In 1982, the Nobel Prize in Medicine was granted jointly to Sune Bergstrom, Bengt Samuelsson, and Sir John Vane, which, in essence, explained the mechanism for the analgesic effect of aspirin.
The Nobel Summary pointed out that prostaglandins and related substances constitute part of a new biological system formed from unsaturated fatty acids, primarily arachidonic acid. It further noted that the Nobel Laureates had made fundamental contributions to the elucidation of the significance of this new biological system in which aspirin was shown to block the synthesis of the prostaglandins.
“Thanks to this important discovery [of] the mode of action of aspirin, the most frequently used drug all over the world, was clarified. It also provided the prostaglandin researchers with a useful tool in their analyses of the role of these compounds in various biological processes”(1). Thus began a new chapter in the century-old saga of aspirin.
The Era of NSAID Proliferation
The finding that analgesia produced by aspirin was due to its ability to block conversion of arachidonic acid (AA) to inflammatory eicosanoids opened a goldmine for the pharmaceutical industry. To a biochemist’s ear, the words “aspirin blocks conversion” suggest that aspirin inhibits the enzyme that catalyzes the procedure. To “inhibit” means to prevent the enzyme’s action by somehow inactivating it.
Consider the fortune that could be made by a drug that competed in the same manner as aspirin in relieving pain but was not tainted by the disdain of the medical profession. Importantly, at the time, aspirin was no longer under patent protection or patentable. It was inevitable that aspirin would become the model for the class of new patentable pharmaceuticals known as non-steroidal anti-inflammatory drugs (NSAIDs) and that a massive program by the pharmaceutical industry to develop competitors for aspirin would ensue.
But the going was not easy. The cyclooxygenase enzyme, now commonly known as COX by the consuming public, was the enzyme of concern in the search for aspirin substitutes. It was an unexplored enzyme and not completely understood by the research community. One of the first findings during NSAID development was that the COX enzyme had two forms: COX-1 and COX-2.
COX-1 is the constitutive form of the cyclooxygenase enzyme, which means that it is always present and available in the body. It can be thought of as a housekeeping form of COX that attends constantly to prostaglandin activity, which, among other things, involves protection of the stomach against bleeding.
The COX-2 form of the enzyme was found to be inducible, which means it is only produced when there is a demand for it, such as an illness or trauma that requires immediate first aid treatment. The COX-2 form is the form that causes the pain associated with illness or injury.
The existence of two forms of COX complicated the task of NSAID research teams. It changed the ultimate goal of the pharmaceutical effort to a search for drugs that would inhibit only COX-2 without interfering with the ability of COX-1 to protect against stomach bleeding. The extreme difficulty of the goal is confirmed by the fact that, to date, no NSAID has met its requirement.
In the decades since 1982, many different versions of COX-inhibitors have been synthesized to add to the aspirin-NSAID group. Currently about twenty generic varieties are available, the majority of which are sold only by prescription. Of the many generic varieties that have been prepared, only four generic forms have been proven to be of adequate safety to be sold over-the-counter. They are celecoxib, diclofenac, ibuprofen, and naproxen. Only two, ibuprofen and naproxen, are widely available under numerous brand names as over-the-counter painkillers.
Despite the tremendous investment in time and money in NSAID research through the decades, clinical experience has shown that no NSAID has been found that is more effective or safer to use than aspirin.(2) Further, a few NSAIDs have been recalled because of unacceptable adverse effects. Interestingly, the excellent safety record of aspirin has done nothing to improve the acceptance of aspirin by the medical community. The decades have rolled by quietly with family and emergency room physicians routinely rolling their eyes when the word “aspirin” is mentioned.
But then, on a quiet July morning in 2015, the US Food and Drug Administration (FDA) notified the medical community:
FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes.(3)
Aspirin was excluded from the warning with the exception of the statement that certain NSAIDs could undo aspirin’s cardioprotective effect:
“Some NSAIDs, including those in OTC products such as ibuprofen and naproxen, can interfere with the antiplatelet action of low dose aspirin used for cardio-protection by blocking aspirin’s irreversible COX-1 inhibition.(3)
WHAT HAPPENED? Nothing more happened than USFDA finally acknowledging that NSAIDs cannot serve as a replacement for aspirin; something scientists and students of lipidomics have known for more than ten years.
