higher than snorting it. But I am very skeptical of this idea, because it just doesn't make sense. Where does the other 90% go? I can understand that it might be faintly possible that enzymes in your nasal tissue are capable of metabolizing morphine, but I seriously doubt it would happen before all of the morphine diffuses into the bloodstream, since snorting morphine does produce effects within 10-15 minutes, while morphine's half life in the liver, let alone the nasal cavity (lol), is on the order of hours. The only other way I could see that snorting morphine would only deliver 10% of the drug to your bloodstream, would be if you sneezed it out before it started dripping.

I started writing this thread while I was considering what to do with my last morphine pill. I was interrupted by my friend letting me know he would deliver my gram of smack right to my house if I gave him my last morphine pill, so I obliged. Unfortunately, this thread is no longer relevant to my life (at least for now) since I am now happily tarred and feathered... But I love writing and I love bluelight, so I thought I would share my idea and put it up for debate. If anybody somehow knows a lot about the metabolic processes in the nasal cavity, I'd love to hear your take on the whole thing. If somebody reads this and sees that it makes sense, I invite you to do both trials yourself and post the results. If anybody reads this and says "god this guy is an idiot," please show me my mistake (or post a totally moronic theory in response to mine so we all get some laughs out of it).

Really, it seems to be a huge difference... I mean, I have literally never snorted morphine because I always assumed that if I snorted a 30mg pill I would only absorb 3mg. But it just doesn't make sense. Where do the other 27mgs go? It all makes sense now - the scientific studies merely measured nasal absorption, as the studies were not tailored to recreational drug users. They must not have cared about or considered the possibility that the 90% not absorbed would eventually enter the stomach and be absorbed into the liver.

Thanks for your consideration guys hopefully we get to the bottom of this. I would be pretty shocked to find out that I am the first person who considered this possibility, but you never know. People often look at the numbers in scientific journals and don't consider what the numbers might specifically be referring to.

 

[Psychedelic Jay]

When you snort 100 mg of morphine, some gets incompletely absorbed and then some is destroyed by your liver... Leaving 10mg...

You absorb some percent and then your body destroys some percent from first pass metabolism.

The way you state it doesn't work that way.

Bioavailability doesn't equal total absorption, it equals how much isn't destroyed and actually circulating in the bloodstream.

Picture it this way:

Bioavailability = Total absorption (plus) First pass metabolism (subtracted from) 100%

 

[recyclethepandas]

I know that's what you think, but actually you are incorrect. First pass metabolism is a term used to describe the amount of drug metabolized by your liver. You are actually completely mistaken - the liver is not connected to the nose any more than it is connected to the circulatory system. The liver is actually in series between your stomach and your intestinal system. First pass metabolism only applies to oral dosing. It's clear you did not read my whole post.

Source: Biochem major, not claiming to know it all, but it is very obvious that snorted drugs do not enter the liver any more than injected drugs. If mucosal membranes were directly connected to the liver, then inhaled, intravenous, sublingual, buccal, rectal, and intramuscular administration would be no more effective than oral dosing. And if you read the mathematic paragraph that I posted, you would see that I have a firm grasp of the very basic mathematics used to describe simple metabolism. It is obvious, actually, that oral bioavailability = Total absorption minus quantity metabolized by liver enzymes, but other bioavailability = Total absorption, period. To give you some context, when you inject a drug, 100% of it is absorbed into your bloodstream, and 0% of it is metabolized immediately by liver enzymes, since the drug obviously reaches your bloodstream before it reaches your liver. In another context, rectally, some percent of it is absorbed into your bloodstream, while the rest of it appears to become dislodged in fecal matter or cilia, where it cannot be absorbed into the bloodstream. Just because rectal administration does not produce 100% bioavailability, does not mean that the anally administered drug is metabolized by liver enzymes. You ought to recognize that the stomach is actually the only organ of your body that passes matter into the liver before it can be diffused into your bloodstream - the cells in your stomach wall are specialized for this sole purpose, to prevent poisoning.

