Hydrocodone: Prodrug? Non-prodrug? In between?

[resorcinol]

Hydrocodone is one of the most commonly used drugs in the united states, both medically and for fun. Vicodin, Lortab, Norco, and the like are ubiquitous -- names that a vast many people have at least heard. Of course most people are ignorant about hydrocodone and probably think it's "of the devil" or something of that sort, hell, all opioids are viewed that way by a still politically damn significant drug warrior populace. It's sad, but that's a discussion for another thread (we've already got plenty).

For being a commonly used drug, we run into something odd about hydrocodone. There seems to be disagreement in scholarly articles about whether hydrocodone is a prodrug or not; this is mainly due to the nonexistance of a study concerning the issue.

I'm wondering, based on the experience you guys have with dosing hydrocodone combined with research you've done, whether you tend to believe hydrocodone is a prodrug like codeine or a significant mu agonist in its own right before being metabolized.

*A pro-drug is a drug that is inactive itself, but has an active metabolite that exerts the desired effects.

Hydrocodone does have a very active metabolite: hydromorphone. Some people feel that hydromorphone is primarily responsible for hydrocodone's effects (that hydrocodone IS a prodrug).

Others believe that while hydrocodone has an active metabolite hydromorphone which contributes to the overall effects of hydrocodone dosing, that hydrocodone is active in its own right as a mu agonist and that preventing hydromorphone formation would only make hydrocodone a bit weaker (maybe 3/4 its usual strength). I'm talking full on blockade of hydromorphone production when I say "preventing"... a full block on this metabolic pathway is possible only in theory afaik, so I'm just hypothesizing that perhaps hydro would only be 3/4 its usual strength if this situation of blocking hydromorphone formation totally could occur. This group believes that hydrocodone is fundamentally NOT a prodrug.

I'm in the latter group. I believe hydrocod is NOT a prodrug for these reasons:
1)People who DO take cyp2d6 inhibitors don't generally see their hydrocodone high diminished like what would happen with codeine, from trip reports I've read. cyp2d6 inhibits hydromorphone formation from hydrocodone.

2)Hydrocodone has a more rapid onset than codeine when taken orally, and those who have injected it intravenously report no rush, but a rapid onset. I think there's no rush just because hydrocod isn't very strong. Even oxycodone doesn't have much of a rush according to most IV users.

3)No apparent ceiling effect. There are people who have highish tolerances (usually from oxy) who have done massive CWEs on norcos and vicodins and dosed 200 mg - 400 mg doses of hydrocodone with euphoric results similar to half that amount of oxycodone. This can't be confirmed completely, but there doesn't seem to be a WALL the way there is with codeine.

4)The high is different. If hydrocodone's high was mostly due to hydromorphone, it would feel a lot like a hydromorphone high, like codeine feels like a weak morphine buzz. All opiates feel similar, but they do have "personalities", we all know that. I've seen lots of people describe hydrocodone as speedy, often saying it's not as speedy as oxycodone but still less noddy than morphine, for example. I've seen people describe hydromorphone as very sedating, more like morphine, and actually not much to write home about besides the rush. You guys can chime in more about this... do you think hydrocod and hydromorph feel distinct?


So, I believe hydrocodone is mostly not a prodrug. Oxycodone is DEFINITELY not a prodrug, this is common medical knowledge. As for dihydrocodeine (DHC), I believe it is a prodrug, but not as much of one as codeine... I think DHC has more intrinsic activity than codeine as an opioid -- hence the lesser ceiling issues.

What do you guys think?

[Narkotikon]

I voted for in between.

Back when my tolerance was low, I used to love hydrocodone. I miss those days when 40mg would make me nod and before I knew what w/d was. Anyway, I voted "in between" because I used to take it by itself most of the time, but a few times I tried the grapefruit juice thing. I did NOT like it nearly as much when I drank grapejuice an hour or so before I took the hydro. It definitely cut down on the euphoria. It did make the body high last a bit longer, but it wasn't nearly as pleasurable. So, yes, I think it exerts some action on it's own, but I think it works better as a pro-drug for the delivery of hydromorphone.

Now, though, hydrocodone doesn't do much of anything for me. I'm totally fucked if I"m in real pain and need something, because I don't know of any doctor who's going to give a junkie a strong pain med simply because they're a junky and have a high tolerance. Usually, in those cases of being honest, you get shit. But, if you're not honest, you get Vicodin and it's completely useless because of your tolerance. The only way I can see getting adequate pain meds when in actual need and the doctor knowing about my history is if it was something really serious, like a major car accident or surgery. But, a sprained ankle. I'm either getting shit or hydro, and both of them won't work.

[jonny-5]

*A pro-drug is a drug that is inactive itself, but has an active metabolite that exerts the desired effects.

by this definition, if hydrocodone has any activity at the mu receptor, or any receptor for that matter then it cant be a prodrug.

