why so few nsaid/narcotic combo's?

[stoic]

howdy -

i've got another thread that's floating around in the forum. This question is kind of an extension of something I ask in the other thread.

BTW, a little background so you don't like i'm some random crazy looking for med advice on the net: i'm a first year med student and longggggggg time SDN'er. I'm doing a rotation this summer in rural primary care (as in very rural, 2 docs and no specialiest for like 100 miles). i'm trying to get up to date on some of the clinical stuff they don't teach in the basic science years. i've taken a particular interest in the management of pain in the primary care setting... hence poster in this forum.

so as i've been learning and reading about pain management, it strikes me that there are very few NSAID/narcotic combo's available. Almost everything is compounded with APAP. A few with aspirin. (but this you guys know). And only one, vicoprofen, compounded with ibuprofen - and available only in one strength (7.5/200).

NSAIDS are sorta like the backbone of non-narcotic, primary care based pain management. Generally speaking, ibuprofen - unless contraindicated - seems to simply be a more powerful painreliever than APAP.

So it seems strange to me that there are about 20 different formulations of codeine/hydrocodone/oxycodone with APAP but only one forumulation of hydrocodone/ibuprofen.

Am I missing something there? Is there are reason for this? I know part of the purpose for APAP is to discourage overuse. Is it so important (the inclusion of APAP as an abuse deterent) that there is a fear of formulations with ibuprofen would be massively abused b/c of the less well advertised toxicity profile?

For example, If you've got a patient taking hydrocodone 10/325 TID for a moderately painful chronic condition, what is the advantage of 325 APAP over say 400mg ibueprofen?

And also, outside of the scope of chronic pain, I would personally be more inclined to prescribe 1-2 hydrocodone 5mg/200mg ibuprofen QID (if it were available) over 5mg/500mg APAP for things like acute sprains/dental pain/etc. I'm pretty sure I've seen research showing that ibuprofen is vastly superior to APAP in most acute injury situations?

So... thoughts? comments?

And please, reply, engage me, discuss, argue... all of these things will keep me on SDN instead of studying neuroanatomy (i'd much rather talk medicine)

Thanks,
Dave

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[Aether2000]

APAP has a long track record of relative safety compared with NSAIDs that are associated with thousands of yearly deaths due to GI bleeds. The number of hepatic failures due to APAP is rather small, and a survey I did a few years ago suggested the number was approximately 300 per year. Stats on deaths due to GI bleeds range up to 16,500 per year.
There are other issues, such as patent law protecting Vicoprofen and Combinox (oxycodone/ibuprofen), but the megabucks required to submit a new drug (combinations are considered new drugs by the FDA) application dissuades many potential manufacturers of combinations unless the costs passed onto the patient are astronomical as is the case with Combinox that is per equivalent dosing, the most expensive drug on the market today. With the widespread availability of hydrocodone/APAP as a moderately effective drug, any new drug that would displace such would have to be a blockbuster with an inflated price. Also consider new drugs (or combinations) are a target for lawyers, regardless of how many pages of warnings are printed for patient perusal.

 

[stoic]

so would it be safe to infer that you don't feel the lack of NSAID/narcotic formulations is a problem?

hypothetically, if you could get some narcotic/NSAID combo, what would you choose? are there certain types of patients/pain that you would be inclined to use NSAID/narcotic formulations with (if they were magically available)?

do your patients without contraindications take nsaids as well as there narcotic meds for additional relief? do you recommend that they do so, or would you prefer they did not?

sorry to be prodding for answers you likely consider obviousl... i really appriciate the opportunity to get some info from the very experienced docs that post in this particular forum.

thanks again,
dave

 

[sdn1977]

so would it be safe to infer that you don't feel the lack of NSAID/narcotic formulations is a problem?

hypothetically, if you could get some narcotic/NSAID combo, what would you choose? are there certain types of patients/pain that you would be inclined to use NSAID/narcotic formulations with (if they were magically available)?

do your patients without contraindications take nsaids as well as there narcotic meds for additional relief? do you recommend that they do so, or would you prefer they did not?

sorry to be prodding for answers you likely consider obviousl... i really appriciate the opportunity to get some info from the very experienced docs that post in this particular forum.

thanks again,
dave

stoic - I'm a pharmacist so I can't give you analgesic choice based upon a particular diagnosis, but I can give you my perspective on why more NSAID/narcotic choices are not on the market from a pharmaceutical market perspective only. First, APAP is in its own particular class, with a limited range of doses for adults. It acts as an adjunct to narcotics & the dose is usually not an issue for safety so works for lots of situations. Safety becomes an issue if used in large doses or for long periods of time & in my experience, these patients are ususally followed by pain management folks who monitor well.

Currently, there are about 20 NSAIDS on the market and the choices of drug & dosing vary so much more depending upon what is being treated (gyn pain responds better to naproxen sodium than ketoprofen for example, a 220 lb 30 yo man with lumbar pain will have a different ibuprofen dose than a 75 yo 120 lb woman with degenerative arthritis, etc....). So...the combinations become almost endless with each trying to obtain part of the market.

