A Sad Tale of Unintended Consequences

It all began in 1984 when the prestigious Noble Prize in Medicine was awarded for the revelation that the lowly drug Aspirin prevented the COX-2 enzyme from converting the biochemical arachidonic acid to pain-producing inflammatory end products.

Bonanza!  Here was the solution to the unpatentable Aspirin: create competitor drugs that duplicated Aspirin’s inhibition of the COX-2 enzyme in people with pain. Lo and behold, very efficiently and rapidly, a new pharmaceutical industry was born. Imitation aspirins ultimately became known as NSAIDs (non-steroidal anti-inflammatory drugs) and were hailed as miracles of pharmaceutical innovation.

This well-known tale is now decades old. The billion dollar NSAID industry produced an untold number of candidate drugs; however, only a few were safe enough for clinical application. The survivor NSAIDs mimicked the pain-killing effects of Aspirin but never achieved its record of safety or the wide range of diseases in which it displayed significant health-promoting effects.

What went wrong? Excluding relief of pain, why did NSAIDs not behave the same as Aspirin as they were intended to do?  The answer was provided a little over a decade or go by a brilliant young scientist named Charles Serhan who was virtually unknown outside his field of lipidomics.  Serhan identified the biochemical mechanism used by Aspirin to kill pain.

Serhan’s studies of Aspirin’s interaction with the COX-2 enzyme revealed that the 1984 assumption that Aspirin inhibited the COX-2 enzyme was in error.  Aspirin prevents arachidonic acid from being converted to inflammatory end products but NOT by inhibiting the COX-2 enzyme.  Enzyme inhibition has a very specific meaning; an inhibited enzyme has turned off (inhibited) its ability to perform a function it normally performs.

The biochemical mechanism by which Aspirin interacts with COX enzymes is quite detailed; however, the outcome of the interaction is relatively easy to explain and be understood.  In summary, Aspirin changes the function of the COX-2 enzyme so that it converts arachidonic acid to ANTI-inflammatory end products rather than inflammatory ones.  As a result, pain is stopped and arachidonic acid can do no further damage because it ceases to exist.

By contrast, NSAIDs inhibit (turn off) the COX-2 enzyme thereby preventing arachidonic acid from being converted to inflammatory end products.  The NSAID action stops the pain but the arachidonic acid spared by the NSAID is not acted upon, eliminated, or changed in any way.  Instead it is sent to another inflammatory pathway to do it’s damage at another site.

In review, Aspirin prevents arachidonic acid from causing pain and from doing damage elsewhere.  On the other hand, although NSAIDs kill pain, they do not interfere with arachidonic acid’s ability to cause mischief in other parts of the body. It does so by moving arachidonic acid to another inflammatory pathway. This transfer to another inflammatory pathway is a normal biochemical response for arachidonic acid when it is blocked from action by agents such as NSAIDs.

This difference between Aspirin and NSAIDs in the fate of targeted arachidonic acid is the key for why the miracle NSAIDs have caused sad, unintended consequences.  By not eliminating arachidonic acid in the process of relieving pain, NSAIDs have failed in their goal of creating a substitute for Aspirin that would equal or surpass Aspirin’s excellent medical history.

The untended consequences rest in the totality of medical literature that show NSAIDs have created a new and significant source of medical ills.  The failure of the goal may be forgiven, but the unintended consequences add an unacceptable medical burden on a society already under stress.

10 Responses to “A Sad Tale of Unintended Consequences”

  1. Two questions: 1) the warning I repeated hear about aspirin is the possibility of (possible) serious intestinal bleeding. I have attempted to discuss aspirin with several doctors and the discussion abruptly ends with the dangers from bleeding. To the extent I am able to judge the evidence this does seem a real possibility. Do you have any opinions on how to evaluate the risks vs rewards of using aspirin?
    2) Do you know if willow bark (as a source of salicin) have the same cox 2 enzyme effects?

    • Good to hear from you again, Ward. In a previous post we neglected to acknowledge your recommendation of the Medical Biochemistry Page (1) for information about the biochemistry of aspirin. It is an excellent source for people with some background in biochemistry. Please accept our belated thank you.

