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Ibuprofen May Not Be as Safe as was Thought (time.com)
127 points by metafunctor on Nov 16, 2016 | hide | past | web | favorite | 96 comments



Honest question, is it possible this article or the study it mentions is a paid ad for Celebrex? It somehow feels more pushy than impartial, and it didn't mention the cost difference between Ibuprofen and Celebrex, which is to put it mildly, enormous.

I have taken too much "Vitamin-I" over the years, and it finally caught up with me and started causing stomach and esophagus problems. I've wanted to try Celebrex, but it's way too expensive. Have tried Meloxicam and it's much gentler than Ibuprofen, but let's just say it did come with some side effects on my gastrointestinal system.


Not really, this study was required by the FDA to be performed by Pfizer. That's how drug safety studies are always conducted in the US, by the drug maker under the supervision and guidance of the FDA.

http://www.fda.gov/drugs/resourcesforyou/consumers/ucm143534...

"Q: Does FDA test drugs?

A: No. It is the responsibility of the company seeking approval to market a drug to conduct laboratory and animal tests on the safety and effectiveness of a proposed new drug and then to submit that information to FDA for review by CDER physicians, statisticians, chemists, pharmacologists, and other scientist."

http://www.fda.gov/Drugs/ResourcesForYou/SpecialFeatures/ucm...


This of course is a very bad situation.


Well it could certainly be more ideal, but how you could achieve a better situation would require rearchitecting a significant chunk of the US healthcare system.

I'm personally in favor of publicly funding drug research and open sourcing the results, but fat chance that'll happen anytime soon.


The FDA is a joke then. So any greedy business man can fake the data or some of the data and just send it to the FDA for approval?


No, the FDA is staffed by myriad professionals in biotech and drug testing and any number of relevant fields. They pour over the methodology, the results, and ensure that the study was conducted accurately and appropriately.

We have these regulatory agencies for a reason. The FDA is in fact far stricter about drug testing and approval than the EU is.


> They pour over the methodology

Minor correction: pore. Confused me quite a bit because I wasn't sure which of the spellings it was...


Ah, thank you, I looked at the definition for both and couldn't figure out which one I wanted. I blame the OS X spotlight dictionary :)


No they actually have to enlist the help of physicians at hospitals and/or academic centers(for drugs) who would put a lot at risk if they faked the data. They also have to have external auditors.


Then how is "The FDA doesn't test the data sent by the corps" true then? I don't understand.


You should check out http://www.fda.gov/drugs/resourcesforyou/consumers/ucm143534..., it gives a good overview of how this works.


Thanks. I just checked, but it's still not clear. As far as I can understand, the drug application, along with results, tests, etc (which is conducted by the company) is reviewed by the staff at the FDA, which is not the same as doing the same tests and getting the same results, am I right?


So, it would be extremely time consuming and cumbersome and expensive for the FDA to replicate the procedures of the manufacturer's study just to confirm the result.

You're right that the FDA isn't replicating the study. But the premise of the system is that this replication isn't necessary, assuming that the process for exploring a new drug and testing its' safety and efficacy is well defined and considered.


Well, that's my point. If they aren't replicating the study, then that's wrong. It's like only validating input on the client and not server-side. It would be much more difficult for a company to fake both FDA results and their own.

And public health is what's at stake here, so there should never be enough tests.


That's understandable. But the idea here is that the entire process of testing a drug is extremely transparent to the FDA. In a typical scientific paper, the researcher worked on something for months or years, all the while keeping the structure of the study and the data they were collecting secret. After they finish, they then write a paper summarizing the methods and findings. This paper is (ideally) then peer-reviewed, and eventually replicated by other researchers to determine if the methods described produce the expected results.

Whereas with a drug trial, the company is telling the FDA from the very start "Hey, we have a drug we think might treat diabetes. We want to get this approved and on the market, so here is our plan for how we will conduct the trial." They then conduct the research in a much more open manner than typical lab studies in other fields.

Finally, there is the Institutional Review Board that is charged with ensuring all academic studies do not harm their participants in any way. Lying about your methodology in a medical study would get you expelled from your profession so fast your head will spin.

http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClin...

