Mar 15 2013
Anti-inflammatory drugs: A closer look at the risks
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Thank you for this informative article. My familiarity with NSAIDs is for the short term relief of pain after some types of dental treatment. It is good to know that the ones I use are on the safer end of the spectrum. I tend to avoid the latest and greatest until they have established a track record. The benefits are generally over rated and the risks still to be discovered.
You say “That is, cardiovascular events are 40-70x more likely among users of diclofenac compared to non-users,”, when I believe you mean “That is, cardiovascular events are 40-70% more likely among users of diclofenac compared to non-users.” The numbers you give are a percentage increase, not a multiple.
Thanks, Scott. I’ll stick with the occasional aspirin or acetaminophen.
Thanks, Scott, but why indeed was the US left out of the study? Doesn’t it represent a lot of data?
When I saw this headline, I was afraid it was going to be bad news. But not so much for me. It’s good to know that the NSAIDs I rely on when I’m getting a flare are the ones with a better safety profile.
I would be curious to know about that Emulgel, though. Is that available in the U.S.?
Scott, great article but I am a little confused and hope you or another blogger can help. My understanding is that low-dose daily aspirin is associated with decreased heart attack risk (data from Framingham etc). But here we are seeing (presumably) higher-dose NSAIDs increasing that risk. Is the explanation that we looking at an inverted U-shaped curve with respect to dose? Or is this a structural issue related to COX affinity and/or pharmacokinetics? or all the above?
Thanks in advance for any info – we spend about 30min on essential fatty acids and eicosanoids in my biochemical nutrition course, and I’d like to get it right.
See Health Affairs, oct. 2012. Timbie, Fox, Van Busum and Schneider. Five reasons that many comparative effectiveness studies fail to change patient care and practice. These are:
Financial incentives (not so relevant in this case, maybe)
Ambiguity of study results that hamper decision making
Cognitive biases in the interpretation of new information
Failure of the research to address the needs of end users
Limited use of decision support by patients and clinicians.
I’d add two more: Doctors just don’t keep up with the latest, clinical findings are spewed out constantly as from a firehose and docs are busy. It’s easier just to keep doing what you’ve been doing.
And, of course, drug company marketing and general obfuscatory tactics.
Angora Rabbit: The convention when referring to NSAIDS is to mean “except for aspirin.” They are aspirin-like drugs, but aspirin reduces heart attack risk, rather than increasing it. It’s not a question of dose, aspirin really is different in this respect. But, aspirin does create a risk of bleeding, and GI bleeding can be a serious problem.
“…On the other hand, that analysis also found aspirin increased the rate of bleeding from 0.7 to 1 per 1,000 people per year, making the authors conclude the drug was of “uncertain net value.”…
“”The number of events that you prevent depends on your baseline risk,” LeFevre concluded. “A blanket recommendation that everybody should take an aspirin is not a good idea.”…”
http://www.reuters.com/article/2011/04/20/us-aspirin-heartattacks-idUSTRE73J7KG20110420
@Angora Rabbit
Aspirin binds to platelets irreversibly interfering with the “stickiness” of them. whereas other NSAIDS bind reversibly which will interfere with the beneficial binding of aspirin.
Fortunately, it looks like the OTC drugs (well, OTC in the USA, which is all that matters
) test favorably compared to the others. Unfortunately, that also means they’re probably easier to get in bulk, resulting in people overdosing because “it hurts a lot and four Tylenol are better than two, right?”
@DugganSC – Just to add, It’s my understanding that one of the major causes of tylenol overdose has been people taking multiple products that have tylenol added to them without realizing it. So possibly someone was taking prescription Vicodin (with tylenol) for pain, then also taking a cold medicine or sinus medicine without realizing that it also contained tylenol. This was why the FDA called to eliminate those combo prescription drugs like Vicodin and Percocet. It probably doesn’t help that the people who are most likely to be taking any sort of pain medicine or anti-inflammatory (people over 40) need to get out a magnifying glass to read any of the labels on the bottles.