 

[recyclethepandas]

Again, first pass metabolism only applies to drugs absorbed through the liver. Since most substances cannot diffuse through the stomach membrane directly into the blood, they seep into the intestines, where bile and other digestive fluids and enzymes break down the molecules to be absorbed through the epithelial cells. The liver has the function of modifying molecular structure before materials can reach the bloodstream.
When you smoke something, that substance is absorbed, along with oxygen, through the alveoli into capillaries. Capillaries are tiny blood vessels. This means the substance is delivered directly into your bloodstream, without any hepatic involvement. The only metabolism that occurs in this process is through trace enzymes in the alveoli and the blood vessels. MAO-B is a good example of an enzyme found outside of the liver. However, cytochromes are not generally found outside of the liver, so opiate metabolism actually only happens in the liver! Thus, we have shown so far that smoking opiates and administering opiates rectally is not subject to the bioavailability limitations produced by 'first pass' metabolism. We will find that virtually every method besides oral involves directly blood vessel or capillary absorption. When you inject a drug intramuscularly, the substance diffuses into the local capillaries the same way blood does. Your arteries send oxygenated blood to your muscles, and when the oxygen is transferred, the deoxygenated blood is transported directly back into the capillaries. It does not go to the liver before it enters the capillaries, which would be an extremely inefficient process. This means that substances injected into the muscle enter, with the deoxygenated blood, directly into the capillaries, then the veins, then the heart. There is no liver involvement with rectal, inhaled, or intramuscular administration. Next up - sublingual and buccal. When you take a drug sublingually or buccally, you are actually exposing your capillaries almost directly to the substance. Under your tongue and gums lies a meshy matrix of veins and capillaries. This is why the inside of your mouth is red. Specifically under the tongue, there is a very thin mucous membrane separating the air from the capillaries. Water and oil pass through this membrane very easily, so water-soluble drugs and especially lipid-soluble drugs are ideal candidates for sublingual administration. You place the drug under your tongue, it dissolves into the mucous membrane, and then diffuses directly into the capillaries, where the drug travels to your heart. Again, this process has nothing to do with 'first pass' metabolism. Sublingual, buccal, rectal, inhaled, intramuscular so far. Next we got intravenous, but that is pretty obvious. All you do is skip the capillaries and go straight into the vein. Finally, intranasal. Well I'm sure you already guessed what is happening here, but I will make it clear to anyone who thinks that intranasal administration involves liver metabolism. Why do people snort drugs rather than swallow them? Because the onset is much quicker. Why is it quicker? Because instead of having to pass through the esophagus and stomach into the intestines, where the drug can be absorbed, you are placing the substance onto a mucous membrane with a matrix of capillaries directly underneath. Intranasal administration is actually exactly like sublingual administration. The only difference is that your mouth is covered with saliva, making intranasal slightly more reliable. When you snort a drug, it dissolves through the mucous membrane, and then immediately diffuses into the nasal capillaries. Even if you don't read the scientific literature that has been around on intranasal drugs for hundreds of years, we know this is true because cocaine addicts have withdrawn and burst nasal capillaries. Basically, the drug goes through the capillaries, through the veins, into the heart, where it is pumped into the brain. There is no liver involvement.
This may lead you to wonder why I asked the question... My question is, where does the rest of the drug go? If only 10% of it is absorbed into the capillaries, where does the other 90% go? Psychedelic Jay, it is obvious that the other 90% is not metabolized by the liver. I hope you realize that this is biomechanically impossible. The other 90%, I believe, drips down into the throat, and that is where the scientific study of the sheep stopped. They didn't have any desire to take into account the fact that the other 90% will be absorbed into the stomach, where 22.5mg will be eventually absorbed into the bloodstream.

I encourage you to read the whole post and edit your post once you have attempted to understand what I wrote
It is very clear that oral administration is the only form subject to 'first pass' metabolism. The other routes of administration are, however, subject to trace metabolism by enzymes like MAO-B, which exist all over the body. For example, tryptamines and other monoamines are by-and-large metabolized by MAO-A and MAO-B. The difference in duration you see across the board of different monoamines is due, in part, to each individual drug's affinity for the MAO enzymes. Like receptors, enzymes also have affinity values. MAO exists in massive quantities in the stomach and liver, and in lesser quantities in the brain and lungs. This is why DMT can be smoked, but not eaten without an MAO inhibitor. DMT has much greater affinity for MAO than LSD does, so once each drug makes it to the brain, LSD produces a substantially longer trip than DMT does. It's no coincidence that taking an MAOI not only makes DMT orally active, but also causes the trip to last 3 hours.
Anyway, there are other enzymes like MAO that exist in non-hepatic tissues, but I am not familiar with a single enzyme outside of the liver that breaks down opiates. Cytochromes appear to be the only ones that do the job, and these exist solely in the liver. I would say that there is a chance that some of the morphine is broken down in the nasal tissue before it is all absorbed in the capillary, but for 90% of it to be broken down before it is absorbed would require morphine to have extreme affinity for whatever enzyme is breaking down 90% of it, and if there were an enzyme with that much affinity for morphine, we would have heard about it by now, and it would certainly exist in the liver. What that means is that, if 90% of morphine is broken down outside of the liver because of a trace enzyme, more than 95% of it ought to be broken down inside the liver, where much larger quantities of every trace enzyme exist than they do outside of the liver.
Basically, I have shown through mathematics and logic, that the only reasonable place for 90% of the morphine to go, is down the throat. Only 10% is absorbed into the capillaries because of simple biomechanical properties. Morphine is poorly lipid-soluble, so it makes sense that it would not pass through membranes very well. It gets 100% IV BA, so one must acknowledge that there is nothing in the capillaries that is destroying 90% of the drug, meaning that 90% of it is merely transported somewhere else, and we all know the simple fact that when you snort drugs it comes down your throat. It takes another hour or two for it to absorb through your stomach, so it seems obvious to me that the sheep blood plasma concentration samples were taken immediately after the nasal administration, and before the drug could have absorbed through the stomach. Again, the only way to know for sure (though I am very confident in my justification now) is to snort a bunch of morphine, swallow the drips, and see how you feel.
If anyone doesn't wanna be the guinea pig, you can send me a bunch of morph and I'll do it for you FREE OF CHARGE! haha