      Your first question, concerning the possibility of aspirin causing serious intestinal bleeding, is a very important one. One of the functions of the housekeeping COX-1 enzyme is to prevent secretion of hydrochloric acid (HCl) by the stomach when food is not present (2). Aspirin inhibits all functions of the COX-1 enzyme, thereby eliminating this protective effect. Theoretically, if some event that stimulates HCl secretion in an empty stomach occurs during the period when COX-1 is inactivated, the stomach lining could suffer severe ulceration, which could lead to bleeding. This is a much-simplified explanation of the very complex mechanism by which aspirin causes stomach bleeding..

      Thus, the answer is “Yes, the risk of aspirin causing stomach bleeding is very real.” However, a many-decade search of the medical literature for cases of aspirin-induced stomach bleeding is rather unproductive. Hence it must be relatively uncommon.

      A separate problem attributed to aspirin relates to its anticoagulant effects. This seems to be the misguided basis for the medical proscription against aspirin. Blood clotting is an essential component of the acute response to trauma when there is need to stem bleeding (3). Blood clotting is governed by the local tissue environment; inflammatory environments favor clotting whereas anti-inflammatory environments do not. Aspirin’s anti-inflammatory action protects against untoward clotting.

      Case reports prior to the introduction of NSAIDs of medical problems caused by aspirin’s anticoagulant activity are difficult to find. Currently, the few cases of excessive bleeding that are reported either exclude aspirin or do not separate aspirin data from NSAID data. We conclude that although aspirin-induced bleeding may be a difficult event when it occurs, the population affected is very small.

      In summary, these data support our judgment that the benefits of aspirin use far outweigh the risks.

      Your second question about willow bark (salicin) is one we have not paid much attention to except for its interesting history in herbal medicine. We recalled your advice to check the internet and googled salicin-COX-2. We found references 4 and 5, which say that salicin does inhibit the COX-2 enzyme and provide interesting information about herbal anti-inflammatory compounds.

      Thank you, Ward, for your stimulating comment. Happy reading

      1.) https://themedicalbiochemistrypage.org/aspirin.php/
      2.) https://www.ncbi.nlm.nih.gov/pubmed/11595412/
      3.) Serhan CN. Lipoxins and aspirin-triggered 15-epilipoxins are the first lipid mediators of endogenous anti-inflammation and resolution. Prostaglandins, Leukotrienes, and Essential Fatty Acids (2005) 141-162.
      4.) https://www.hchs.edu/literature/COX-2%20Inhibitors.pdf/
      5.) http://www.clinicaladvisor.com/alternative-meds-update/willow-bark-relieves-pain-and-inflammation/article/204756/

  2. Katherine

    Thank you! A beautiful explanation. I hadn’t really understood it before.

    And thanks to you I so rarely have to make a choice between aspirin or other NSAIDs any more.

    • Thank you, Katherine, for your very kind words. There is nothing more gratifying to us than to be able to make some rather complex biochemistry understandable for people who care about their health and want to know how to help themselves. Thus, we really appreciate your writing to tell us we have helped, you.

      Your happy tone tells us you are dong well. You will never regret the time you spend in learning to care for the remarkable body that Nature has designed for us. Keep up your good work.

  3. michael goroncy

    Thanks Alice and Fred
    I have never found fault with anything you have written, and Bravo! To you both.
    I don’t think many of your readers realise that you are both old enough to be just about everbodies grandparents.

    Although, sort of related, would be ‘PPI’s (proton pump inhibitors) that have over the last few years gained momentum as have quite negative effects, and to be avoided.
    PPI’s at first seemed to have marvellous relief symptoms…but now, put in the deleterious category (although still heavily subscribed).
    Guess the old ‘One death at a time’ pace applies.

    Just to allay any fears regarding ASPRIN. Readers can read your past posts from 2015:


    • Oh, Michael, you embarrass us. But we must admit your words are good to hear. We will have to write a disclaimer to assure readers that you are not on our payroll.

      Actually, we are very pleased to hear from you. We have been wondering how you have been. From the tone of your comment you sound well. Interestingly, your mention of our ages (Alice will be 96 next month; Fred is a couple of years younger) points to the reason why you have not heard from us recently. The minds are willing, but the bodies are very reluctant.

      Meanwhile, we thank you for your generous comments and will get a note off to you soon.

      • Katherine

        Good heavens! Please grant me the opportunity to wish both of you Happy Birthday and many more!

        I dare say, you are walking the walk! (And eating the eat? LOL)

  4. michael goroncy

    I say Yo! Katherine
    “I dare say, you are walking the walk! (And eating the eat?”

    Wonderful line…that says much.

    Disclosure: I am on the payroll.
    I get paid with good advice from Alice and Fred.


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