The FDA should regulate typographical point size on drug labeling.
If they start attempting to control consumption by bottle size, I will get really aggravated at the waste of packaging when I have to buy four bottles of ibuprofen rather than one.
@Angora Rabbit, in addition to Cervantes and drsteverx’ comments, note the following sentence, “ Importantly, other NSAIDs interfere with the beneficial effects of ASA (aspirin) on platelets that can give protective effects against cardiovascular disease.”
I had the same question, but a re-read turned up that nuance.
@cervantes:
I invoke the spirit of Ben Goldacre MD and a half-remembered post of Dr. Hall in saying that it might be a little more complicated than that; I recall reading somewhere that pharmapimping is indeed a factor in driving up the cost of care and shoddy tactics to alter prescription habits, it is also a factor in increasing the uptake of new drugs that are genuinely more valuable and effective by doctors. While there are negatives to pharma reps, there are also upsides.
Now if only I could find the source…
@mousethatroared:
My father finds that as he gets older, his arms seem to get shorter, which is interfering with his eyesight
mousethatroared,
I believe there are other significant contributing factors to acetaminophen overdose, such as simple lack of attention to timing of doses as well as actually following a prescription on the label (as you understand it).
Anecdote:
I recently had a kidney stone, and unlike the two previous times I have had kidney stones, the pain from this one lasted for many days rather than just a 2 or 3. I was prescribed the generic equivalent of Vicodin 5/500. The recommended dose on the label was 1-2 tablets every 4 hrs as needed.
My pain was so severe and continuous that I was constantly on Vicodin for about 4 or 5 days straight. Since I am well aware of the risks associated with acetaminophen, no mater how miserable I was, I always paid very close attention to when I took my last dose, and only once took more than 1 tablet in a 3.5 hr period (trying very hard to keep total acetaminophen to no more than 3000mg/24hrs). There were many times where the intensity of the pain returned after only 2 or 3 hours, and I had to hold out until at least the 3.5 hr mark on my own.
So, here are my key take away points:
1. When miserable and in bed, it can be very difficult to be aware of what time it is when you take medication (or to remember it several hours later), but it’s conversely very easy to be aware of when pain or discomfort returns. Beware taking acetaminophen containing (or most any other) medication based solely on perceived need rather than also paying close attention to timing of doses.
2. If I followed the prescription label as many people might have, I would have ended up taking 2 tablets every 4 hours, receiving 6000mg of acetaminophen over each 24 hrs, well over the recommended max. (2000-300mg over, depending on who you talk to.) In my opinion, the label needed the addition of “TAKE NO MORE THAN 8 TABLETS OVER 24HRS.”
KarlW – Yes, of course, thanks. I didn’t mean to imply that was the only concern.
Also, KarlW – All of your points are excellent. I’m pretty sure if it were me, I would have made the mistake of taking 2 tablets every 4 hours.
WLU “My father finds that as he gets older, his arms seem to get shorter, which is interfering with his eyesight.”
Now I’m depressed by the fact that I’m probably old enough to be WLU’s mother – yet still have to think young enough to keep up with my 8 and 10 year old children…finding the One Direction station on my Pandora now.
And why do several opioid medicines (not just Vicodin, but also the codeine I was prescribed after recent dental surgery) contain acetaminophen? Is it just to reduce the amount of opiates used, or is there a synergistic effect?
I suspect the presence of acetaminophen with codeine is to make the codeine more difficult to abuse without liver failure.
What are the adverse cardiac effects with opiates? I suspect there are essentially none, short of death from overdose (which can be stopped easily with Naloxone).
And there is reason to doubt that acetaminophen is as benign as previously thought with respect to adverse cardiovascular effects
http://www.ncbi.nlm.nih.gov/pubmed/22039164
This is often suggested, but I’ve never seen solid evidence for it. If one looks at (U.S.) DEA scheduling, there are certainly examples in which the dual formulations are Schedule III while the single-opioid version are Schedule II. (Does not apply to Percocet, which is just as Schedule II as plain oxycodone.) And one is stuck with the fact that such dual formulations also come in aspirin varieties.
