Don't take two aspirin (but call me in the morning)

There is a new paper in the Journal of Immunology I found more than a little disconcerting. University of Rochester scientists have found that the cells in the immune system responsible for antibody production, the B-cells, also express high levels of the enzyme cyclooxygenase-2 (Cox-2). Overproduction of Cox-2 can cause pain and fever, which frequently accompany reaction to infection. The problem is that treatment of B-cells with inhibitors of the enzyme (Cox-2 inhibitors) also markedly affected the ability of the B-cell to produce antibody. What are some Cox-2 inhibitors? Aspirin, Ibuprofen, Alleve, Celebrex, that is, the NSAIDs (non-steroidal anti-inflammatory drugs). The evidence comes from both animal experiments and studies on humans:

For the animal portion of the study, researchers vaccinated normal mice and mice engineered to be cox-2 deficient with a component form of the HPV vaccine. They analyzed the amount of antibodies the animals produced, focusing on the critical virus-neutralizing antibodies. The cox-2 deficient mice made 50 to 70 percent less of these key antibodies.

The same experiment was done on preserved blood samples from people who had been vaccinated against HPV-16, the strain linked to cervical cancer. Scientists reactivated the B cells in the blood samples and watched them churn out antibodies, as expected. But when researchers treated the B cells with a cox-2 inhibiting drug, the cells significantly diminished their production of antibodies - showing that cox-2 is essential for an optimal immune response against HPV 16. (Press release, University of Rochester Medical Center)

The data were generated in a study of HPV, but in principle the same effect would hold for any vaccine, whose job it is to induce B-cells to produce antibody. The Rochester investigators speculate the heavy use of NSAIDs by the elderly might be a reason they respond less well to influenza vaccines. They recommend these drugs not be used to relieve pain at the injection site or the transient fever that sometimes comes with vaccinations.

Yet there is an even bigger issue here. If it were just vaccinations at issue, public health authorities could advise people not to take aspirin or ibuprofen. But vaccines work by educating your immune cells to react much more quickly upon repeat exposure to the target bacteria or virus or to a repeat infection from the same agent. The Cox inhibitors are among the most used for the symptoms of cold and flu. This means that when you start to feel lousy and fill yourself up with aspirin or ibuprofen, you could also be interfering with this "recall response" of your immune system. In effect, you would be canceling or at least diminishing your immunity.

There remains much work to be done on this. We still don't know how Cox inhibitors work to dampen antibody response, how much they do inhibit it during illness (if they do), and whether timing is important and if so, how.

But this is new and somewhat troubling information.

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For a long time we debated how much NSAIDs inhibited both COX isoforms. Proverbial wisdom indicated that NAIDSs did not inhibit COX-2 as much as COX-1, which was one of the reasons the coxibs were developed, such as Vioxx. In retrospect, this was probably not too smart as we learned that tot al inhibition of COX 2 for long periods of time leads to all sorts of problems.

Here's another paper by Carey et al published a year ago in the Journal of Infection that is also interesting.

Wild type (WT), COX-1-/-, and COX-2-/- mice were infected with H3N2 influenza (A/Hong Kong 8/68) and the course of the infection monitored by measuring levels of IL-1β, IL-6, TNF-α, IFN-γ, PGE2, and the leukotrienes, LTC4, LTD4, and LTE4, obtained from bronchoalveolar lavage. Less severe illness was observed in the COX-2-/- mice, compared to the other two groups, and mortality rates were also lower. In addition, the COX-1-/- mice had enhanced inflammation and an earlier appearance of pro-inflammatory cytokines, compared to the COX-2-/- mice, although lung viral titers were raised in the COX-2-/- mice by day 6. In addition, levels of PGE2 were substantially reduced in the COX-1-/- mice.

Is this earlier work at odds with the results of this new paper? Not so sure. Okay, antibody production is down, but it seems preventing hypercytokinemia might be more important. Originally, I had thought that this earlier paper (and other research) supported a limited treatment of Coxibs (4-5 days) for avian influenza in conjunction with an antiviral, but the evidence is still limited. The research by Carey et al also suggests that inhibiting COX-1 is not good; that takes away our basic OTC treatment for flu. In the end, it's about balance, and that's always a tough objective.

So was this research funded by Tylenol? Just kidding. But I am curious if this means Tylenol, or acetaminophen, is a better alternative.

My wife gets aggaravated at me when I won't "take something." I tell her I prefer to go to bed and try to "sleep it off." Especially low grade fevers. I tell her the fever is the body's way of fighting back and taking something to reduce the fever just prolongs the fight. I had a grandmother that took every vitamin and "supplement" out there, but she shunned "modern drugs." Some biases are hard to overcome ;-).