Altho many of my CII narcotics are written by pain management MDs (the other specialty being oncology), most of my "moderate" pain rxs are written by IM/family practice/ob-gyn/otho/dentists & a vicodin/lortab generic is sufficient and inexpensive. If an NSAID is indicated, they will add it separately & not worry about the APAP since it will not detract from therapy. A new analgesic combination will have to try to break into a market which is saturated with generics, so even a 17 year patent protection won't recoup the expense. Vicoprofen does not sell for a couple of reasons. The ibuprofen strength is too low - 200mg/tablet, the hydrocodone too high for some pts & it is much more expensive than 2 rxs -for generic Vicodin & a generic NSAID which can provide sufficient therapeutic possibilities. Any new combination will face the same outcome, so manufacturers won't spend their money trying to bring it to market.

 

[stoic]

APAP has a long track record of relative safety compared with NSAIDs that are associated with thousands of yearly deaths due to GI bleeds. The number of hepatic failures due to APAP is rather small, and a survey I did a few years ago suggested the number was approximately 300 per year. Stats on deaths due to GI bleeds range up to 16,500 per year.

This is a good point that I hadn't thought about - but it does make sense. Just out of curiosity, how much APAP are you comfortable with patients using on a chronic basis (years, not months)? Do you order regular liver panels on your patients who are around your "upper limit?"

There are recent reports that indicate a good percentage of APAP induced hepatoxicity is the result of chronic intake. I recall one study - a big, multi center one I think - putting the number at 50% of cases reviewed where chronic, moderate doses of APAP were reported. I recall dose ranges from like 3g to 7g being reported in the chronic, unintentional cases. Do you buy this? There was some speculation by the authors that in the absence of contributing factors (protein malnutrition, etoh abuse) there was under-reporting of APAP (and probably hydrocodone/oxycodone) use by patients claiming to have failure from long term APAP use. What are you thoughts about that?

Finally, I've recently become aware that NAC is available OTC as a dietary supplement. What are your thoughts about recommened supplementation for individuals on chronic APAP therapy? Would it do any good? Could it be dangerous by virtue of giving patients with a propencity towards abuse the impression they were no longer bound by the usual intake restrictions?

Thanks again. It's really great to be able to log on and get this sort of info from the experts. It's sooooo much more interesting than the histology of the medulla.

Dave

 

[bananaface]

This is a good point that I hadn't thought about - but it does make sense. Just out of curiosity, how much APAP are you comfortable with patients using on a chronic basis (years, not months)? Do you order regular liver panels on your patients who are around your "upper limit?"

I'm curious about this topic too. In pharmacy school we are taught that 2.3g/day is the safe limit for chronic use of more than 6-12 months. But, I've never been able to find that value in any reference. All I have ever found published is the 4g/day limit for short term use.

 

[C. Krause RPh]

One of the main reasons you will find a substancially larger amount of Hydrocodone Bitartrate/Acetaminophen combinations on the market vs. Hydrocodone Bitartrate/Ibuprofen combinations has to do with simple marketing. The pain management market has been saturated for years now, and no company is going to spend the money to develope a new product, conduct the clinical trials, and push it through the FDA. The reality is that they just won't see any type of a return.

Another reason has to do with what you yourself mentioned earlier. Although the products were originally developed as "combination therapy products" (eg; They didn't initially set out to add APAP/ASA in soley for the purpose of being an abuse deterant), the fact that the products contain APAP/ASA is an added bonus to deter abuse of the medications. However, this is where an extremely important difference between Ibuprofen and Acetaminophen surfaces. Acetaminophen toxicity in the liver has a cumulative effect. Researches STILL are not sure how this works, but the liver slowly builds a tolerance to Acetaminophen. Reports have been filed of patients (opiate addicts) taking nearly 30-40 Vicodin/day while sustaining no liver damage. Ibuprofen doesn't have this effect. So with the Hydrocodone Bitartrate/Ibuprofen combinations, you lose that "safety net" if you will. Also, the sales for Vicoprofen were extremely disappointing, which is why the patent for the medication has been handed from Knoll Pharmaceuticals, down to Sanofi-Winthrop Pharmaceuticals (the original developers of Demerol), and then down to Abbot Labs, which currently holds the royalties.

I still believe the largest reason is market indicators though. When Purdue Pharmaceuticals had to remove Palladone (Hydromorphone HCL-ER, an extended release form of Dilaudid) from the market after only being available for months, due to safety/abuse concerns, it really didn't bother them that much. After all of the money spent developing the drug, they only got to make money on it for a few months and then VOLUNTARILY pulled it from the market. When Palladone first hit the market, Purdue was shocked by how minimal the sales were, and it's because OxyContin (another Purdue product), etc. is already out there. Currently the formulations for Hydrocodone Bitartrate/Acetaminophen are as follows: (Norco-->)2.5/325, 5/325, 7.5/325, 10/325, then (Zydone-->) 2.5/400, 5/400, 7.5/400, 10/400, (Vicodin-->) 2.5/500, 5/500, 7.5/500, 10/500, and then there is still variations with Acetaminophen in 650mg, 750mg, etc.