On its face, it seems to come down to the notion that the analgesic really will enhance or extend the effect of opioid. Whether this is actually the case, I do not know.
^ Sorry about the typos. “But one is stuck,” and “the effect of the opioid.”
Recently Abbott, the manufacturer of Vicodin has changed (lowered) the dose of acetaminophen that is contained in its 5mg., 7.5 mg., and 10 mg. tablets, to be in compliance with an FDA advisory to limit the dose of acetaminophen to 325 mg. for each dose of drugs that contain acetaminophen in combination with another drug.
http://www.philly.com/philly/blogs/healthcare/Less-acetaminophen-in-each-tablet-of-Vicodin.html
“In January 2011, the US Food and Drug Administration (FDA) asked drug companies to limit the amount of acetaminophen in all prescription medicines to 325 mg per tablet. This would help reduce the risk of taking too much acetaminophen, particularly if the medicine is taken every 4 to 6 hours around the clock.
Abbott, the company that makes the prescription pain medicine Vicodin (hydrocodone and acetaminophen), will be decreasing the amount of acetaminophen in all of its Vicodin products to 300 mg per tablet. The amount of hydrocodone will remain the same based on the prescribed strength – 5 mg, 7.5 mg (called Vicodin ES), and 10 mg (called Vicodin HP). It is unclear at this point regarding the many generic versions of Vicodin and whether they are complying with these changes in the acetaminophen strength. So, use caution when adding up the amount of acetaminophen. Generic versions of Vicodin may not be exactly the same as the “new” Vicodin because of different amounts. When you drop off or pick up your prescriptions, ask your pharmacist how much hydrocodone and acetaminophen are in each tablet.”
I have a prescription for the generic form of Vicodin (hydrocodone) combined with acetaminophen and the dispensing pharmacy has marked the medicine vial with a label “HYDROCODONE/ACET 5/500 MG.”
If you are fortunate to have drug coverage, you are “encouraged” to go with generic drugs, because the brand name drugs co-pay is far more costly.
Karl – In the UK (and the parts of continental Europe I’ve visited) all paracetamol-containing products carry the “Do not exceed 8 pills in any 24 hour period”.
Products such as cold medications have a warning saying “THIS PRODUCT CONTAINS PARACETAMOL” and something about not using said medication alongside other products that contain paracetamol. If they’re being bought OTC the pharmacist will ask what other drugs are currently being taken.
There’s also the advice “If symptoms persist after three days of treatment then seek medical help”.
WRT COX-2 inhibitors – I used to take etoricoxib which was prescribed for pain related to endometriosis. It worked marvellously, and was convenient to use as it was taken once a day. However it was withdrawn from use (by NICE or the MHRA) due to the risk profile, and I was put back onto *drum roll* Voltarol! (Diclofenac) which apparently has the same risks associated with it, and which has never done anything for me except making me feel like I’d been swigging battery acid.
Lilady – Good info and urgggggh, as if people are going to keep track of that.
Regarding adding tylenol to Vicodin. I think the idea that idea that they are trying to cause liver damage in addicts is strange. The two drug control pain in different ways, it make sense that they are combing them to lower overall pain. I don’t know that it’s effective…but I don’t see a need to leap to the idea of drug companies plotting against addicts.
My goggleU (google acetaminophen NSAID combination) course and my personal experience suggests that tylenol and NSAID (Aleve or Ibuprofen) are more effective when taken in combination for inflammatory type pain. My recent experience suggests that prednisone works better than both of those – but the risks are higher
D2U-
I don’t know about ‘cardiac’ but I imagine there have been significant episodes of hemorrhagic stroke caused by patients straining to take a crap
(only half kidding here)
Thanks for the article. The only NSAID I use is ibuprofen and now it seems a sensible choice. BTW, I also used Voltaren Emulgel to ease joint pain and it seemed to be working (although I cannot be really, sure, maybe the problem resolved on its own).