 

[Psychedelic Jay]

Do you really think it has that big of an effect? I highly beg to differ.

These ROA pass any kind of first pass metabolism correct... You still are missing a whole chunk of the picture.

Any non injective route has barriers that all affect absorption... How well they permeate these barriers also have major effects on bioavailability. <We all got this...

So to your question of where do the percentage of drug that didn't get absorbed nasally?

It is either absorbed too slow and/or destroyed and excreted digestively to have any significant effect... That's plain and simple.

These bioavailability numbers are not static numbers to begin with... It does vary between individuals.

 

[wastEDDY]

you are indefinitely correct through theory and testing i have been eating IV 10 MGs for years on occasion i just tried sniffing today among eating (which feels more placebo with a slight definite drowse ) twice, eating was as usual a let down eating two 10MGs within two hours, yet sniffing gives me an instant and stronger buzz very calming much stronger, I am also on amphetamines benzodiapines and weed which all stimulate me so IN is what i recommend to all reading.

 

[Lorne???]

They account for the drip; some drugs have a second peak a couple of hours after nasal administration because of the drip

And they take that into account when calculating AUC, to put it, simply(?)

Point is, they know what they are doing, and it a ually varies like 5-15% if not mistaken(ballpark estimate)

Your foul is incomplete research, or even lack of studies (not just about morphine, which is poorly lipophillic, leading big to a slightly delayed peak and longer than expected onset, and also it’s water solubility is less than 100mg/ml, which is fairly low for an opioid; the combo means that most ROA’s are eliminated

Also, check out opioid superthread by Lorne; it has links, demonstrating that morphine BA% is actually dose dependent, and increases with chronic use; which means the average BA% P.O. is tad higher than we think if your an a chronic user, and especially with higher doses; still not like injecting, however snorting morphine is pointless, and snorting MScontin is a waste of time (and yes, those are mscontin(*) (please use Google) so snorting them is gonna result in probably close to zero administration; trust me, morphine was my drug of choice when couldn’t afford grams of good H -anyway check out recent threads for P.O. studies - (Note: not a pill ID, stating a fact, he may have meant MSCONTIN/morphine SR, though encourage him to edit to simply say morphine SR, or something without the imprint

If only there were a way could do it myself 8)

Your/this theory that surely others share is wrong, case closed- no disrespect, enjoy super Bowl weekend(unless in Bay Area! Then wait for the ridiculously drawn out NBA playoffs) etc

 

[tacodude]

Those are not immediate release pills....

 

[Backfromthebrink]

You guys know this thread is 4 1/2 years old right?

 

[tacodude]

Ha I wasn't even paying attention my bad

 

[ovo1024]

They account for the drip; some drugs have a second peak a couple of hours after nasal administration because of the drip

And they take that into account when calculating AUC, to put it, simply(?)

