The FDA’s Mixed Signals on Pain Pill Policy

Prescription opioids like hydrocodone are remarkably useful for acute pain relief but are also capable of fomenting addiction and overdose. The most effective public policies regarding these medications keeps both of those realities in mind rather than yielding to an extreme anti- or pro-opioid stance. No federal government agency grapples with this challenge more than the Food and Drug Administration, and the evidence of the last week is that it has yet to come to an internal consensus on how to proceed.

First, the FDA recommended after years of study that hydrocodone combination products like Vicodin would be moved from Schedule III to the more restrictive Schedule II. This is a significant tightening of control over the most widely prescribed drugs in the U.S. (not just for pain, for anything). The impetus was the leading role of hydrocodone combination products in overdose deaths and emergency room admissions.

Yet 24 hours later, the FDA overruled its own expert panel and approved Zohydro, a pure hydrocodone pain medication that is 5 to 10 times more potent than Vicodin. In the process, FDA also overturned a precedent it had set only six months ago to not approve easily abused-opioids. After refusing in April to approve generic oxycontin because it lacked abuse-resistant properties, the FDA approved a drug whose full potency can be instantly released merely by crushing it or dropping it into alcohol (Get ready for a rash of Zohydro-cocktail deaths).

What the country needs on prescription opioids is carefully designed, balanced and consistent policy. What we are getting is policy that contradicts itself month-to-month and even day-to-day.


  1. Mike says

    The sure result of this change will be more suffering and hassle for legitimate patients. It’s unclear if it will have any effect on the black market at all, except perhaps to push pill-heads towards heroin.

    On the other hand, most coverage of the issue simply ignores the issue of how many suffer illness and death from abuse of these mixed opioid/acetaminophen drugs. Apparently part of the logic in adding an over the counter pain reliever to an opioid to make it Schedule III was that acetaminophen’s toxicity would discourage abuse. The problem with that is those who abuse these substances don’t pay much attention to things like warnings of liver failure, etc. Take a bunch of these things and get a good buzz, avoid ODing and you’re good, right? Your liver is going to hate you or possibly kill you with much of that.

    I’d sure like to see some numbers on deaths due to opioid overdose versus those due to acetaminophen intoxication, liver failure, etc on these drugs. That might be rather enlightening. I really doubt we’d see anyone proposing to make acetaminophen Schedule II because it’s killing people. But you’d be just as dead as you would from opioid overdose.

    • Bill says

      This is a good comment, which OP should respond to. There is nothing inconsistent in the FDA decisions. The dangerous (because of acetaminophen toxicity) drug Vicodin became more stringently regulated while a less dangerous (because lacking the toxin) drug was approved. That they happened close together in time suggests that the FDA wisely is trying to induce substitution from the poisonous drug to the not-poisonous drug. Seems eminently rational to me.

      • Ed Whitney says

        The FDA schedule of controlled substances is actually based on abuse potential. Acetaminophen may be hepatotoxic in doses greater than three grams per day, but it is not a controlled substance. The reclassification of hydrocodone to Schedule II applies both to Vicodin and Zohydro. The presence or absence of acetaminophen does not appear to bear on the schedule classification of either drug. For non-controlled substances like acetaminophen, the FDA can require other kinds of precautions such as warning labels when toxicity is a problem.

  2. RickG says

    In a perverse way, the policies are consistent with catering to “preferred” constituencies. On the restrict side, expect abject nonsense and lots of suffering and inconvenience for those attempting to manage pain both acute and chronic. The crackdown community is pleased.

    Zohydro sounds like and I believe is, a new patented drug. One can charge more for it, thus we have another preferred constituency. So the Extended Release formulation is easy to abuse? After the requisite number of years on patent, they can reschedule it just in time to screw over possible generic formulations.

  3. Bruce says

    A good friend, who lost one leg in an accident years back, heard the news an thought it was fantastic that he has an option that won’t kill his liver. So there is that.

    Is the time-release formula patented somehow? And is that why it’s not just routinely used? What’s the precedent for using eminent domain to seize useful medical patents in the name of the public good?

  4. etv13 says

    I had surgery on my hand a few months ago and was given a prescription for Vicodin afterwards. It was very effective at relieving pain, but didn’t feel the least bit recreational. Is that the normal situation?

    • strayan says

      Yes. Not only do most people who take opioids have no compulsion to use it for recreation, a large percentage of people don’t ‘rate’ (like) them at all. For example a twin study examining the use of a very potent and short acting opioid called Alfentanil reports that:

      “65 participants liked the drug, 31 disliked it, 14 neither liked nor disliked it, and 118 both liked and disliked it at different times”

      Of course you won’t hear this from a prohibitionist. It would call into question their claims that opioids are highly addictive and that we need tough drugs laws else EVERYONE would be taking them.