As for aspirin and its antiplatelet properties – well, due to low platelet count and tendency to extended bleeding (genetic issue, my father and sister also have it, not life-threatening, so you just learn to live with it) I was strictly forbidden to take any ASA-contaning medicines.
And then, there is the tentative link between ASA and Reye’s syndrome, which is enough to scare some people from using aspirin.
Managing the rheumatoidal arthritis flare-ups is becoming a real pain, an isult added to injury. I have read recently about using aspirin and omega-3 fatty acids in combating inflammation by stimulating resolvin production. The article which prompted the media alerts seems to be this piece by Serhan, Petasis et al. (sorry if I had the main authors mixed up but they seem to be doing the talking to the press). They found the effects to be real in mice – has anyone heard anything aout human studies? It would be a blessing if we could really manage inflammation by a small daily dose of aspirin and fish oil!
Just for the record:
1. The accepted (main) mechanism for many of the NSAIDs is blocking the COX enzymes.
2. The COX enzymes (together with other enzymes) metabolize omega-6 fatty acids into series 1 prostaglandins.
3. Series 1 prostaglandins are considered “more inflammatory”, to put it mildly.
4. The standing recommendation by the ADA, the AHA and others is to increase consumption of seed oils.
5. The main constituent of most seed oils is linoleic acid (on the order of two thirds for safflower oil, one of the worst offenders).
6. No other naturally occurring food enables it to consume as much omega-6 fatty acids as seed oils, and seed oils are evolutionary novel.
7. If you massively increase the consumptions of omega-6 fatty acids through seed oils (above the levels encountered during our evolution), the body will produce more inflammatory prostaglandins.
Now, should any of this be considered controversial?
Or, is any of this new?
And have you heard of the doctors Sune K. Bergström, Bengt I. Samuelsson and John R. Vane?
(I know the eighties sucked and everybody tries to forget what happened back then, but not everything was bad, you know.)
And why is the regular consumption of NSAIDs is (rightly) considered problematic by at least some, but not the consumption of supernatural levels of omega-6 fatty acids?
Should seed oils be considered as a supplement?
And could an increased consumption of seed oils be somehow connected to the increased consumption of NSAIDs?
And why do I have to think of the word “prostaglandin”?
And is the word prostaglandin safe for work?
Is there any evidence (as in clearly identified metabolic pathways that benefit, and not epidemiological meta analysis of peer reviewed op-ed pieces) for the actual need to consume supranatural levels of omega-6 fatty acids?
And what is a loaded question?
Compared with what? Sesame oil, which is high in linoleic acid, has certainly been around for a few thousand years, and one might imagine that the consumption of seeds, which contain seed oils, has been around longer.
I was a little shocked by the large RR of cardiac events reported in the RCTs for ibuprofen. Admittedly, the error bars reach all the way down to a 10% increase, but can anyone with access to either of those studies elaborate as to why the RR comes out so high?
And just in case someone needs a diagram to drive the point home:
http://en.wikipedia.org/wiki/File:EFA_to_Eicosanoids.svg
Forget calories in, calories out.
The new black is: Linoleic acid in, series-1 prostaglandins out.
.
.
.
I wrote: “seed oils are evolutionary novel”
Narad wrote: “Compared with what? Sesame oil, which is high in linoleic acid, has certainly been around for a few thousand years, and one might imagine that the consumption of seeds, which contain seed oils, has been around longer.”
Yes, seed oils like sesame oil “has been around”, but not available universally, and surely not in the amounts we produce industrially. How much sesame oil could a pre-industrial society produce per person and per year? Again, in other words: The ability to consume large amounts of omega-6 fatty acids every day is evolutionary novel.
Yes, seeds themselves “have been around” and contain omega-6 fatty acids (duh!). But not as concentrated as seed oil. How much seeds do you have to eat to get the amount of omega-6, that is contained in the recommended amount of seed oils? And how much seeds could a pre-industrial society produce per person and per year?