David: As Marissa notes (thanks, Marissa for the cites, BTW) this is an evolving area and there may be countervailing effects. In addition, you need to be careful with tylenol. It is the single greatest cause of liver failure in the US. It is in many OTC and prescription drugs and it is easy to overdose. Take only as directed and make sure the othe things you are taking don't contain acetominphen.

Thanks revere. As you and Marissa both point out, it is a evolving area, which is why my approach to all medications is that I take as little as possible and as infrequently as possible. Note well, the few times I've had to take antibiotics, I do finish the course!

The link revere provided for NSAIDS leads to a wikipedia article, which at the bottom lists all the kinds of NSAIDS out there, for those who want to be sure. I for one, if fighting a 1o3-4 degree fever and body aches, might take some tylenol and worry about my liver later. Revere, please clarify re the liver damage thing: how much acetominophen and for how long before liver damage occurs. I am guessing the occasional use isn't harmful?

By mary in hawaii (not verified) on 07 Dec 2006 #permalink

MiH: We blogged this back when here. In a case series, there were reports of failure with as little as 10 grams per day for 3 days. Each extra strength tylenol has .5 grams, so this is 20 tablets a day with .5 grams of tylenol. That's a lot of tylenol, but if you combine it with other OTC cold remedies or pain killers like percoset, you can do it unknowingly. And a lot of people apparently do. See this New Scientist article.

Would NSAIDs have an impact on the cytokine inflammatory reaction?

Would NSAIDs have an impact on the cytokine inflammatory reaction?

So we take tylenol or not? Me I am an aspirin man myself. I can take Tylenol but non of the others.

By M. Randolph Kruger (not verified) on 07 Dec 2006 #permalink

So we take tylenol or not? Me I am an aspirin man myself. I can take Tylenol but non of the others.

By M. Randolph Kruger (not verified) on 07 Dec 2006 #permalink

This is an interesting post. When I was in clinical veterinary practice, it was not uncommon for young dogs and cats to receive their final DHP or FFE immunisaion (ie the one timed to definitely be after the waning of maternal immunity) at the time of desexing. Desexing was always followed with a shot of meloxicam for post-op pain relief. We didn't see that many cases of parvovirus or "cat flu" in vaccinated animals. However, it would be interesting to look at the proportion of parvo/flu cases occurring in the 12 months following vaccination, which were correctly vaccinated but which had meloxicam at the time of vaccination. Of course, many such animals would receive a booster vaccination, without meloxicam, at least annually - although the older animals on daily meloxicam (I have a few of those) would be an interesting study also.

By attack rate (not verified) on 07 Dec 2006 #permalink

While using or not using NSAIDs for transitory illnesses is a matter of choice, as Revere hints, for some people it is a matter course. And it's not only the elderly... people of all ages with chronic pain from a variety of ailments and diseases are unable to work, sleep, or function at minimal levels without painkillers of some kind. And while NSAIDs have their drawbacks, steroidal or narcotic painkillers have plenty as well.

So for many, regardless of the eventual outcome of this research, they'll keep taking their medicines, until the development of better drugs or the cures for their conditions are developed.

In 1997, I co-authored a paper in the journal, Annals of Pharmacotherapy, on the observation of necrotizing soft tissue infections associated with the use of NSAIDS. At the time, I was working at the FDA in the drug safety surveillance division. While rare, these cases do occur particularly in the young, in postpartum women, and among children with varicella. Since the FDA reports are voluntary, it is impossible to determine a cause and effect relationship. Out paper included a literature review. The research you cite in the Journal of Immunology could provide a possible physiological explanation for this finding.

The abstract is available at:…

Dear Reveres -
Thank you for all that you have posted about all of your topics, from religion to liberty to of course, H5N1. I am finally posting after reading you every day for 18 months.

I take Zyflamend, an herbal treatment, daily for osteoarthritis because it seems not to have the bone-inhibiting effects of the normal Cox 2 inhibitors (I also have osteoporosis...). This research is a bit scary, but Zyflamend, from New Chapter, uses stuff like rosemary, basil, ginger, green tea, etc. for results that are supported by some medical folks at a major facility in NYC.
Is there any reason to think that the anti-inflammatory effects of this herbal combo might not pose the same danger as the pharma Cox 2 inhibitors?
I should add that I have only taken the stuff for a month and that I have NO connection to the manufacturer except to enrich them.
Thank you!

By DeadAhead (not verified) on 09 Dec 2006 #permalink

DeadAhead: I don't have a definitive answer to your question but here are two important things about the post to keep in mind. (1) the results reported in the J. Immun. paper are of unknown significance. They require some careful follow-up to see what the practical consequences are. So jumping to conclusions isn't warranted at this point. (2) They are restricted to drugs that interfere with Cox-2, which is a specific enzyme and only one way of affecting inflammatory response. If your herbal treatment works in some other way (and there are many possibilities) then the paper says nothing about that remedy. Without knowing how the hearbal dug works, it isn't evn possible to know whether it is something you should keep your eye on. I expect this isn't that helpful but it's the best I can do with what we know at this point.