      • Mike says

        Good evaluation of the situation. Because a few people have an atypical reaction, i.e. become enthralled with the idea of getting a high off of opioid, and because it can be physically addicting in larger quantities, reinforcing the psychological reinforcement, the government feels it must interfere with the sorts of normal relationships these patients have with their doctors that are completely innocent and effective.

        Yeah, really good results with that policy approach.

        H. Beaver has a good point on the naloxone. If concern about patient safety was the prime directive here, then it would be easily and widely available.

        I have a chronic medical condition that requires daily pain relief. It varies from 1/2 a tab to 2 a day of the typical hydrocodone, largely because I don’t have access to proper medical grade cannabis to supplement my meager ration of dronabinol. I don’t like taking any more than needed, because of the acetaminophen issue and because doing so would likely push me into a different and more obnoxious clinical protocol. Now the DEA and FDA think I need a shove. They don’t have a clue, but they do have the power to abuse their ignorance in imposing it on patients across the country in the name of doing _something_.

    • Phil says

      The few times I’ve had to take Vicodin or other opiods for more than a few days – e.g., when I was recovering from orthopedic leg surgery – the only thing it’s done for me besides relieve pain was make me sad and depressed. Not exactly what I consider “recreation.” Every other time, I’ve taken when I needed pain relief, and usually ended up with several pills still left in the bottle.

      • prognostication says

        And I know people who have gotten badly addicted to opioid painkillers and nearly destroyed their livers before they got clean. Anecdotes! So useful!

        • Mike says

          Want to avoid liver destruction? Get the FDA to order them to take acetaminophen out of these drugs. If there’s the need for opioid pain relief, there’s no reason to add over-the-counter, but known to be toxic substances to it. It’s a “poison pill” installed to discourage abuse…except that the people likely to abuse these drugs are unlikely to be dissuaded by the danger. Policy FAIL.

          Obviously, the government could sharply cut the number of deaths inflicted by these drugs by just relying on the straight opioid formulations. But then it wouldn’t be punishing those who defy it by rotting their livers. Paternalism is so much more important than health and safety under these circumstances, doncha know?

  5. James Wimberley says

    That’s a Cochrane review. The gold standard. You can’t put it in red, so I will.

    • strayan says

      But James, surely it’s more important to take a balanced approach to every issue – and mix a bit of a ‘bad, illogical, scientifically illiterate’* response with an even amount of a ‘good, logical, scientific’** response.

      *Stick more opioids in Schedule II, create surveillance programs which target doctors and pharmacists and toughen penalties for diversion.
      ** Make opioids legally available for recreational use including opium and pre-filled syringes containing diamorphine so people can buy what they prefer and don’t end up mix and matching a variety of short through to long acting prescription and illegal opioids of differing potency and varying formulations (powder, patch, tablet, film etc) which tends to end in disaster.

      • James Wimberley says

        I have no horse in this particular race. However, I remain scandalised at the non-provision of opioids to cancer and other patients in poor countries, though my support for legal opium cultivation in Afghanistan got precisely nowhere. It’s unclear what share of this is due to the extra=medical demonizing of opioids translating into red tape barriers, and how much simply to bad and unequally available medical care.

        A reminder from Rilke of what this is all about.

      • Mark Kleiman says

        For those keeping score at home, “diamorphine” is the UK term for diacetylmorphine, more often known by its original trade name, “heroin.” So Strayan thinks that anyone who disfavors legalizing the use of heroin ad libitum is “bad, illogical, and scientifically illiterate.”

        Ain’t civil discourse wonderful?

  6. Ed Whitney says

    I have always had difficulty understanding “enriched enrollment” study designs for analgesic drugs. The trials screen participants for their responses to the drug and only randomize those who tolerate it and have some therapeutic response. This may not threaten the internal validity of the study, but knowing how to generalize the results for external validity would seem to be impossible. This new formulation of hydrocodone appears to have used these study designs in the approval process.

    Any insights out there? I bet that someone on this site can help me with this issue.

  7. wmd says

    On the subject of hydrocodone with acetaminophen the wikipedia entry on hydrocodone says the FDA is requiring a decrease in the amount of acetaminophen to no more than 325 mg per dose by January 2014.