Linoleic acid content per 100 grams:
Safflower oil: 50.176 grams
Soy oil: 52.85 grams
Safflower seeds: 16.706 grams
Soy beans: 2.479
Wheat: 0.512 grams
(All numbers according to the german Bundeslebensmittelschlüssel BLS – your local numbers may vary, but only slightly)
So yeah, seeds contain omega-6 fatty acids, as do most foods. Duh.
I think it is generally recommended to consume 20–35% of the total energy from fat, and that mostly from seed oils (instead of animal fats with their mostly saturated and mono-saturated fat). So run the numbers and construct a pre-industrial diet with some (lowish) amounts of seed oil. And then run the numbers if you replace most of the animal fat with seed oils. And don’t use olive oil for the numbers, as most industrially produced food nowadays contains safflower oil or soy oil, as they are the cheapest. And don’t assume that the pre-industrial society eats their animal products in low-fat form – after all, they haven’t been counseled yet how utterly utterly bad saturated fat is and how utterly utterly bad animal fat is. Meat might be scares, but the animal fat will not be shunned. So you need for comparison a pre-industrial society where people eat safflower seeds, and nothing but safflower seeds, all day, every day, the whole year round. Then you could come to the numbers recommended by the ADA/AHA and others. Maybe.
And then please show me the real life pre-industrial societies where omega-6 fatty acids were consumed in the amounts (or even more) that is generally recommend as “healthy” by the ADA/AHA and others. I think you will be hard pressed to find one.
Again: The ability to consume large amounts of omega-6 fatty acids every day is evolutionary novel.
Damn, forgot series 2 prostaglandins. It is series 1 *and* series 2 that are produced from linoleic acid. And it is the series *2* that is the bigger problem.
People, you need to check what I write. Seriously. After all, you’re the pros, not me.
It’s unclear to me why you would say “don’t use olive oil,” as you’re making an argument from antiquity and “industrially produced food” wasn’t at issue in the first place. Anyway, do I know the efficiency of ancient seed presses? No, I do not. It is certainly the case that the Egyptians were aware of safflower as an oil source, however. Whether it was common among the cooking oils used is something I also do not know; perhaps it was mainly medicinal. It is true that modern industrial-scale production of safflower oil only got started in the middle of the 19th century.
Cooking oil was a form of currency among ancient Egyptians, it’s how taxes were gathered (and tax inspectors only collected the good, unused stuff).
Ah, Tony. When all you have is a hammer…
“The risks from diclofenac, the most popular NSAID in the world, is at least as high as Vioxx: A 1.39-1.69 relative risk. That is, cardiovascular events are 40-70x more likely among users of diclofenac compared to non-users.”
If the relative risk is 1.69, wouldn’t adverse events be 1.69x more likely? I don’t understand where the seventyfold increase comes from.
In addition to being bad for people, diclofenac probably caused an ecological disaster by wiping out vultures in India (they were poisoned by dead livestock that had been treated with the drug). See the Wikipedia entry for diclofenac.
have been lurking.. great site!
@ mousethatroared- yes, the gel is called Voltaren
http://www.voltarengel.com/consumer/default.aspx
I have a neurological condition (severe pain/nerve damage) and have used the gel- works well for minor – irritating aches, it comes with measuring stick so you know dosage. Was not expensive and got 8 tubes! I still have 5 left
In Australia it’s called Voltaren Emulgel.
I’ve used it for the occasional mild tendonitis and enthesitis that I get from running in the hils – in fact I’m presently using it over my left tibial tuberosity and comparing it with no treatment of a similarly affected right side. Not much difference yet.
Chi_girl – Thanks for the link to the Voltaren. I see it’s prescription. I’ll have to ask my doctor about it.
It’s OTC here in Australia!
Austraila is a bit of a drive for a OTC drug run, BillyJoe. Usually we Michiganders just go to Canada for that sort of thing. (not sure the status of Voltaren in Ca, though)
No big deal, I have a doctor’s appt coming up, anyway.