I would argue that the flipside of this being a public health matter is that people are suffering and dying of a condition that could be helped by a drug that we have to test for years and years. If we can conduct a transparent and rigorous double blind study and determine the safety and efficacy of the drug, we should be doing it.


I mean, it's literally in the article that pfizer had to pay for the study, so it wasn't exactly impartial from the start.


Pharmaceutical manufacturers are always required to perform safety studies on their drugs in the US. There's nothing unusual about this.

There's no prescription drug you can take here that is actually tested by the FDA. They work with the manufacturers to ensure the testing is thorough and accurate, but the company's themselves fund and conduct the testing.

http://www.fda.gov/drugs/resourcesforyou/consumers/ucm143534...

"Q: Does FDA test drugs?

A: No. It is the responsibility of the company seeking approval to market a drug to conduct laboratory and animal tests on the safety and effectiveness of a proposed new drug and then to submit that information to FDA for review by CDER physicians, statisticians, chemists, pharmacologists, and other scientist."

http://www.fda.gov/Drugs/ResourcesForYou/SpecialFeatures/ucm...


It's not unusual, but it's still a massive conflict of interest. The drug companies are clearly incentivized to hire laboratories that just happen to come up with the "right" results. Alternatively, they can just hire a hundred studies and just use the one that happens, by chance, to turn out the way they want.


But that's not how drug trials in the US are conducted. Drug companies work with the FDA from the start to get a drug through phase-1 and phase-2 trials.

There's just simply no opportunity to test out a drug in 100 different studies with 100 different groups of people and cherry pick the study you want to submit to the FDA. The process doesn't work like that.


That's how the FDA works.

The FDA is required to approve the study plan, the pharma (or really, the contract research organization (CRO) acting on its behalf) reports back to the FDA. The FDA decides based on the reported study result (reported to the FDA) whether the drug can be marketed and under what constraints.

Why should tax payer pick up the tab on a clinical trial like this? Over the life time of a modern drug, the clinical trials required can easily approach $1B.


And this is a one reason why our medical costs are so high.


I was in Florida visiting family over the weekend and this exact study was mentioned by the local news with a series of interviews. It was completely obvious that it was a commercial and nothing more.

One of the key things that tipped me off was that they compared "prescription strength" Ibuprofen to Celebrex once, then didn't mention it again. I get that it is like for like (prescription for prescription), but the vast majority of people taking Ibuprofen are not taking prescription strength dosages.

This should not be "news" it should be given to doctors to consider. We probably need a medical body to review these types of papers to determine whether they are actionable by medical professionals.


A prescription strength dose is only 3 normal ibuprofen tablets. That is an extremely common dose for people to take on their own with OTC ibuprofen, but it is also prescribed by a doctor in a single pill for convenience and to make it easier for insurance to cover it.

The point of the study is to compare long-term, daily use of NSAIDs. It isn't saying that you should take Celebrex for a headache (nor could you as it requires a prescription).

You shouldn't be so quick to dismiss a study that you think is "obviously a commercial" if you aren't familiar with the subject matter at hand.


You do realize that Celebrex is generic now and Pfizer has lost almost all of it's market share? If they promote Celebrex, they have little to gain from it.


The fact they were forced to pay for the study does not imply they had any saying on how it was conducted.


Perhaps, but it does suggest they had influence to make the authors not publish if the results didn't go there way. There's so many ways to distort information.

I'm not saying this study is bad, but studies paid for by corporations for their own gains should be the last we see running through news headlines. But of course, that is partly the effect they'd want from them...


The FDA mandated that this study be conducted. There was no chance of Pfizer sweeping the results under the rug, as the FDA was watching the whole process.


that's not how it works.

if you don't toe the line with the result of your study, that'll be the last one you do for the entire industry.


Celebrex is generic now. Pfizer has lost most, if not all, of it's market share. They have no incentive to promote it at this point in time.


It could very well be [0]

[0] http://www.paulgraham.com/submarine.html


Are those dosages a fair comparison (ibuprofen 600x3, celecoxib 100x2, and naproxen 375x2 daily)? Do they each provide the same level of pain reduction?

If not, there is literally no way to compensate for that level of statistical bias. Stomach/kidney/heart damage is not linear, and there's no mention of when people gave up taking the medications.