Aspirin Does Not “Inhibit” Cyclooxygenase
The fact that aspirin and the non-aspirin NSAIDS exerted their analgesic effects by different means was not recognized until about a decade ago when Serhan and co-investigators discovered the biochemical pathway by which aspirin worked.(4) By that time, the pharmaceutical industry had already spent a fortune producing a host of NSAIDs, all of which actually accomplished the original goal of producing analgesics by inhibiting the COX enzymes.
Unfortunately for the pharmaceutical industry, it was later discovered that aspirin did not inhibit COX enzymes in order to prevent them from metabolizing arachidonic acid to pain-producing inflammatory eicosanoids – as they had assumed. Serhan and colleagues discovered that aspirin did not inhibit the COX enzymes but rather modified their structures by acetylating them.(4) Aspirin thus prevents conversion of arachidonic acid to pain-producing inflammatory eicosanoids by changing the products made from arachidonic acid rather than by inhibiting the COX enzymes.
This elegant but complicated mechanism responsible for the remarkable phenomenon of changing inflammatory arachidonic acid into anti-inflammatory eicosanoid end products is described in the next section. It helps explain why “no NSAID has been found that is more effective or safer to use than aspirin.”(2)
The Biochemistry and Benefits of Aspirin
The cyclooxygenase enzymes occur in two isoforms, COX-1 and COX-2. They are similar in many, but not all respects. Each has two catalytic sites. The first active site converts arachidonic acid to a prostaglandin called PGG-2. The second active site changes PGG-2 to prostaglandin PGH-2. PGH-2, is further processed by specific isomerases that generate three eicosanoid groups; prostaglandins, thromboxanes, and prostacyclins.
COX-1 is the smaller of the two enzymes in both size and eicosanoid production capacity. COX-1 can process only arachidonic acid. It exists primarily in what is called the constitutive form. This means COX-1 is constantly present and active in most tissues. COX-1 has been called the housekeeping enzyme because it does its work by continually releasing small amounts of eicosanoids as required to regulate normal cell activity.(5)
The prostacyclins biosynthesized by COX-1 are generally protective. For example, they are antithrombotic (prevent clotting) when released in the endothelium, the layer of cells that line the inside of blood vessels, the heart, and some other closed cavities. They are cytoprotective when released by the gastric mucosa, the thin lining of the stomach that secretes a protective slimy substance called mucin.
COX-2 exists primarily in inducible form. This means that COX-2 is not detectable in most healthy, resting cells. COX-2 is induced and made active by increased levels of its substrate arachidonic acid and by inflammatory stimuli, such as cytokines and trauma. Cytokines are a group of biochemicals that trigger inflammation by recruiting other eicosanoids and immune cells to fight infectious organisms and foreign bodies including cancer cells. COX-2 can process a wider range of fatty acids than COX-1, including arachidonic acid, dihomo gamma linolenic acid (DGLA), eicosapentaenoic acid (EPA), and other lipids.(6)
When COX enzymes are acetylated by aspirin, they trigger the biosynthesis of lipid mediators inside the body that are biochemically similar and slightly more potent than the naturally-formed lipid mediators known as lipoxins, resolvins, protectins, and maresins. In brief, aspirin “jump-starts” the endogenous (within the body) pathways of resolution and healing by triggering the biosynthesis of pro-resolving lipid mediators.(7)
Biochemically, aspirin works by acetylating and blocking both of the two active catalytic sites in the COX-1 enzyme and blocking one of the two active catalytic sites in the COX-2 enzyme. COX-1, when disabled by aspirin, benefits individuals with cardiovascular diseases because the COX-1 enzyme can no longer produce anything, including thromboxane, and other inflammatory eicosanoids.
The single site that remains active on the acetylated COX-2 enzyme causes COX-2 to produce the prostaglandin 15R-HETE from arachidonic acid instead of the usual inflammatory PGE-2 series prostaglandins, thromboxanes, and prostacyclins. This 15R-HETE is immediately transformed by the enzyme 15-LOX-1 to 15-epi-lipoxin A4, also called ATLXA4 (aspirin-triggered lipoxin A4). Aspirin literally forces the COX-2 enzyme to produce anti-inflammatory eicosanoids from arachidonic acid, which normally is a major source of proinflammatory compounds.
