The role of nonsteroidal antiinflammatory drugs (NSAID) in pain and inflammation has been evaluated in many forms over the last decade. Much of what we know about NSAID is from studies in animal models or patient populations that are not equivalent to the active sports medicine population. As physicians caring for athletes who are at high risk for acute musculoskeletal injury, it will be important to understand the benefits and risks of different NSAID and extrapolate this knowledge to the sports medicine arena.
MECHANISM OF ACTION
NSAID inhibit cyclo-oxygenase (COX) enzyme activity via two distinct isoenzymes: COX-1 and COX-2. It is well known that the COX-2 inhibition reduces prostaglandins associated with pain and inflammation, whereas the COX-1 inhibition reduces prostaglandins associated with gastric protection, platelet aggregation, and renal blood flow. Traditional NSAID have been available for decades and are not selective in blockade of COX activity. Selective COX-2 inhibitors (Coxibs) were developed to selectively target pain and inflammation and not impact the gastrointestinal (GI), renal, or clotting systems adversely. This will be discussed more thoroughly in later sections of this article when reviewing adverse effects.
NSAID IN TREATING SPECIFIC SPORTS MEDICINE INJURIES
Regardless of COX selectivity, numerous studies show that NSAID reduce pain associated with minor sports injury. This class of medications was the most commonly used medication for athletes at both the 2000 and 2004 Summer Olympics (9). When compared with placebo, the number needed to treat for a positive effect from NSAID is three to four (15). The analgesic property of this class of medications is clearly effective. However, NSAID may impact healing differently when comparing bone, ligament, tendon, and muscle.
Muscle contusions and strains may be the most common type of athletic injury. Injured muscle heals by a three-phase process: injury or destruction, repair, and remodeling (5). The remodeling phase results in reorganization of myofibers into new and different scar tissue. This is different from bone healing where new bone identical to the prior bone is formed. Ideally, NSAID would reduce the destruction phase of a muscle injury to allow pain relief and faster healing. Unfortunately, while NSAID may limit the destruction phase and thereby limit pain, they also may limit the repair and remodeling process. Some animal studies show that piroxicam initially results in improved contractile force in muscles postinjury. But this early improvement may be outweighed by a more long-term delay in collagen deposition and ultimate muscle regeneration (1,13).
Animal studies, of course, do not always translate into useful clinical knowledge. The studies that examine muscle healing in humans are limited, but a general conclusion of several small studies shows a positive response in pain reduction and no strength loss following a muscle injury (11). More studies are needed to evaluate the long-term muscle remodeling in patients who use NSAID for an acute injury.
NSAID have the most clear beneficial response in ligament sprains. The injury and recovery in ligaments is similar to that seen in muscle injury, with destruction and inflammation, repair, and remodeling phases. Several studies show that NSAID improve return-to-play time and decrease pain after an ankle injury (12,19). Like muscle injuries, more information is needed to evaluate long-term ligament repair when NSAID are used early in an injury.
We now more clearly understand that tendon injury is not an inflammatory response, but instead involves complex histological changes that include neovascularization, fiber thinning and disorientation, and hypercellularity. On a cellular level, there is a paucity of inflammatory cells in tendinosis. Therefore, NSAID should not be used for their antiinflammatory actions in tendon injury. There may be a more useful role in acute tenosynovitis, where the initial injury has some inflammatory component (12).
The impact of NSAID use with complete fractures and stress fractures is unclear. It is theorized that prostaglandins play an important role in osteogenesis. Therefore, blocking prostaglandins with NSAID may inhibit new bone formation and lead to greater rates of nonunion with fractures. Some studies support this theory, whereas others show no significant change in fracture healing in patient populations. Koester and Spindler have an excellent review of studies assessing impact of bone healing with NSAID use in their 2006 article (7). Of note, there is little information available beyond case reports when studying the effects of NSAID on stress fractures (21). Although there is no clear evidence that fracture healing is definitely delayed with NSAID use, some studies show a connection to delayed healing or fracture nonunion, and one should use NSAID with caution in bone injuries.
Once the decision has been made that NSAID medication may improve outcome in an injury, the benefit of the drug must be weighed against its potential for an adverse effect. Because of the nonselective nature of traditional NSAID, injury from the blockade of COX-1 can lead to unwanted GI, renal, and platelet aggregation effects. Nonselective NSAID have been shown to result in a host of effects, including gastric ulceration and perforation and renal damage (4).
In the 1990s, Coxibs were developed to reduce these unwanted effects while maintaining the pain reducing and antiinflammatory qualities of this medication class. Although the initial studies from rofecoxib and celecoxib were controversial, systematic reviews confirmed that the Coxibs did, in fact, have a statistically significant reduction in adverse GI effects, including ulceration and bleeding in patients with rheumatoid arthritis (20). The role that Coxibs play in reducing renal side effects is unclear. It also is important to note that Coxibs may adversely affect cardiovascular health, but that discussion is beyond the scope of this article.