For someone who actually wants to read the study, here's the link: http://www.nejm.org/doi/full/10.1056/NEJMoa1611593#t=article

tl;dr - they admit that taking more than 200mg of celecoxib does some damage, and 800mg doses (they apparently were limited by regulations to 200mg/day) showed the same heart damage they expected to see. Time magazine is a horrible source


I've done both Ibuprofen 400x3 and naproxen 500x2 daily for knee problems, and would say the pain reduction from Ibuprofen is much greater than Naproxen. So much so, that I would say its not a fair comparison, particularly at 600x3.


Tacking on more anecdotal information, I'm a chronic pain sufferer and I've taken every OTC and several prescription NSAIDs at various points over the decades... in my case, ibuprofen was not only harsher on my stomach (roughly as bad as diclofenac), it helped less with pain even at huge doses - it helped more with tension and strangely was better at tooth pain, but far less with my particular joint and muscle pains.

I would have guessed similar to the article - Naproxen was the softest on my stomach for as long as I could take it, but over the years I both built a tolerance for it and it wasn't strong enough so I switched to meloxicam (the gentlest on my stomach and the strongest pain reliever of the group, but only available by prescription) and was on it for nearly a decade. I'd go back on it too if I were able - it was definitely the best thing I've ever taken for my pain. Celecoxib was just more expensive ($20 copay vs $4 generic) and didn't work as well. I'm very sad that NSAIDs are no longer an option for me, as they both reduced the pain and treated it, but unsurprisingly 20 years of taking NSAIDs daily caught up with me... medicine still hasn't come up with a better solution for long term pain management, despite the desperate need.


They are different pain medicines and mileage varies with the person and type of pain you have - and sometimes, your preconceived notions. (some folks have brand biases and so on).

I react well to both of them. Since ibuprofen is cheaper, I am more likely to use it. Though honestly, for my worst recurring pain, I take both ibuprofen and paracet (Tylenol), on advice from the doctor. The same seems to help my spouse with dental pain.


I've noticed this to be very individual dependent. Ibuprofen does nothing for me for pain relief; Naproxen does.


I have to switch between multiple anti-inflammatories as my body seems to adapt to what I take to manage chronic arthritic pain


Just as a suggestion, you might want to try going the other route and working with your body instead of fighting it.

Have you looked into prolotherapy before? (sugar water injections)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2831229/


Yes because my body has such a hard time making sugar water

\s


I'm not as skeptical of prolotherapy.

The idea is that it acts as an irritant which increases blood flow and other healing responses to that area. Tendons in particular are thought to heal slowly because they don't have great blood flow. This strikes me as similar to the ideas of dry-needling and platelet-rich plasma injections.


The study authors made clear (in another article [1]) that they are not trying to discourage people from infrequent ibuprofen/naproxen use. This study was about prescription doses and daily use.

> "I don't want the public to think that if you take an occasional ibuprofen or naproxen that you're going to have kidney failure or you're going to die," Nissen says. "We didn't study that. We studied daily doses in arthritis patients [taking] ... high doses of these drugs."

The headline doesn't reflect this, but it probably wouldn't get as many clicks if it said "daily use of prescription-level ibuprofen may not be as safe as was thought".

1: http://www.npr.org/sections/health-shots/2016/11/13/50103343...


here is input from my pharmacist friend on this article:

"Just saw this study come out a few days ago and it kind of is no news. The harm of nsaids has been known and the warnings are out there. I tell patients everyday not to take advil/naproxen if they are older than 40/50 because of the heart and stomach issues.

Will be interesting once they release celebrex as over the counter, this latest study will definitely catapult that process exponentially.

In the mean time, only take nsaids if u really need to, with food and i tell patients to eat frequently and not too much salt to combat the water retention which causes the heart issues."


Isn't aspirin regularly promoted as being good for your heart?


It is, as well as prevention of stroke and prevention of colon cancer. While in the same general category of NSAIDs, you should think of it as really being a different animal. It has more of an antiplatelet effect than the other NSAIDs these articles are talking about which lead to decreased clotting.


Correct. Promoting aspirin as "good for the heart" is too generic of a phrase; such generalization may lead to healthy people unnecessarily taking a daily aspirin just because it is "good for the heart".