[gameface]

"2)Hydrocodone has a more rapid onset than codeine when taken orally, and those who have injected it intravenously report no rush, but a rapid onset. I think there's no rush just because hydrocod isn't very strong. Even oxycodone doesn't have much of a rush according to most IV users"

I may be wrong but I thought IV'ing even a 100% pure hydrocodone solution can cause pulmonary edema? Scary scary shit.

Oxycodone IV does have a decent rush imho, just not that of hydromorphone.

As far as the pro drug thing, I am leaning toward it slightly being one. I guess this means I'm of the in between opinion. There is no doubt some of it does get metabolized into hydromorph, but how much is up for debate, Also once its turned into hydromorph, what is the bioavail. of said hydromorph?

I'm on the fence with this one, but whether or not its a pro drug are almost a matter of semantics it seems.

[bigNasty]

This is a great thread. I voted its not a pro-drug cuz they feel different but now that i think about it hydroc feels best 2.5-4 hours after taking it.

And 30mgs of hydroc gets me good and I IV'd a 4mg dilly last week and the rush was great but not that fucked up after that so i'm thinking my hydroc tolerance made me have a higher hydrom tolerance.

I know all opiods have cross tolerance somewhat but 4mg dilly IV'd should have fuct me up if 30mgs of hydroc fucts me up

[resorcinol]

by this definition, if hydrocodone has any activity at the mu receptor, or any receptor for that matter then it cant be a prodrug.

Thing is, with pharmacology, like everything in life, rarely are things existing only in black and white. So by "inactive", pharmacologists mean that it's activity, if it has any at all, is extremely insignificant.

Codeine, for example, is strictly speaking an agonist at mu opioid receptors, but it's so extremely weak compared to morphine and maybe codeine-6-glucuronide that it is a prodrug. Codeine, while not totally inactive as an opioid, is essentially inactive realistically.

I look at it like this: if a drug's effects are primarily caused by an active metabolite (like, for example, 85% or more due to an active metabolite) then I label it a prodrug even though it has ever so slight activity of its own. I'm not sure what percentage pharmacologists use to determine it; it may differ on a case to case basis -- that makes the most sense.

This is one of the reason I believe hydrocodone is not a prodrug. Hydrocodone has robust activity of a mu agoniost when compared to codeine. Saturating that double bond between position 7 and 8 and oxidizing the hydroxide group at position 6 to a carbonyl group really increases potency as a mu agonist when both modifications are present, as in hydrocodone. This is how hydrocodone differs from codeine chemically. I even think that perhaps hydrmorphone is responsible for up to 30% of hydrocodone's effects, but I don't consider that grounds to call hydrocodone a prodrug, since hydrocodone (if that is in the ball park of the truth, no studies have actually been done on how much activity hydromorphone imparts to the hydrocodone experience; 30 percent is just my educated hunch) in that situation is producing 70% of the opioid activity. It's all a matter of degree.

Thanks for the input everyone, I really value everyone's thoughts. This is something I'd love to do a study on sometime in my life if nobody else does. There's a gap in knowledge about the pharmacodynamics and pharmacokinetics of this common drug. Nobody can tell you 100% for sure whether or not hydrocodone is a prodrug at this point in time.

[resorcinol]

I may be wrong but I thought IV'ing even a 100% pure hydrocodone solution can cause pulmonary edema? Scary scary shit.


AFAIK this isn't true. It's codeine that you're thinking of.

I think a lot of people see "codone" in hydrocodone and also see hydrocodone as a milder opioid like codeine, and extrapolate codeine's harmful effects when IV'ed to hydrocodone. Again, AFAIK, hydrocodone is much safer to inject than codeine.

Oxycodone also has "codone" in it's name and yet there doesn't seem to be a pervasive notion that IVing it can cause P Edema like there is with hydrocodone. Perhaps it's because people see it as stronger and more heroin like.

Keep in mind though, hydrocodone is much, MUCH stronger than codeine -- even more than the converter on the globalRPh site says, IMO. It's closer in nature to oxycodone than codeine.

Don't take this as an assurance that it's totally safe to shoot it up though, I'm not 100% sure. Hell, nothing, especially stuff from pills, is safe to shoot up, but you guys know what I mean.

[gameface]

This is a great thread. I voted its not a pro-drug cuz they feel different but now that i think about it hydroc feels best 2.5-4 hours after taking it.

And 30mgs of hydroc gets me good and I IV'd a 4mg dilly last week and the rush was great but not that fucked up after that so i'm thinking my hydroc tolerance made me have a higher hydrom tolerance.

