By Kenneth Proefrock, NMD

Aspirin is, arguably, the world's favorite pain reliever. It has been around for at least 3,500 years as a constituent of many botanically based medicines, and since 1898 as a pure drug. Despite its long usage by humans, we did not really understand how it worked until research by a scientist named Vane in the early 1970's discovered that aspirin acted to inhibit a cyclo-oxygenase or “cox” enzyme. Cox enzymes are enzymes that convert a common fatty acid found in the membranes of your cells, arachidonic acid, into certain eicosanoids. An eicosanoid is a compound that has a 20 carbon chain backbone and acts like a “sub-hormone”, they set the stage for other hormones to work, but eicosanoids are extremely short-lived, most lasting less than a few seconds in the body. Some of these eicosanoids are helpful in the repair of your tissues, and have an anti-inflammatory, pain relieving quality. Many of these eicosanoids are proinflammatory and increase the perception of pain in our nervous systems while they inhibit appropriate healing responses. Aspirin was the first cox inhibitor to be described, and now, there are over 50 distinct cox inhibitors currently in use. There are three different subtypes of cox enzymes, cox 1 is considered to be the most beneficial and is involved in membrane repair and immune function, cox 2 and 3 are considered to be more inflammatory. Aspirin is an indiscriminant and, in many cases, an irreversible inhibitor of all three of the different classes of cox enzymes. It has the most notable side effects of inhibiting repair of the gastrointestinal tract and promoting the formation of ulcers due to its effects in cox 1 inhibition. One of the most common accidental poisonings to present in the emergency room is from over-ingestion of aspirin. This continues to be true especially for children less than 5 years old despite safety packaging laws. Overdose is most common after several days of a larger therapeutic dose, this is typically a dosage that lies within the safe therapeutic range for acute conditions, just used for longer than intended.

Acetaminophen is anything but a safe and harmless alternative to aspirin. Its toxicity has been well documented since the 1960's, and there are currently over 100 over the counter products on the market that contain acetaminophen. These include many products directed towards the pediatric population in liquid, capsule and tablet form. The symptoms of toxicity are very different from those of aspirin; symptoms don't usually develop until 48 hours after ingestion, and include liver failure. Acetaminophen and ibuprofen seem to have a greater affinity for cox 3 receptors, but still affect cox 1 and 2, the side effects are similar to those of aspirin, decreasing the ability of the gastrointestinal tract to heal itself, leading to the formation of ulcers. Alcohol ingestion dramatically increases its toxic nature.

One of the biggest challenges in the field of drug development has been to develop agents that specifically inhibit the inflammatory cox 2 and 3 enzymes, without adversely affecting the beneficial cox 1 system. Enter specific cox 2 enzyme inhibitors like Vioxx, Celebrex and Bextra. The promise of these agents was that they could specifically reduce the inflammation associated with many pain syndromes, without the nasty side effects and toxicity associated with the more broadly acting cox inhibitors. The introduction of theses agents in the early 1990's was met with the expectation that now modern medicine would have a viable answer for the millions of people who suffer from chronic pain. On Sept. 30, 2004, Vioxx was the first of these agents to be voluntarily recalled from the market by its manufacturer, Merck Pharmaceuticals, because of some very life threatening side effects. It turns out that the entire model that we just discussed and that ushered in these potential panaceas was probably wrong in several different aspects. We now know that there are even more cox subtypes than the three discussed, we also know that inhibiting one subtype tends to make the other major subtypes proliferate, increasing their potentially harmful effects.