    Since personal anecdotes are being shared – I had prescriptions for both Oxycodone (for both acute and base line pain) and hydrocodone following orthopedic surgery 2 years ago. I still have medication from that time; never saw any recreational potential in them. When I was doing physical therapy I told my PCP/GP I was concerned about the amount of acetaminophen I would be taking in order to tolerate the activity; I asked for 10 mg/500 hydrocodone which I intended to cut in half prior to PT. She prescribed 5/325 which kept me under 3000 mg of acetaminophen per day.

  8. H. Beaver says

    Yeah, foment is an odd word choice. It’s an attempt to give opioids evil magical powers, like little demons. I guess opioids are the demons, and those in the addiction treatment industry are the priests that will save us.
    I just wonder who will save me from legal cheeseburgers that are fomenting obesity.

  9. Mark Kleiman says

    Glad to hear that prescription opioids aren’t really dangerous. I suppose those
    15,000 overdose deaths per year
    must be imaginary, then. Good! One less thing to worry about.

    Mike, what’s “obvious” to you is, alas, false. Deaths from acetominophen toxicity are two orders of magnitude rarer than deaths from prescription opioid overdose.

    Yes, most people don’t like opioids.

    Yes, most people who do like opioids don’t abuse them. (About one non-medical user in seven has an abuse problem.)

    And yes, death is rare, even among those with an abuse problem (less than 1 death per 100 dependent-user-years).

    So yes, the people who suffer are a minority of all users, and those who die are a minority of that minority.

    But as the number of users goes up, so does the size of that minority.

    Five out of six people who play Russian Roulette do so without injury. The odds on driving home with a BAC of .15 are even better than that: the relative risk is very high (something like 50 times baseline) but the baseline fatality risk of driving is almost negligibly small. Still, if enough people do risky things, some of them will get hurt.

    The successful campaign of the pharmaceutical industry to encourage opioid prescription has helped relieve the problem of under-treatment of pain, and has also helped unleash a wave of opioid abuse. Those are just facts. Anyone who wishes to deny them may go elsewhere.

    There are lots of libertarian and anti-drug-war websites where it’s possible to share angry ignorance safely and harmlessly. But I’m tired of having every RBC post on drug policy hijacked by fanatics. If you have actual knowledge to share and are prepared to do so calmly and without attributing bad motives, feel free to join in, especially if your viewpoint differs from that of the poster. But from now on, I’m going to be ruthless about zapping offending comments and banning offending posters.

    Strayan, Brett, Dilan: yes, this means you.

    • Mike says

      Thanks, I appreciate the comment. I will note that I never indicated that deaths from opioids aren’t a problem, just that I believe the underlying justifications should be balanced from the viewpoint of patient safety. The fact that levels of acetaminophen will be reduced is indicative that the problem has been recognized, but not prioritized by simple elimination is disturbing.

      But I think we’re still not to the bottom of this. The article seems to refer to deaths directly attributable to acetaminophen toxicity, but not to what is certainly a far larger problem of liver damage, whose long term morbidity is likely not reflected by stats that seem to refer to acute toxicity.

      From the cited article:
      “Taken over several days, as little as 25 percent above the maximum daily dose – or just two additional extra strength pills a day – has been reported to cause liver damage, according to the [Food and Drug Administration]. Taken all at once, a little less than four times the maximum daily dose can cause death.”

      Yes, I do understand the difference between death and liver damage. I just don’t think the 1,500 deaths wholly accounts for the damage from acetaminophen. And I still don’t understand what it’s doing at all in an opioid pain medication. Many people don’t read labels. And if labels are effective for dealing with the dangers of acetaminophen, why not the opioid itself?

      I still think there’s a gap here between what is known about harm to consumers and what action is being taken.

      And there still appears to be no metric of increased patient suffering and unnecessary expense taken into account. Good public policy would at least address that forthrightly, instead of prioritizing certain aspects of the situation while overlooking others that don’t receive the same attention in the press.

      • Mike says

        Oh yeah, forgot to ask. Isn’t the comparison between 15,000 opioid deaths and 1,500 acetaminophen toxicity deaths just a single order of magnitude? Sorry, not good at math, as I’m a historian, or I’d know the answer to that.

        • James Wimberley says

          The usual base ratio for orders of magnitude is 10. So 15,000 is indeed one order of magnitude greater than 1,500. There are other schemes of scaling. Computer data goes up (from byte to kilobyte to megabyte …) by ratios of 1024; money by ratios of 1000 (million, billion, trillion). You would be confusing people to describe these jumps as orders of magnitude.