The naturally-formed lipid mediators that aspirin copies in aspirin-triggered form (mentioned above) are chemically the same except that the former are synthesized from 15S-HETE rather than 15R-HETE, the stereochemistry of which is slightly different. The difference is that an alcohol moiety (OH) is connected to carbon number 15 at an unusual angle in the aspirin-triggered 15R-HETE. This dissimilarity does not materially change the effectiveness of the ATLXs except that the ATLXs remain biologically active in the human body for a longer time and are more potent than those naturally formed.(8)
A very important benefit of aspirin is the fact that arachidonic acid is disposed of when it is converted the prostaglandin 15R-HETE; arachidonic acid is no longer available as a substrate for inflammatory eicosanoids. This is an important difference between aspirin and NSAIDS in their interaction with the COX-2 enzyme. NSAIDS do not eliminate arachidonic acid but merely prevent it from being metabolized by the COX enzymes to inflammatory, pain producing eicosanoids. This has positive, immediate pain-relieving effects; however, the unused arachidonic acid is diverted to the 5-lipoxygenase enzyme where it is converted to inflammatory leukotrienes that do damage elsewhere in the body. Hence, NSAIDs have the potential for adverse effects not seen with aspirin.
Another benefit of aspirin relates to the fact that although COX-2 is not normally expressed (not active) in the body, it is constitutive (always expressed) in blood vessels due to the fluid motion of blood flow. During chronic inflammation, this active COX-2 within the vascular system is constantly converting arachidonic acid to inflammatory PGE-2 series prostaglandins and thromboxanes. This is an important cause of cardiovascular diseases.
On the contrary, when COX-2 is acetylated by aspirin, this damage cannot occur because acetylated COX-2 transforms arachidonic acid to 15R-HETE that is further converted within the vascular system to pro-resolving ATLXs. The statement in the FDA notice confirms that NSAIDs can interfere with aspirin used for cardio-protection by blocking aspirin’s irreversible COX-1 inhibition.(3)
Biochemical Lesson: Aspirin alone without the long chain essential fatty acids, will not produce maximum health benefits. Dietary arachidonic acid is usually ample in the modern American diet, but dietary supplementation with EPA and docosahexaenoic acid (DHA), the principal essential omega-3 fatty acids in fish, cod liver, krill oils, and animal fats, in a low-carbohydrate or ketogenic diet are required for aspirin to do its work.
Aspirin is Not Just an Analgesic Anymore
Aspirin is a unique medication. There is no other drug known that can do what aspirin does. As important as aspirin is in its fundamental role in modifying inflammatory eicosanoid pathways, perhaps of even greater consequence for the health and well being of present and future generations are the more recent discoveries of the hitherto unsuspected role of aspirin in resolution (the healing process) and the unanticipated existence of whole new classes of aspirin-triggered anti-inflammatory eicosanoids and docosanoids, also termed lipid mediators, that have been uncovered by the research into aspirin’s mechanism of action.(9)
“Inflammation is now widely appreciated in the pathogenesis of many human diseases. These extend from the well-known inflammatory diseases such as arthritis and periodontal disease to those not previously linked to aberrant inflammation that today include diseases affecting many individuals such as cancer, cardiovascular diseases, asthma, and Alzheimer’s disease”.(4)
nobel_prizes/medicine/ laureates/1982/press.html Accessed July 03, 2015.
- Metcalf E. Aspirin: The Miracle Drug. New York, NY: Avery: a member of the Penguin Group, 2005.
Drugs/DrugSafety/UCM453941.pdf Accessed July 03, 2015.
- Serhan CN. Lipoxins and aspirin-triggered 15-epi-lipoxins are the first lipid mediators of endogenous anti-inflammatory and resolution. Prostaglandins, Leukotrienes, and Essential Fatty Acids. 2005; 73 141-162.
- Vane JR, Botting RM. Mechanism of action of anti-inflammatory drugs. In: Szczeklik A, Gryglewski, RJ, Vane JR, eds. Eicosanoids, Aspirin, and Asthma. New York, NY: Marcel Dekker, Inc., 1998.
- Christie WW. Eicosanoids and Related Compounds, Lipid Library. http://lipidlibrary.aocs.org/
Lipids/eicintro/index.htm Accessed July 03, 2015.
- Serhan CN. Novel Lipid Mediators and Resolution Mechanisms in Acute Inflammation. American Journal of Pathology, 2010; 177(4) : 1576-1591.
- Serhan CN, et al. Anti-inflammatory and pro-resolving lipid mediators. Annual Review of Pathology. 2008; 3: 279-312.
- Ottoboni A, Ottoboni F. The Modern Nutritional Diseases and How to Prevent Them,Second Ed. Fernley, NV: Vincente Books, 2013.