The bottom line is that nobody is going to spend the money to develope an entire line of products containing Hydrocodone/Ibuprofen. There isn't a realistic demand for it.

 

[Aether2000]

We are seeing an influx of "me too" drugs lately including more combinations of oxycodone/APAP (surprisingly in their advertising claims to have the lowest amount of APAP available with oxycodone, conveniently forgetting oxycodone is available without any APAP) and hydrocodone/APAP in lower doses.
Now we have oxymorphone available as an oral agent as opposed to the old Numorphan suppositories.
At least one company is developing a SR hydrocodone although this is already available from compounding pharmacies. Apparently the company is concerned about abuse of the drug since hydrocodone is the most abused prescription drug in America due to family doctors and just about every other specialty freely writing scripts for this drug without any controls or repercussions for patient abuse. Some PCPs write up to 10-12 per day Norco 10/325 a day for patients erroneously believing because it is a Schedule III that it has less abuse potential than the equivalent dose of oxycodone ER 40mg Q8H, a schedule II drug for which they would never write a prescription. Go figure....

 

[Mister Mxyzptlk]

here's a brain teaser:

oxycodone = C-II
hydrocodone = C-II


oxycodone + APAP = C-II
hydrocodone + APAP = C-III

I guess APAP makes hydrocodone safer but not oxycodone. 🙂

 

[Aether2000]

Actually, hydrocodone is only a CII if it is 15mg or more. Hydrocodone without any additives is technically a CIII at 5 and 10mg, but apparently either no one has approached the FDA/DEA about releasing the most abused prescription drug in America in a more abusable form, or the FDA has denied permission....
From a compounding pharmacy, hydrocodone tablets without additives and less than 15mg are a CIII.

 

[Mister Mxyzptlk]

Actually, hydrocodone is only a CII if it is 15mg or more. Hydrocodone without any additives is technically a CIII at 5 and 10mg, but apparently either no one has approached the FDA/DEA about releasing the most abused prescription drug in America in a more abusable form, or the FDA has denied permission....
From a compounding pharmacy, hydrocodone tablets without additives and less than 15mg are a CIII.

Have your compounding pharmacy check again. The 15 mg threshold is for combo products. See http://www.deadiversion.usdoj.gov/schedules/schedules.htm

There is no mention of a 15 mg threshold for pure hydrocodone. The same holds true for codeine, which is C-II in the pure form, and C-III as a combo up to 90 mg per dose unit.

 

[Aether2000]

Hmmm...it appears you are correct and the compounding pharmacist is wrong. The DEA website lists pure hydrocodone as a schedule II drug and combinations containing 15mg or more of hydrocodone are also schedule II. It makes the Scheduling of narcotics appear to be ludicrous given that one can prescribe 10-14 hydrocodone per day for a patient without exceeding the limits on the co-drug. A couple of years ago, the DEA was considering making all hydrocodone Schedule II, but there were many protests over that move, and it was tabled. Some of the abuse would be curtailed if it were Schedule II since doctors would not so freely prescribe it, and could not have 5 months of refills written on one script.

 

[Mister Mxyzptlk]

Hmmm...it appears you are correct and the compounding pharmacist is wrong. The DEA website lists pure hydrocodone as a schedule II drug and combinations containing 15mg or more of hydrocodone are also schedule II. It makes the Scheduling of narcotics appear to be ludicrous given that one can prescribe 10-14 hydrocodone per day for a patient without exceeding the limits on the co-drug. A couple of years ago, the DEA was considering making all hydrocodone Schedule II, but there were many protests over that move, and it was tabled. Some of the abuse would be curtailed if it were Schedule II since doctors would not so freely prescribe it, and could not have 5 months of refills written on one script.

The CSA of 1970 and its fallout didn't do us any favors. Everyone thinks a C-I is a drug without a legitimate medical purpose, but heroin is an excellent analgesic and cough suppressant, and MJ works for glaucoma & nerve pain, methaqualone is a good anxiolytic, etc. OTOH, thanks to powerful lobbies they exempted tobacco and alcohol, which have no medical use (unless someone is still using ethanol for fat embolism and tobacco enemas for who knows what), and you can buy those addictive, destructive, nontherapeutic substances by the carload. The hypocrisy is astounding.

Similarly, there was some idiot notion that putting APAP into a pill made it less addictive or abusable, as if addicts worried about APAP toxicity. You can find recipes on the Internet for APAP separation to produce pure narcotic.

I think we will see another attempt to make all hydrocodone preps C-II. I predict if they make it C-II one of the side effects will be that the street price will go up due to decreased prescriptions, and eventually there will be more hydrocodone-related violent crime like pharmacy robberies. When things get scarce the price goes up. When the price goes up, people are more willing to up the ante with risky behavior like violent crime. That's why illiterate sociopaths in Columbia are billionaires.

The point everyone seems to be missing is that you can't stop substance abuse with police. They admitted that when they repealed the 18th amendment.

 

[mola4ever]

When it comes to morphine/heroin related subjects like why is it allowed vs marijuana (why not) ahhh it just makes me sick ...