Aspirin is prescribed for some specific conditions due to its antiplatelet effect. From what I understand, for normal healthy people, there isn't much benefit of daily aspirin. And, there is potential for some side effects -- in addition to the same stomach problems / heartburn issues that plague other NSAIDS also has some bleeding type issues due to the antiplatelet effect.


> Correct. Promoting aspirin as "good for the heart" is too generic of a phrase; such generalization may lead to healthy people unnecessarily taking a daily aspirin just because it is "good for the heart".

Well, Bayer runs (or ran) ads encouraging just that behavior.


> Well, Bayer runs (or ran) ads encouraging just that behaviour.

Such a thing would never fly in Europe. They'd get laughed out of the room and sued.


Be that as it may, their German scruples didn't stop them from running a huge ad campaign in the US to this effect.


I remember those ads. Googling, it looks like the FTC did rebuke Bayer for their behavior in 2000. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1070790/


IIRC isn't the number needed to treat on aspirin pretty high, like in the thousands?

I'm not sure how that compares with other treatments or the average but offhand it seems pretty high to the point of asking whether it's worth it.


It depends on what you're trying to prevent and what your risk factors are.

For patients with existing heart disease or prior strokes, the NNT is between 50 and 333 depending on the outcome you're considering. Source:

http://www.thennt.com/nnt/aspirin-for-cardiovascular-prevent...

For prevention of a first heart attack or stroke, the NNT is between 1667 and 3000 depending on the outcome. Notable is that no deaths were prevented by the therapy. Source:

http://www.thennt.com/nnt/aspirin-to-prevent-a-first-heart-a...


Ah, that makes more sense. I saw the 1667/3000 numbers and was very put off by them.


Yeah the NSAIDs warnings are quite consistent. I've been sensitive to them but can tell the benefit as long as I'm taking them appropriately (e.g. infrequent doses, usually with good amount of food). Kind of surprised me Naproxen Sodium is still a script drug some places outside of the US whereas Codeine would otherwise be OTC, basically speaking. I know which I'd rather have access to for pain management.


I have always avoided nsaids if I can, and when I have to take them I always am asked to also take previcid to protect my stomach. I very quickly start to lose hunger and have stomach issues without something else to protect against the nsaid.


> people were assigned standard doses of 100mg celecoxib twice a day, 600mg ibuprofen three times a day, and naproxen 375mg twice a day

> In almost every measure, ibuprofen looks worse, naproxen is intermediate and celecoxib is the best.

> the heart concerns led the FDA to require its maker, Pfizer, to pay for additional studies to ensure that celecoxib did not put people at increased risk of heart trouble

And afaik Celecoxib is the only one marketed solely by Pfizer, at prices 5 times higher than the other 2.

Am I being paranoid thinking this at least deserves more study, not conducted or paid for by pharma?


> Am I being paranoid thinking this at least deserves more study, not conducted or paid for by pharma?

Do their rivals have an incentive to check Pfizer's work? If they're publishing bogus studies to get through regulatory checks, it could delay the new drug from being released.

Further, if they're publishing bogus studies, it seems like the FDA would be partially responsible. So one might expect the FDA to possibly run trials of their own on a random sample of drugs, and compare with what the drug companies published.

Also, Trump has mentioned speeding drugs through the FDA process. There might be less incentive to cheat the results if they don't need to do it to release their drug.


The FDA has these funny rules where you only need one successful study to be accepted. So as long as you can pay for study after study you can just wait until chance works out in your favor and you're out on the market. This is known. FDA does not care.


And afaik Celecoxib is the only one marketed solely by Pfizer, at prices 5 times higher than the other 2.

It's generic now.

https://www.goodrx.com/celecoxib?drug-name=celecoxib


I would also like to add that not all Ibuprofen pills are equal. Biological availability should be taken into account too. 400mg pills with 90% of availability will have the same effect for pain as 600mg pills with 60% of availability. But they'd likely have different effects on stomach/kidney.


Is this quality listed somewhere? I've never heard of it.


The wikipedia template for these drug descriptions include basic bioavailability / excretory data. Would still need to dig a bit for comparative BA figures for tablets/caplets/liquids/etc, but at least the core number is there.