I know all opiods have cross tolerance somewhat but 4mg dilly IV'd should have fuct me up if 30mgs of hydroc fucts me up

I think that 4mg of dilly IV'd is waaaaaay more of a dose than 40mgs of hydrocodone orally. I'd say for me that 4mg of IV dilly is what would get me off if my hydrocodone tolerance was say 75-100mg orally. in fact 8mgs of IV dilly did me right when i was doing about 1/2-1 gram of shitty tar a day. on the pulmonary edema thing, I aint about to guinnea pig it. Better yet has anyone repeatedly done so without any ill effect? Regardless we all know shooting pills is bad.

[repeek]

When I was getting compounded 15/80 hydrocodone I did cwe and IV'ed for about a year without any problems. There is a light rush at 45mg/ml but below that not much.

[Duckfeet]

Used to be u'd only see it in tussionex cough syrup, long before vicodins and norcos and lortabs and oxys and middle class white kids getting all strung out...so whenever we'd get a cough, we'd all run down to the doc, but I'd get hydro*morphone* cough syrup, which they compounded in the pharmacy, and when they finally *did* come out w/vicodin and lortabs, we'd buy'em, but never were *that* thrilled by them: at least you could fix percodans and tylox--nasty procedure tho it could be--but the few brave ones who fixed the garbage in hydrocodone pills only did it once...usually...

It's a low level high--right above tylenol 3's and darvocets, and right below percocets, percodans and tylox...,and useless once you get yer tolerance motor running...I didn't even bother picking up 10mg norcos anymore, hell morphine sulfate made me yawn, and I'd rather have an ice cream cone and a beer than anything w/ hydrocodone in it: no matter *what* the chemical relationship is, hydrocodone is *way* crappier than hydromorphone...I mean, propoxyphene is some kind of cousin to methadone, too, but try doing darvocets when yer on a good methadone withdrawl weekend hahahaha....

Sure, CWE away, but by the time most of us get to that stage, we're beyond feeling anything beneath sched II hard case opiates, or good old tried and true heroin, not this tar-crap that goes by the name...

[repeek]

There is some real Mexican heroin on the border right now, like back in the 60's early 70's. you can see and feel the crystals...............nice clean, has legs just like the old days.

Can't say I expect it to be around for long, but sure am enjoying it while I can.

[Duckfeet]

What's that old song: "Hola Mexico, and bye bye baby to you..." hahaha: got me laughing, man: I figured right around the time I just about succesfully detoxed after this little two year run, the dope would get better: story of my life...oh well, something to look forward to, *next* time...but I did kind of figure that eventually they'd get some good chemists down there, and quit producing this arm destroying morphine/sewage water crap they now sell, and if it starts getting good, on the border towns, it'll be *really* good up in Chicago and elsewhere...


There is some real Mexican heroin on the border right now, like back in the 60's early 70's. you can see and feel the crystals...............nice clean, has legs just like the old days.

Can't say I expect it to be around for long, but sure am enjoying it while I can.

[jonny-5]

there is good heroin produced in mexico you just gotta know the right person/people i guess. even the good shit tho still kills your veins.

[Duckfeet]

Oh I've had *knockout* mexican tar: it just never gave me the euphoria that good clean white dope has...I thought it was just me, but a pal sent me some baltimore dope, and I got the old "happy" stomach warming body rush, that I've never gotten off of mex dope...oh, I know it's some kind of morphine extract or something, but it would have to get really good for me to think it's up there w/burmese or afghan white...tho I hear Columbia has got it together now....but I've been wrong about most everything else in my life, wouldn't surprise me to find that some enterprising mexican finally gets it together to make it right...but junkys are such a seller's market, that we'll buy just about anything, so who knows...;

there is good heroin produced in mexico you just gotta know the right person/people i guess. even the good shit tho still kills your veins.

[Nu Jerzey Devil]

This is one of the reason I believe hydrocodone is not a prodrug. Hydrocodone has robust activity of a mu agoniost when compared to codeine. Saturating that double bond between position 7 and 8 and oxidizing the hydroxide group at position 6 to a carbonyl group really increases potency as a mu agonist when both modifications are present, as in hydrocodone. .


Yea I have to agree with you here, it seems that all ketone-ated (at position 6) versions of the Phenanthrene opioids are significantly stronger than the natural ones (which have the hydroxyl group). Now this is the basis for my arugument that it is somehwere in between. It demonstrates mixed properties, which makes me think that you cannot contribute all of the effects of the drug from (it being metabolized in the liver through O-Demethylation) hydromorphone. Resocinol brings up a good point, the ROA's that bypass 1st pass liver metabolism will still lead to some pronounced opioid effects.

I have never shot hydro, but plugging it will give definitly get me high. It is metabolized almost the same way as oxycodone is and we all know that you can shoot/plug oxycodone and still get the same effects. Chemically oxycodone and hydrocodone are very similar... the only difference I believe is bonded to Carbon-14 is a hydroxyl group instead of a hydrogen. They both get broken down as part of the metabolism into a small amount of oxymorphone and hydromorophone respectively.
Since oxy is not a prodrug, I tend to think that hydro isn't either.
Really really interesting post though!

