This is part two of the series: NSAIDs And Athletes. The first part dealt with the biochemical mechanism of action of NSAIDs and the surprisingly high frequency of use of NSAIDs by athletes, even just before and during competitions. This part deals with the potential adverse effects of NSAIDs, with particular attention to athletes.
Most of the important effects of NSAIDs come from their ability to block the activity of the cyclooxygenase enzymes, called COX-1 and COX-2. These COX enzymes catalyze the rate-limiting step in the formation of prostaglandins. These prostaglandins, in turn, have undesirable effects, such as worsening of pain and inflammation. The goal, therefore, of NSAID use, is to reduce pain and inflammation. But prostaglandins also have desirable actions, such as protecting the lining of the stomach, protecting normal kidney function, and promoting normal aggregation of platelets to form clots. So, NSAIDs, in blocking the production of prostaglandins, can have both beneficial and detrimental effects.
NSAIDs are not uniformly the same. Their differences lay in the relative degree of inhibition of the COX-1 vs COX-2 isoforms, which, in turn, determines the relative risk of side-effects. In this article, however, since all NSAIDs can have detrimental effects, NSAIDs will generally be grouped together as a whole. Your physician can help you make a more nuanced choice of a NSAID, if necessary for your care, with careful consideration of the balance between benefits and risks.
There are a number of side-effects of NSAIDs that are applicable to everyone regardless of level of athletic activity:
All NSAIDs increase the risk of gastrointestinal injury, with up to 60% of users experiencing this effect. The level of severity can range from mild heartburn and an upset stomach to life-threatening events, such as bleeding in the upper-GI tract, perforation of the the upper-GI tract, and obstruction of the stomach. These side-effects are dose- and duration-related. In other words, higher doses (or the use of more than one NSAID) for longer durations increase the risk of GI side-effects.
NSAIDs increase the risk for cardiovascular side-effects, including myocardial infarction (heart attack) and cerebrovascular accident (stroke). While NSAIDs that selectively target COX-2, such as rofecoxib and celecoxib, have more often been associated with these risks, less-selective NSAIDs have also been shown to increase these risks, especially at higher doses and longer duration of use. In a recent nested case-control study of 8,852 nonfatal myocardial infarctions, patients taking NSAIDs had a 35% increased rate of myocardial infarctions. This finding was for all NSAIDs grouped together. When the individual NSAIDs were separated, naproxen was found to be the only NSAID that was not associated with increased risk of myocardial infarctions. Cardiovascular risk associated with NSAIDs has been shown to be higher in older individuals with preexisting cardiovascular disease. However, even in an apparently healthy population of people age 30-50, there has been shown to be an elevated (but still very small) risk of myocardial infarctions (63 deaths per million person-years) associated with taking NSAIDS. In another recent study, which involved the review of the records of more than 1 million healthy people, median age 39 years, there was a significant association between ischemic strokes and the use of diclofenac or high-dose ibuprofen. With regard to hemorrhagic strokes, this study showed that diclofenac or naproxen were associated with an increased rate of these events.
For athletes, there are additional specific dangers to using NSAIDs:
Prostaglandins are important to maintaining renal blood flow and glomerular filtration. While the effect of reducing the formation of prostaglandins on kidney function may not be very great in most non-exercise situations, this effect can become extremely important during strenuous exercise. This is because renal blood flow and glomerular filtration are reduced by 40-50% during strenuous exercise. This reduces the ability of the kidneys to remove free water. Taking NSAIDs, and, consequently, reducing the amount of prostaglandins, further reduces the ability of the kidneys to remove free water. This leads to retention of water and dilution of the blood which, in turn, can lead to an elevated risk of developing potentially life-threatening hyponatremia (low blood sodium).
NSAIDs have variable effects on the function of platelets, which are essential to forming clots and controlling bleeding. Anti-platelet effects are especially potent for aspirin, which is similar to NSAIDs, but affects the COX enzymes in a different way. In athletes at risk for crashing, falling, and other other forceful impact, especially to the head, the use of aspirin and some other NSAIDs can lead to increased risk of dangerous bleeding.
Increased risk of injury
One of the intended effects of NSAIDs is to mask pain. But pain is an essential mechanism by which the body prevents injury. By reducing the ability of the body to signal, through pain, that an injury is imminent, the use of NSAIDs can lead an athlete to push too far and become injured.
Another effect of NSAIDs that can increase risk of injury has to do with musculoskeletal adaptation. As previously mentioned, NSAIDs, by blocking the COX enzymes, reduce the synthesis of prostaglandins. These prostaglandins are important in the synthesis of the extracellular matrix, containing collagen, which confers strength to musculoskeletal tissues. By reducing the formation of the extracellular matrix, there is increased risk for injury, such as stress fractures, and reduced tissue adaption to mechanical loading.
To elaborate, mechanical loading associated with exercise typically increases bone formation to increase skeletal strength. But a number of studies in animals and humans have shown that this load-induced formation of bone is reduced when NSAIDs are given before the challenge of a mechanical stimulus. Similarly, animal studies have shown that use of NSAIDs before exercise also reduces hypertrophy of muscle.
Reduced repair of musculoskeletal tissues after injury
Since prostaglandins are important in the formation of collagen, which is required in the repair of musculoskeletal injuries, NSAIDS, if taken before exercise or for extended durations of time, can lead to reduced repair of such injuries. Animal studies have shown that NSAID use delays healing after bone, ligament, tendon, and muscle injuries. Similar findings have been reported in human studies of the effect of NSAIDs on recovery from exercise-induced muscle damage. For example, NSAID use decreases the typical increase in prostaglandin formation after high-intensity eccentric exercise, which, in turn, decreases the exercise-induced increase in numbers of muscle satellite cells and increase in protein synthesis. These effects could potentially lead to reduced muscle hypertrophy after exercise and reduced muscle repair after injury.
By affecting the production of prostaglandins, NSAIDs have important beneficial and detrimental effects. The detrimental effects are not trivial and can undermine the intended effects of NSAIDs or even lead to death or permanent disability. As previously mentioned, NSAIDs are actually a spectrum of medications with variable effects on the COX-1 vs COX-2 isoforms and, therefore, different typical benefits and side-effects. But all NSAIDs can cause harm.
This installment of this series has a largely theoretical tone. Stay tuned, because the next installment of this series will deal with the effects of NSAIDs as reported in real-life endurance race situations.
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