NSAID use and endurance running: foundations of a patient advisory

AMAA Journal, Winter, 2004 by Jeff Venables

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common self-administered and prescribed drugs in the U.S. These agents are primarily used to reduce inflammation and pain, which makes them exceedingly popular with athletes. At an estimated economic impact of $2.5 billion a year, nonsteroidals are the largest drug class in the world. However, we annually spend an additional $4 billion treating their side effects. What are the current controversies in prescription and over-the-counter (o.t.c.) NSAID use among the exercising population and, in particular, endurance runners? When all the factors weigh in, how might clinicians make meaningful recommendations regarding NSAID use? At the Virginia Hospital Center in Arlington, VA, on Friday, October 29th, the 2004 AMAA Sports Medicine Symposium at the Marine Corps Marathon devoted a series of lectures to finding out.

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THE "NONSELECTS"

Traditional (a.k.a. nonselective) NSAIDs include o.t.c. medications such as ibuprofen (found in Advil[R] and Motrin[R]) and naproxen, which, though widely prescribed as Naprosyn[R], is also available o.t.c. in Aleve[R]. Less common traditional nonsteroidals include piroxicam and sulindac. Acetaminophen (found in Tylenol[R] and Excedrin[R]) is not considered an NSAID because it lacks anti-inflammatory properties; it is largely analgesic.

NSAIDs are cyclooxygenase (COX)-1 and COX-2 inhibitors. They control swelling, but by blocking the production of COX-1 enzymes, can cause or contribute to gastrointestinal (GI) problems. Even the widespread and principally analgesic acetaminophen, when ingested in amounts greater than 2 g per day, can lead to bleeding and perforations. At 650 mg per capsule, two capsules of Tylenol Arthritis Pain Extended Relief[R] need only be taken twice a day to exceed this dose. One study found, through endoscopic means, a 19% incidence of gastric ulcers in patients taking 1,000 mg of naproxen daily--at the end of one week. As Nicholas Scarpa, M.D., FACR, pointed out in one of his discussions, "There is no such thing as gastric adaptation. Those people who are at risk [of ulcers] are at risk in the first week or the first month, just as much as if they were taking it for six months."

Scarpa, who serves as Medical Director of Rheumatology at the Arthritis Research Center of New Jersey, went on to explain that approximately 30% of these bleeds occur in the lower GI tract--where proton pump inhibitors fail to work. Furthermore, by some estimates, up to half of all endurance athletes suffer GI symptoms anyway. Under certain biochemical and biomechanical stresses associated with certain types of exercise, the integrity of the GI mucosal block can become damaged, leading to an uptake of toxic substrates. So a more enzyme-selective, safer group of drugs, the COX-2 inhibitors (coxibs), was devised.

COXIBS AREN'T THE SAVIORS WE HOPED

Unfortunately, we now acknowledge a dilemma in prohibiting COX-2 enzymes also. In his discussion, Joseph Chorley, M.D., an assistant professor of Pediatrics and Director of Education of the Primary Care Sports Medicine Fellowship at Baylor College of Medicine, provided a nice overview of renal system changes that occur during distance running. This helped illuminate the role that all NSAIDs--even coxibs like celecoxib (Celebrex[R]) and valdecoxib (Bextra[R])--may play in hypervolemic hyponatremia among endurance athletes.

Hyponatremia risk. While COX-1 enzymes are vital to what Chorley calls "normal housekeeping functions" (including gastric regulation), COX-2 were always seen as "the inducibles"--enzymes responsible for colon tumors, pain and inflammation, undesirable cellular transformation, and even osteoarthritis (OA). But eliminating them is not a cure-all. For one thing, proper cellular regeneration from certain types of soft tissue injuries can be blunted by coxibs. And there are COX-2 receptors in the kidneys; whatever we once thought of them, we now recognize that COX-2 enzymes, prostaglandins (PGs) in particular, perform important regulatory functions as well.

By inhibiting the production of PGs, as both nonselective NSAIDs and coxibs do, these agents can exacerbate--and theoretically cause--fluid imbalance, electrolyte disorders and kidney problems during a marathon. This is particularly true in older runners (who also happen to be more likely to rely on NSAIDs to get through a long race). Though marathoning may put you in a PG-dependent state--particularly via dehydration and exercise in high temperatures--most marathoners are not in such a state during the course of a race. Yet runners in their 50s and 60s will see renal changes sooner just by virtue of their age. Above 50% VO2max, urine production decreases by as much as 60%, half the amount of blood is filtered through the kidneys, and sodium excretion decreases by 40 to 60%. Chorley, who is assistant medical director of the hp Houston Marathon[R], tells us that marathoning at as slow as 12-minute mile pace puts a 20-year-old male above 50% VO2max; for a 30-year-old, 14-minute miles will do it; if a 60-year-old male runs faster than 18-minute miles, he is above 50% VO2max.