[jonny-5]

.but junkys are such a seller's market, that we'll buy just about anything, so who knows...;

aint that the unfortunate truth. maybe one day ill see what youre talking about and try some good white dope, but until then im happy that i havent, and that i can enjoy this shit still...it sucks to do your doc and not really feel satisfied, and i know all about that.

[resorcinol]

Yea I have to agree with you here, it seems that all ketone-ated (at position 6) versions of the Phenanthrene opioids are significantly stronger than the natural ones (which have the hydroxyl group). Now this is the basis for my arugument that it is somehwere in between. It demonstrates mixed properties, which makes me think that you cannot contribute all of the effects of the drug from (it being metabolized in the liver through O-Demethylation) hydromorphone. Resocinol brings up a good point, the ROA's that bypass 1st pass liver metabolism will still lead to some pronounced opioid effects.

I have never shot hydro, but plugging it will give definitly get me high. It is metabolized almost the same way as oxycodone is and we all know that you can shoot/plug oxycodone and still get the same effects. Chemically oxycodone and hydrocodone are very similar... the only difference I believe is bonded to Carbon-14 is a hydroxyl group instead of a hydrogen. They both get broken down as part of the metabolism into a small amount of oxymorphone and hydromorophone respectively.
Since oxy is not a prodrug, I tend to think that hydro isn't either.
Really really interesting post though!

I definitely agree that the rapid onset by parenteral administration is even better evidence that hydrocodone isn't a pro-drug than the rapid onset by oral consumption (although that too is somewhat suggestive of this). My personal experiences with the two when my tolerance was lower was that codeine took 20 to 30 minutes to kick in orally and hydrocodone took 10 to 20 minutes. This is by no means proof of anything, as there are many things that could make two similar drugs have a distinct noticeable difference in time to start coming up. It's just suggestive when looked at within the larger picture and other possible evidence. Parenteral fast come up is stronger evidence; codeine taken parenterally (snorted/IM/plugged ... do NOT IV codeine, it can cause a rapid histamine reaction that is way more intense and dangerous than that of other opioids) will work, contrary to popular belief, but it will actually take LONGER to come up than oral codeine. Oral codeine brings the drug right to the places where the cytochrome enzymes are located (GI tract and liver), which facilitates a pretty quick start to the codeine -> morphine reaction catalyzed by cyp2d6 and decent first pass conversion of codeine into morphine (and, unfortunately, decent norcodine production from cyp3a4 too; most if not all N-demethylated phenanthrene opioids are inactive -- that N-methyl -- making that amine tertiary -- is one of the most important structural features for mu agonist activity. There are other groups that can be used here that are active agonists, and some substitutions create even stronger full agonists, but this is a risky risky spot to tamper with, as equally many substitutions here create mu ANTAGONISTS -- look at naloxone and naltrexone. But yeah, secondary amine = little to NO activity for phenanthrene opioids). Parenteral codeine is absored rapidly into the bloodstream too, but filters through the liver, where cyp2d6 is, only slowly and in dilute concentration, slowing the conversion to morphine. Prodrugs which are metabolized hepatically and in GI tract by cytochrome enzymes are best taken orally.

Note that while heroin is a prodrug, its metabolism is simple hydrolysis which is done by enzymes located all over the body in abundance, that act quickly and efficiently to hydrate the ester linkage and break it, so heroin is a weird prodrug in that it's better it's much stronger metabolites. GBL is like this too, some would say. That was a tangent... anyway, back to the point...

Hydrocodone seems to onset almost immediately following parenteral administration despite the lack of a rush (MOST people who've IV'd it say they didn't feel a rush. This is likely simply because hydrocodone is on the weak side and/or doesn't cross the BBB fast enough -- the latter is probably more important, as pethidine, which is weaker than hydrocodone, does have a rush). The rapid onset parenterally suggests hydrocodone's activity is mostly from the parent drug, since the conversion to hydromorphone is a slow hepatic demethylation. That reaction type is much, much slower and more ineffcient compared to something like heroin's hydrolysis.

Yes, oxycodone is simply 14-hydroxy hydrocodone. Substitution at position 14 on phenanthrene opioids seems to almost always add to potency and euphoria, and -OH is a popular substitution. Some other substitutions there to this family of opioids can create etorphine potency opioids (see my sig).

Sorry for length, I got a bit carried away there.

[SeVeN]

I really don't know, but I am pretty sure what you mean by prodrug. I.E. Carisprodal (sp) would be a pro-drug, right?

I voted no. I think hydrocodone in itself is the active metabolite, and is noticably different from other opi's Ive had experience with, but it probably is in between. Still I voted no because I think its main ingredient is its active one.