Point is, they know what they are doing, and it a ually varies like 5-15% if not mistaken(ballpark estimate)

Your foul is incomplete research, or even lack of studies (not just about morphine, which is poorly lipophillic, leading big to a slightly delayed peak and longer than expected onset, and also it’s water solubility is less than 100mg/ml, which is fairly low for an opioid; the combo means that most ROA’s are eliminated

Also, check out opioid superthread by Lorne; it has links, demonstrating that morphine BA% is actually dose dependent, and increases with chronic use; which means the average BA% P.O. is tad higher than we think if your an a chronic user, and especially with higher doses; still not like injecting, however snorting morphine is pointless, and snorting MScontin is a waste of time (and yes, those are mscontin(*) (please use Google) so snorting them is gonna result in probably close to zero administration; trust me, morphine was my drug of choice when couldn’t afford grams of good H -anyway check out recent threads for P.O. studies - (Note: not a pill ID, stating a fact, he may have meant MSCONTIN/morphine SR, though encourage him to edit to simply say morphine SR, or something without the imprint

If only there were a way could do it myself 8)

Your/this theory that surely others share is wrong, case closed- no disrespect, enjoy super Bowl weekend(unless in Bay Area! Then wait for the ridiculously drawn out NBA playoffs) etc

Well said Lorne. BTW go Philly, then when NBA playoffs come. Go Houston

 

[Scrofula]

Some topics never die. weastEDDY bumped this thread cause he got excited about his morphine pills, and I left it open rather than can it in the archives, because I had a feeling there was more to the story . . . like sarcasm.

I got bored after the second post, though. Bioavailability per route is how much winds up in your plasma after you take it by that route. It's not complicated.

Always 100% for IV
Always less for PO, loss due to non-absorbance and first-pass metabolism.
For IN, all your MS Contin goes down your throat or out your nose as a polymer booger. Which, if you swallow your MS Contin loogies means some will be available to your bio. Technically PO? or still IN? Maybe his 10%.

I'm not sure recycledpandas isn't a stim person with that much verbiage even I can put into one line. That's longer than the wikipedia entry on "nasal administration".

 

[Lorne???]

^ They claim Valium is 100% bioavailable in some cases

TECHNICALLY, they determine BA% based upon AUC; so technically if a drug already has a very high BA%, like 80-90%+, you could take moderate strong enzyme inhibitors, or even simply a load of grapefruit juice, with 400-800mg cimetidine(preferably multiple doses) and THEN after you take med, say methadone, take a bit of baking soda or something else, to then insure increased urine PH, which dramatically effects methadone clearance (T1/2 can be double with a modest increase, yet is decreased by 25-50% with a decrease-acidic urine) and, in addition to likely pushing absorption to nearly 100%, you can drastically slow down clearance, and, the result, compared to subjects who aren't cheating, could push BA% above 100%, simply based on over. 90% absorption, and. T1/2 being almost tripled, yielding an "apparent" BA% of say, 110%

Obviously though, you can't absorb more. Than 100% of a drug relative to IV, and PO results in first pass like Scro said, both prehepatic extraction and hepatic first pass, not to mention the conditions of the stomach and small intestine (many substances are effected by PH) and even other routes have they're own barriers to absorption; like sublingual not being a direct line to circulation and CNS as some think, and other routes don't go like IV, that is why it is relative to IV, and they measure it for a good while-up 48 hours, even for a medication which has long stopped working (just pointing out the weirdness of inhibitors and mechanics)

 

[Deemgd]

snorting morphine is pointless, and snorting MScontin is a waste of time (and yes, those are mscontin(*) (please use Google) so snorting them is gonna result in probably close to zero administration; trust me, morphine was my drug of choice when couldn’t afford grams of good H -

Snorting MS contin is definitley pointless, I agree. I've been getting a script for them for four years and have done a lot of experimentation in regard to different ROAs. If you try snorting them it's going to be a complete waste. There are much better ways to take them.

 

[Scrofula]

In spending thirty-two hours last night looking up various abuse-deterrent technologies extant across our Midwest, I learned that pointlessness is not itself a enough of one. Now most controlled release opioids seeking FDA favor contain irritants to stymie sticking them up your nose. Where they barely produced effects to begin with.

And I don't want to know (besides the only one mentioned, sodium dodecyl sulfate--ie., soap) what sorts of things Hoffman LaRoche considers an "irritant".

 

[ovo1024]

Some topics never die. weastEDDY bumped this thread cause he got excited about his morphine pills, and I left it open rather than can it in the archives, because I had a feeling there was more to the story . . . like sarcasm.

I got bored after the second post, though. Bioavailability per route is how much winds up in your plasma after you take it by that route. It's not complicated.

Always 100% for IV
Always less for PO, loss due to non-absorbance and first-pass metabolism.
For IN, all your MS Contin goes down your throat or out your nose as a polymer booger. Which, if you swallow your MS Contin loogies means some will be available to your bio. Technically PO? or still IN? Maybe his 10%.

I'm not sure recycledpandas isn't a stim person with that much verbiage even I can put into one line. That's longer than the wikipedia entry on "nasal administration".

I agree on him being a stim user lol he said a lot for not saying much