          • Mark Kleiman says

            It’s 15,000 acute opioid deaths per year versus 1500 acute acetominophen deaths over a decade. Yes, of course there are also chronic-disease deaths and reduced quality-of-life from acetominophen. The same is true of opioid abuse.

            So “two orders of magnitude” is correct. Shouldn’t an historian know how to read a document?

            Matthew Meyer, no need to apologize. No doubt your anger got the best of your reason, or your reading ability, whichever came first. But one more dumb, rude comment will get you banned.

          • Mike says

            Hah, that’s a statistic. I tend to skim, specially when I’m taking a break from writing to read here…but OK, I see the two orders of magnitude.

            Now I’m even more certain that the 1,500 deaths from acetaminophen toxicity (over 10 years) fails to reflect the full impact of the consequences of liver damage if the rates of hydrocodone abuse are what they say they are. I’d almost bet there at more than 150 deaths per year from suicide by Tylenol alone. So I’m still thinking that we’re doing apples vs oranges, instead of apples vs apples, when comparing those specific rates.

            One more factor to throw in. If acetaminophen therapeutic dosages are as little as 1:4 what the fatal dose might be, what’s the comparison for therapeutic to fatal dosage for hydrocodone? I guess I’m still trying to get at some valid reason other than my “poison pill” theory for mixing an opiate with acetaminophen. I just see no clinical reason for its presence in these medications. And if the theory is, “First, do no harm…”?

      • Maynard Handley says

        I have nothing to add here except to point out that “liver damage” like “prostate cancer” is one of those scare phrases that is easy to use to make a POLITICAL not a “factual” point.
        In the case of prostate cancer, the point is that the cancer is (usually) so slow-growing and rare to metastasize that it’s just not big deal.
        In the case of liver damage, the point is that the liver is kinda designed to sustain damage; that’s par for the course given the job it does, and that’s why it regenerates itself.

        Given this is there any reason to believe that there is a serious problem of “long term morbidity is likely not reflected by stats that seem to refer to acute toxicity”? My baseline assumption would be that, yes, if you overload the liver you will die, and yes, if you poison the liver at sub-lethal levels for long enough (eg alcohol) you will die; but poisoning the liver at sub-lethal levels for short periods of time is unlikely to have any long-term effects.

        • Mike says

          30% mortality from acute liver damage sounds serious enough to me. Let’s do some math simple enough for me to understand.

          I take between 1/2 and 2 of a hydrocodone/acetaminophen 7.7/500 mg tablet daily. When things have been bad, there’s a time or two I’ve taken four even though I know the limit is three. Not likely to be a problem.

          Some kid breaks into my house and is “lucky” enough to find my meds. I’ve just refilled. He takes a couple, good buzz! Then a couple more and…well before the day is out he’s taken 10, 15, and I believe somewhere around 20 is where things get scary, but if he’s a first timer, unlikely to get there and would be in trouble if he tried too quickly over 24 hours. Hasn’t a clue about acetaminophen. Maybe a one time thing. Gets sick, thinks it’s the dope and maybe it is. Hope he isn’t predisposed to liver failure…

          Then you take someone who’s been hitting these things hard for some weeks now. Kid is smart, instead, sells most of the pills to his pill-popping buddy (and buys something safer, like weed), who has built a bit of tolerance, but like with all opiates, tolerance just means you can get that much closer to fatal before you get a real buzz. This guy ain’t bright. I don’t know, can you take 8 of these at a time? Sounds scary. I knew folks when I was a kid who might do something like that. Then repeat, and again (I was unlucky enough to have just refilled, remember?)

          So how much acetaminophen is the average hydrocodone freak huffing down? I don’t know. But it can’t be too far from the magic 1:4 ratio — if they can just get their hands on them. And if so many people are dying of hydrocodone and there’s a big enough market to sustain all these pill mills, etc, then what is the relationship of liver failure to addiction in terms of social and health costs? It seems like it would be showing up more because of the association between the two drugs. Seems like a worthy an area of study is all I’m saying. It may not have the sexiness of an opiate, but acetaminophen’s still an issue, not for only political reasons (mainly because if people are forcing us to do things for our health, then sometimes it’s instructive to look at how related health threats are treated to understand what’s really going on) but because a syndrome which should seemingly be showing up somewhat more in statistics associated with opiate morbidity seems relatively poorly associated as far as the statistics referenced.

          • Maynard Handley says

            So we’re back in the world of “let’s run the numbers guessing whatever we feel like, to get the result we want”? And this differs from drug warriors, how?

            Mark started this particular comment thread with a plea for data-based decision making, and it was with an eye to THAT plea that I made my point.