Seems to me the best bet for cold remedies is to "mix your own." Talk to the pharmacist, whose advise is freely given and free. Ask about the combination you intend to use, and if that might have interactions with other prescriptions.

For example, "I'm on XYZ prescription for diagnosis Q. I've just caught a cold, and I'd like a pain reliever and a decongestant; what do you recommend?"

You might end up with e.g. a bottle of Tylenol and a package of those new "not quite Sudafed" tablets and a bottle of expectorant cough syrup with one active ingredient. Now you have control of the dosage of each independently, rather than taking one of those OTC mixtures that has a bunch of stuff in it and getting all of it at once whether you need it or not.

So, at one point in the day you might take some Tylenol for aches & pains. Then in the evening you might take the decongestant and the expectorant so you can blow your nose & cough productively. Then at night another dose of Tylenol so you can sleep without a headache. Total thus far, two doses of Tylenol and one each of the other meds, rather than three or four doses of all of it.

An Oldie, But A Goodie

Almost on a daily basis, one may read about a new medication being developed or approved for the benefit of patients. At times, these announcements may praise the innovation and novelty of such new drugs that are available to all in need of it.
But its possible the one super drug is not new and really is a super drug. In fact, its one of the oldest medications available, and that would be aspirin- the first non-steroidal anti-inflammatory drug (NSAID).
Noted as ASA by doctors typically, aspirin effects have been noted for thousands of years, as the active ingredient comes from the bark of a White Willow tree, and long ago, patients with pain or a fever would chew on this bark for relief. Yet due to the harshness of the natural chemical of this bark, Bayer decided to synthesize it to make it more friendly to the user.
Fast forward to over a hundred years ago and Bayer pharmaceuticals (pronounced Beier), which is the same company that brought us heroin and mustard gas, as well as methadone. The company originated in Germany, but presently has its U.S. headquarters in New York. Felix Hoffman, seeking to develop an agent for his fathers rheumatism, was involved in the development of what is known now as aspirin. And it was a difficult task to develop this drug, as it was toxic to the stomach due to the nature of the active ingredient again obtained from the bark of the white willow tree. Dr. Hoffman and others at Bayer developed a drug that proved to be tolerable to patients while keeping the active ingredient in tact through a method of delivery developed by Dr. Hoffmans team at Bayer. After launching the medication, aspirin was priced at about 50 cents an ounce, as at the time it was only available in power form. Soon before 1920, aspirin developed the tablet form of the drug and was then available by prescription. Regardless, aspirin was responsible for one third of sales for Bayer during this time, due to its popularity due to the effects of this medication in need of relief.
While all drugs have side effects, aspirin is one of very few drugs that provides great efficacy and indications, with limited side effects. In fact, some of aspirins additional uses have been recently discovered. This may be why the New York Times called aspirin a wonder drug in the 1960s. In the 1970s, the mechanism of aspirin was isolated, which is the blockage of prostaglandins.
With Aspirin and its potential life-extending benefits:
Aspirin has been associated with decreased risk of asthma and prostate cancer in the elderly. Also, aspirin has been linked with lowering the risk of breast cancer and colon cancer as well. Aspirin is a blood thinner, and has been associated with decreasing the risk of heart attacks and strokes in certain patient populations, as the drug prevents clots. This was first suggested in the 1940s and the FDA suggested that it be the drug of choice for those who experienced a heart attack over a decade ago. Aspirin intake is beneficial for those after coronary bypass procedures. A topical formulation of aspirin was developed recently for those experiencing Herpes pain. The drug has been proven beneficial for those experiencing migraine pains. Aspirin at low doses is taken by many as a preventive drug to decrease cardiovascular incidents that may occur.
Aspirin has been the best selling painkiller absent of the past addictive qualities of opiate meds since the 1950s. It is also the most studied drug- with over 3000 scientific papers published worldwide. Also, over 15 billion tablets of aspirin are sold annually, which amounts to about 80 million aspirin tablets consumed daily by others. This amounts to over 16,000 tons of aspirin consumed during this time, or about 70,000 metric tons of aspirin a year. Over a decade ago, a study was performed and concluded that twice as many people would choose aspirin over a computer, given the two choices, because of the benefits of the drug.
Side effects would include GI bleeding if taken in large amounts, along with an association of Reyes syndrome in children, yet both are relatively rare. Yet all things considered, clearly the benefits of aspirin outweigh any risks of the drug.
Lately, there have been issues with other NSAIDs, such as Cox II inhibitors, without full recollection or knowledge that aspirin is in fact the worlds most widely used drug, and for good reasons.
At times, something newer is not always better

We might die from medication, but we sure killed all the pain. --- Conor Oberst

Dan Abshear