Nonsteroidal Anti-Inflammatory Drugs: General Risks of Prophylactic, Acute, and Long-Term Use.
Heather Gillespie, M.D., M.P.H., is an assistant professor in the Division of Sports Medicine at the University of California-Los Angeles (UCLA). She serves as one of the varsity athlete team physicians at UCLA. Dr. Gillespie runs a pediatric sports medicine clinic in downtown Los Angeles and additionally has an active musculoskeletal practice for children and adults of all ages in Santa Monica, CA. A former collegiate swimmer and water polo player, Dr. Gillespie enjoys an active lifestyle training, competing in triathlons, and the southern California weather.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are used extensively in medicine for the treatment of pain, inflammation, and fever. NSAIDs use is prevalent in athletes and nonathletes and products are available in over the counter (OTC) as well as prescription form. NSAIDs are among the most widely prescribed therapeutic agents because of their effectiveness in treating pain and inflammation, but they also have side effects on various organ systems that should be taken into account when considering their use, especially in certain populations.
There are many formulations of NSAIDs available, including both “selective” and “nonselective” types. The selectivity of the NSAIDs refers to the relative inhibition of the cyclooxygenase (COX) enzymes, with nonselective NSAIDs inhibiting both COX-1 and COX-2 enzymes and selective NSAIDs targeting the COX-2 enzyme, primarily.
When tissues are damaged, such as in musculoskeletal injuries, cells secrete prostaglandins, which lead to inflammation. NSAIDs exert their anti-inflammatory effect by decreasing prostaglandin production and therefore decreasing inflammation. NSAIDs are able to decrease prostaglandin production by blocking an enzyme called cyclooxygenase. Unfortunately, COX does more than just block prostaglandin synthesis in response to tissue injury. As mentioned previously, there are two major types of COX, COX-1 and COX-2, and each plays a different role in the body. COX-1 is involved in the regulation of hemostasis (process leading to stopping bleeding), the integrity of the gastrointestinal (GI) and renal tracts, platelet function, and macrophage differentiation (4). Although NSAIDs are effective in inhibiting COX-1 and reducing inflammation, the adverse effects of NSAIDs are primarily related to the inhibition of these other important functions of COX-1. COX-2 plays a larger role in inflammation; therefore, selective NSAIDs that inhibit COX-2 may result in fewer side effects than nonselective NSAIDs. That said, all NSAIDs have some effect on both COX-1 and COX-2, and none is absolutely selective for COX-2, so there are similar side effects with all NSAIDs (4).
Damage to the upper GI tract was one of the first recognized clinical side effects of NSAID use and continues to cause significant morbidity and mortality. As stated previously, prostaglandins provide a gastroprotective effect, and the use of NSAIDs decreases the production of these prostaglandins; this puts the athlete or patient at risk for GI bleeding. Statistics from a study in the 1990s in the United States found that there were 32,000 hospitalizations and 3,200 deaths annually from NSAID-related GI bleeding. The risk of bleeding is directly related to patient age and comorbidities, and the risk of serious bleeding from chronic NSAID use ranges from 1 in 2,100 for adults younger than 45 years to 1 in 110 for adults older than 75 years (5). In chronic NSIAD use, adding a proton pump inhibitor (that reduces acid production in the stomach) or using a selective NSAID has been shown to help decrease the risk of GI bleeding, but there is still a risk (4).
In addition to GI effects, prostaglandins also play a role in the cardiovascular system. By decreasing prostaglandin production with NSAID use, there has been an associated increased risk of cardiac disease and complications (4). This again is more prevalent in those with underlying pathology and disease but must be factored in with any patient or athlete, especially those who use NSAIDs chronically.
NSAIDs may be associated with slower bone healing and increased risk of nonunion, but there continues to be significant debate in the literature regarding the strength of this evidence. The reason for this is that most conclusions are based on animal models and moderate-quality observational studies in humans (1). That being said, there has been an association shown between exposure to NSAIDs and increased nonunion risk in patients with long bone fractures, and animal models have shown an association between NSAID use and risk of bony nonunion (2,3,6). Although additional research is still needed, based on the available data and combined with the multiple potential medical problems associated with NSAID use, many physicians use caution in the use of NSAIDs in acute bone fractures.
Another potential side effect of NSAIDs is in the renal system (kidneys). NSAIDs have been found to affect kidney function and cause acute renal failure (7). Risk of kidney damage with NSAID use is increased in those with preexisting kidney damage as well as in situations in which plasma volume is reduced. NSAIDs use also has been found to be a risk factor in the development of hyponatremia in long distance endurance events. In athletes who often are in a state of dehydration in training or competition, potential volume depletion and the effect of NSAID use on kidney function becomes very relevant.
NSAIDs are not only used to treat established injuries, but with the extensive availability of these medications, many athletes have taken on the potentially detrimental practice of using NSAIDs prophylactically before competition, during practice, or events (8). This prophylactic use carries inherent risks. By masking pain, and potentially “pushing through” an injury, there may be an increased risk of the athlete worsening an injury that the sensation of pain would normally limit. Additionally, there is a suggestion that COX-2 and prostaglandins are important in the body’s synthesis of collagen, an important soft tissue component (8). If the COX-2 system is inhibited, there may be a decreased adaptation and response of the body to mechanical stress, and this may potentially delay tissue repair in both bone, ligament, and muscle/tendon injuries (8).
With the above risks and side effects in mind, it is generally recommended to consider alternatives to NSAIDs in any athlete but especially those high-risk populations with underlying comorbidities. If NSAIDs are chosen as the treatment of choice, the recommendation would be to use the minimal dose for a minimal duration as short-term use might limit side effects. The use of gastroprotective agents, such as proton pump inhibitors, in those at increased risk of GI side effects also should be considered (4).
In summary, NSAIDs are highly effective for reducing pain, inflammation, and fever. Widely used in our population, in both OTC and prescription forms, we must keep in mind the significant potential side effects of NSAIDs including the risk of GI bleeding, acute renal failure, cardiovascular effects, and potential delayed bone healing when deciding to use or prescribe both selective and nonselective NSAIDs. As always, a patient/athlete-centered approach, balancing the risks, benefits, and alternatives, should be considered when recommending and selecting NSAIDs for use in pain and anti-inflammatory management situations.
1. Dodwell ER, Latorre JG, Parisini E, et al
. NSAID exposure and risk of nonunion: a meta-analysis of case-control and cohort studies. Calcif Tissue Int
2. Gerstenfeld LC, Al-Ghawas M, Alkhiary YM, et al
. Selective and nonselective cyclooxygenase-2 inhibitors and experimental fracture-healing. J Bone Joint Surg Am
3. Ho ML, Chang JK, Wang GJ. Antiinflammatory drug effects on bone repair and remodeling in rabbits. Clin Orthop Relat Res
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6. Simon AM, O’Connor JP. Dose and time-dependent effects of cyclooxygenase-2 inhibition on fracture-healing. J Bone Joint Surg Am
7. Ulinski T, Guiqonis V, Dunan O, Bensman A. Acute renal failure after treatment with non-steroidal anti-inflammatory drugs. Eur J Pediatr
8. Warden SJ. Prophylactic misuse and recommended use of non-steroidal anti-inflammatory drugs by athletes. Br J Sports Med