          • Mike says

            Bad data doesn’t make a point. The acetaminophen numbers seem suspect and there seems to be no explanation for why if so many people are dying of hydrocodone intoxication, the associated acetaminophen issues don’t seem to correlate with what is know about its toxicity.

            Or have all these really not to smart people killing themselves with hillbilly heroin somehow figured out a way to protect their livers that others haven’t if they haven’t managed to OD yet?

            I’m not saying the numbers prove something different, just that there’s something unexplained going on that bears further investigation. Maybe the toxicity of acetaminophen isn’t as great as indicated here? Maybe the nature of hydrocodone abuse prevents the worst aspects of acetaminophen damage simply because those in the illegal market tend to have spotty supplies? I don’t know the answers, but I suspect no one else does either. And it seems of significance if the FDA is actually doing something about it, but no one here seems to know why that is.

            I’ll be quiet now for being such a skeptic. Don’t want to rock the Reality boat.

          • Mike says

            OK, I’ll take back being quiet, found some answers after a brief search. Source is a recent Pro Publica article on deaths by acetaminophen.

            The 150 number is suspect at several levels. First of all, the reporting of drug fatalities permits only the listing of a single drug. Combine hydrocodone with acetaminophen and I suspect that the opioid takes top billing in virtually very case.

            So we simply do not know acetaminophen’s contribution to the hydrocodone fatality rate. Whatever it is, these will be apart from any number cited as as a acetaminophen fatality.

            The article the goes on to cite a variety of potential numbers of deaths involving acetaminophen. The high number is 980 deaths per year from the FDA itself, next is a CDC number of 300, and the poison control people say 113.

            So the answer is no one seems to really know. One thing seems certain. Associating acetaminophen with a popularly abused narcotic is a recipe for excessive damage above and beyond what might be encountered from use of acetaminophen by itself.

          • Mike says

            BTW, refilled my hydrocodone RX today and it came in the new reduced 325mg acetaminophen formulation. So they are beginning to address it as a problem.

  10. Malcolm Kyle says

    Acetaminophen overdoses are the leading cause of acute liver failure (ALF) in the United States, Great Britain and most of Europe. Acetaminophen toxicity accounts for approximately 50% of all cases of ALF in the United States and carries a 30% mortality—More than 100,000 calls to Poison Control Centers, 56,000 emergency room visits, 2,600 hospitalizations and nearly 500 deaths are attributed to acetaminophen in the United States annually.

  11. James Wimberley says

    How far is prescription drug abuse a problem specific to, or especially acute in, the USA? I looked for international statistics but couldn’t find any; however the bulk of the material I did find focused on a US epidemic, going back to excessive and careless prescription.

    It’s possible that the problem may be exacerbated by poor and expensive access to physicians, leading to larger prescriptions and less medical supervision than in countries where patients find it easier to return to the surgery for renewals.

    TB campaigns in Africa have developed effective methods of social control of adherence to the drug regimen – basically a “buddy system”. The object here is to make sure all the pills are taken. But it could also work to reduce the risk of diversion of painkillers.

  12. Ed Whitney says

    Fairness to all requires us to note that there are no easy answers for treating pain. Narcotic overdose is too common; acetaminophen has a potential for liver toxicity, and even the most common NSAIDS like ibuprofen, naproxen, and related drugs are too commonly prescribed for patients with a history of coronary artery disease; even short term treatment of patients who have had a heart attack increases their risk of having another one, often with a fatal outcome.

    An atmosphere of good will is required to come up with beneficial solutions to complex problems.

  13. aisaac says

    Oxycontin may be abuse resistant, but the most commonly used powerful immediate release painkillers, plain oxycodone (not the same thing as oxycontin!), morphine sulfate, and hydromorphone, can all be crushed and abused just like the old, non-crush-resistant oxycontin. Zohydro will be weaker than any of those, just as heavily regulated due to CII status, and expensive because it won’t be generic. It’ll be sort of like having $10 cans of bear vs. dirt cheap rum (oxy, hydromorphone and morphine are all both cheaper and stronger than Zohydro). I don’t anticipate heavy sales for Zohydro, and I don’t see its availability causing a problem.

    What’s really going on here – current law is that hydrocodone by itself is a CII, but hydrocodone cut with liver poison (tylenol) is a CIII. Nobody has bothered selling plain hydrocodone until now for the aforementioned reasons. Now that it will all be CII, they might as well sell it plain. There are people who actually prefer hydrocodone because they get nauseous with the stronger, or they just don’t want to be high as a kite. There won’t be any reason for them to take unnecessary tylenol when the law changes.