GI Effects of NSAID
The GI side effects of NSAID are well established. Major side effects include gastric ulceration, erosion and perforation, and GI bleeding. Minor side effects include abdominal pain, nausea, and dyspepsia. The World Health Organization reports that more than half of chronic NSAID users will experience GI side effects (6). In a case-controlled study, patients with bowel perforation or bleeding were more than twice as likely to have been long-term NSAID users (8). Data suggest that duration of use rather than a specific drug is a better predictor of GI effects. With 28 d of daily NSAID use, the risk of GI complications was 1.54 when compared with nonusers. When exposure time was increased to 365 d, the risk increased to 2.2 (18). In this same study, all NSAID evaluated except indomethacin were relatively equal in the risk for GI effects. While the more selective Coxibs may reduce the adverse effects on the GI system, the COX-2 selectivity of these medications is not complete, and there still is potential for GI effects from these medications.
Renal Side Effects of NSAID: Chronic Kidney Disease and Hyponatremia
Exercise can impact the renal system adversely. Strenuous exercise has been shown to reduce renal blood flow and glomerular filtration rates by up to 50% (2). Athletes who take NSAID may further worsen renal hemodynamics. Prostaglandins are vital to maintaining renal perfusion during times of stress, including exercise. Because NSAID block COX, they in turn reduce prostaglandin synthesis. The already-reduced glomerular filtration rate and renal blood flow associated with exercise are potentiated by NSAID. The adverse effects include possible long-term renal damage and contribution to hyponatremia, the latter especially in marathon runners.
Many athletes take NSAID daily for pain or for prevention of pain. The National Kidney Foundation estimates that 10% of kidney failure is associated with overuse of NSAID. This chronic use of medication has been shown to contribute to several cases of kidney failure requiring renal transplant in amateur and professional athletes (10).
Hyponatremia is another condition associated with NSAID use and renal dysfunction. Exercise-associated hyponatremia has been a frequently discussed topic in sports medicine literature. It has been seen in marathon and ultramarathon competitors. The etiology behind hyponatremia in athletes is multifactorial and largely due to overhydration. When NSAID are used, the consumption of hypotonic fluids is compounded by reduced free water clearance because NSAID inhibit prostaglandins and prevent diuresis of the excess fluid. Severe hyponatremia can lead to cerebral edema and pulmonary edema and death, as has been seen in several runners over the last decade (17). The exact contribution that NSAID have to hyponatremia is not clear; however, several recent studies show that both traditional NSAID and Coxibs impair free water clearance in the kidneys and impair renal function and, therefore, increase the risk of hyponatremia in standard distance and ultramarathon runners (2,19,17). Other factors that contribute to hyponatremia in long-distance runners include being of female sex, slower running pace, high availability of fluids on race course, and race inexperience (14).
ALTERNATIVES TO ORAL NSAID
With the potential for both NSAID and Coxibs to cause unwanted GI and renal side effects, it is important to consider alternative forms of pain management for musculoskeletal injuries.
Topical Administration of NSAID
Topical forms of NSAID were developed in another effort to reduce side effect profiles. When topical NSAID are used, the concentration in local tissue remains quite high, while plasma concentration is low (3). It is thought that local application of an NSAID will reduce systemic side effects, including adverse GI effects. Diclofenac is a well studied topical NSAID. The vehicles vary from gel, ointment, or patch applications. One review found that the diclofenac patch gave the most efficacious vehicle delivery. When compared with placebo, topical diclofenac effectively reduces pain (16). The most common side effect of topical NSAID is local skin irritation at the application site.
Acetaminophen frequently is overlooked as an acceptable and effective analgesic. Acetaminophen's mechanism of action still is poorly understood. One study compared acetaminophen alone, diclofenac alone, and a acetaminophen-diclofenac combination and found that all three options provided similar pain relief for musculoskeletal injury (22). When used at appropriate dosing, acetaminophen may be as effective as NSAID for pain relief.
CONCLUSION AND SPECIFIC RECOMMENDATIONS FOR ATHLETES
Musculoskeletal injuries are very common in athletes. Treatment often includes NSAID to block prostaglandins and thereby reduce pain and inflammation. NSAID may provide more benefit in muscle and ligament injuries than in tendinosis and fractures. The role of NSAID in bone healing is unclear, and some studies show a possible delay in fracture healing or fracture nonunion with NSAID use. The benefit of any medication must be weighed against the potential adverse effects. GI and renal complications are the most common adverse effects of nonselective NSAID. While Coxibs reduce the risk of GI side effects, the impact that they have on renal protection is not clear. Some alternatives to standard oral NSAID include topical NSAID and acetaminophen. Some of the literature about NSAID and their risks is specific to a sports medicine population, but many of the studies pertain to the general population or a chronic illness group, such as those with rheumatoid arthritis. It is reasonable to extrapolate from the available information that NSAID and Coxibs are safe for short-term (fewer than 28 d) treatments in the general athletic population for specific injuries. However, caution should be used when prescribing NSAID and Coxibs to long-distance running athletes, especially just before the marathon distance events, because of the contribution the drugs have in development of exercise-associated hyponatremia.
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