Unfortunately not all manufactures test it and mention it in the pill notes. But some of them are, for example Advil liquid capsules, they mention in the note that it has 90-95% availability


In order to get approved as a generic version of the branded drug, the generic manufacturer has to show data that indicates 80% to 125% bio-equivalence.

If there is a version on the market with only 60% bioavailability, somebody screwed up (the FDA).


This TIME headline seems totally disconnected from the article, which is about COX-2 inhibitors.


Hmm? One of the main results relevant to the wider audience is surely that Ibuprofen no longer looks like the most-recommendable drug because it looks less safe than the alternatives. (Even if some remarks can be made towards the study, that doesn't change the above in terms of presentation and relevance to the audience)


From the paper:

At moderate doses, celecoxib was found to be noninferior to ibuprofen or naproxen with regard to cardiovascular safety. (Funded by Pfizer; ClinicalTrials.gov number, NCT00346216.)

http://www.nejm.org/doi/full/10.1056/NEJMoa1611593

The paper draws no conclusions about the relative safety of ibuprofen. The only claim is that celecoxib is not inferior to the other two NSAIDs.

Note that this research study was funded by Pfizer, the company that markets Celebrex.


Right, so this mentions ibuprofen explicitly, and it talks about cyclooxygenase-2 selective inhibitors too. I still don't get what your complaint about TIME's title is?

Did you think they should've mentioned celecoxib? That's much less known drug. Mentioning ibuprofen means it's more likely to reach the audience that should care about the study.


Yes, but we don't know whether Pfizer is hiding other similar studies that came to different conclusions. This is a general problem with big pharma research disclosure, not just Pfizer.

FYI, celecoxib is the generic name for Celebrex.


The suggestion from the paper (and indeed the body of the article) is that Celecoxib is safer than was being assumed, and very much not that Ibuprofen is more dangerous than was being assumed. In that sense it's a good news article with a bad-news headline needlessly attached.


Seriously.


One major problem with studying medication effects is that to study humans, not only does the experiment introduce more bias by studying different people, it also leads to results that may contradict the next study. I wish there was a more accurate way of measuring a drug's weaknesses, but it seems that these human studies are here to stay a while.


Maybe we should aim to create within the next century a near perfect simulation of us and our world, run it at an incredibly high speed and see if any knowledge regarding this, and many other things, emerges. ;-)


All I can say about this is the following: I used to take a lot of vitamin I (ibuprofen). I've had some knee issues resulting in chronic pain dating back to my teens, and I always used Ibuprofen. And, yes, to be honest, at times I took more than the recommended (OTC) dose, and took it for longer periods of time than you're supposed to.

Then I noticed that they changed the warning labels to point out the increased risk of heart attack from regular use of Ibuprofen.

Then I had a heart attack.

And all of my doctors (GP, cardiologist, etc.) suggested I quit taking Ibuprofen.

Hrrmmm... to be fair, in the case of any individual, they can never really say exactly why you had an MI when and where you did. And I was a little overweight at the time, but I had very few other risk factors. I never smoked, had no family history of early heart attacks, and I was only 41.

So did Ibuprofen play a role? We'll never know, but I'm following my doctor's advice and not taking it anymore. I'd recommend anyone who uses Ibuprofen frequently consider having a chat with their doctor and think hard about the various risk factors involved.


tl;dr: Celecoxib is safer than previously thought for people with heart problems.


causes the same level of heart problems as ibuprofen, but less kidney and GI problems


This would have been a much better and less misleading headline.


WARNING: Autoplay video.

Even if you open it in a new tab and are still viewing the current one (middle click on my computer).


Who in the world doesn't know that NSAIDS are dangerous drugs at this point? It's not exactly a surprise is it, this info has been around for years. Acetaminophen is obviously much worse but still...


There are folks that don't realize that acetaminophen or ibuprofen are in many cough and cold formulations.

But they aren't really dangerous per se. Certain population groups shouldn't take them, some can't tolerate them, and there are consequences to taking them over a long-course (which is what this was comparing). But for most with everyday aches, pains, colds, and so on, they aren't that dangerous.

You know, use responsibly and stuff.


A friend's sister took a few ibuprofen a few days ago on an empty stomach, started throwing up blood for several hours, spent the night in the ER. Now she has an ulcer.

Edit: Ulcer, not hernia.


The warning label on every bottle of ibuprofen specifically says to not take it on an empty stomach for exactly that reason. What was she expecting?


I know; she's an idiot. I'm not sure many people know how dangerous this can be, though. I'm not sure people take warnings on medication as seriously as they should.


Looking at a generic from Wal-mart: the closest warning is "Take with food or milk if stomach upset occurs."


I'm looking at a bottle of Advil right now and nowhere does it mention not to take it on an empty stomach.


I am looking at a bottle of right now and do not see it on there.


I wouldn't be surprised if she had an ulcer before taking the pills and it irritated them or she has an especially sensitive system as some do.

I say this mostly because it is common (though not recommended) to take them on an empty stomach and it seems her reaction to the single pill does was extreme.


Did you know that most people that win the lottery took ibuprofen in the month before winning?


This isn't random chance. Ibuprofen can cause ulcers and blood in the urine if taken on an empty stomach. Not many people know this.


I was mostly responding to the fact that you seemed to be blaming her hernia on ibuprofen.

However, even when changed to an ulcer, it is the kind of anecdotal evidence that keeps urban legends alive. Long term use of ibuprofen is known to cause ulcers. Rare use, on an empty stomach or not, does not instantly cause bleeding and ulcers. It is much more likely that Broken_Hippo is right or that she indeed has been chronically using ibuprofen.


Urgh, medical reporting is almost as bad as Tech reporting. No critical thinking.

this is the gist: "There is a new drug that acts similarly to ibuprofen, but appears to be less aggressive towards kidneys. Equally as bad for the heart."

However 70% of the participants failed to complete the study, so its not long term. No percentage risks are quoted. It also doesn't compare how effective celecoxib is compared to the much cheaper and well understood(interaction wise) ibuprofen.

It also notes that high doses were not tested: "600mg ibuprofen three times a day"

That my friend is a fucking large dose, as in three weeks and you have an ulcer dose.


Actually, that isn't that large of a dose.

The normal tablest in the US are 200mg: Lots of folks take 2 a few times a day: 400mg 3 times a day, as recommended on most of the packaging.

Prescription ibuprofen is 800mg tablets (most times). This is a fairly common dosage, 3-4 times a day.


Sorry good point. I was thinking about over the counter. My fault

600mg four times a day is inline with the BNF daily limit of 2.4g: http://www.evidence.nhs.uk/formulary/bnf/current/10-musculos...

Seriously the BNF is a brilliant resource, it has this to say about celecoxib: http://www.evidence.nhs.uk/formulary/bnf/current/10-musculos...


Really?! Is this among the elderly who already have lots of little aches here and there or the general population? When I broke my arm I took 400mg about six or seven times over three days and for a cold I tend to take one or two paracetamol, but taking pain killers regularly sounds very absurd to me and I don’t know of anyone who takes anything stronger than coffee regularly and more than once a month.


Everything is in general: I might have worked in a pharmacy, but I'm not a pharmacist or a doctor.

But I know a lot of folks will take ibuprofen for 7-10 days at those rates. It is pretty common, and just as common for people to regularly take naproxen a few times a day for chronic pain.

Taking pain killers regularly sounds absurd to you because you don't have that sort of chronic pain. And pain is a funny thing: My mother openly admitted that she would get to a point with migraines where the pain was so bad, the side effects didn't quite seem to matter (She learned to go to the hospital or doctor before then).

More often, however, these pain killers are the very things that makes every day life bearable. Some people it means they can be more active but others it just means they can open doors and grab toilet paper with less pain.

Your method is great for people that have occasional pain or needs: After all, it seems a bit silly to take it for no actual reason. And as far as the folks you know, well, if you are young that is more likely. And if not, it is just something the people you know don't talk about.


thats the difference between acute (short term) and chronic (long term)

In acute cases paracetamol can have an 8 gram daily limit. long term you're going to see problems.

When you have something like arthritis, or and old joint injury, you'll be needing long term anti inflammatories


Do you know anyone with long term chronic pain?


All of the participants in the study had pre-existing heart problems as well.




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