A major breakthrough in NSAID development began in the early 1990s with the discovery of two separate cyclooxygenase (COX) isoenzymes. Initially it was believed that COX-1 was a "housekeeping" protein, and that COX-2 was expressed only at sites of inflammation.12 Although this theory does not completely reflect physiological reality, it is illustrative for the purposes of our discussion. COX-1 is primarily present in the platelets, where it regulates vascular homeostasis, and in the endothelial cells of the GI tract, where it regulates gastric cytoprotection. COX-2 is primarily induced at sites of inflammation by cytokines, endotoxins, growth factors, and other substances.23 COX-2 is also expressed in some brain and renal tissue. Among the many anti-inflammatory effects of corticosteroids is the inhibition of COX-2 expression (see discussion in the following paragraphs).
The discovery of COX-2 and its expression primarily in inflammatory tissues raised the possibility of creating a selective COX-2 inhibitor that could block the production of proinflammatory prostaglandins without interfering with gastric protection or platelet activity. The COX-1 and COX-2 isoenzymes differ by only a single amino acid.36 The smaller valine residue in COX-2 allows an inhibitor to bind and prevent the conversion of arachidonic acid to prostaglandin. Many NSAIDs demonstrate preferential inhibition for COX-2 in vitro, including piroxicam, indomethacin, nabumetone, meloxicam, and etodolac. Actual clinical activity cannot be predicted from these laboratory assays, but the latter three agents have been found to have fewer GI side-effects than other NSAIDs.36,66
The selective COX-2 inhibitors currently available are celecoxib, rofecoxib, and valdecoxib, and more will certainly follow. Although the new drugs have not proven more effective than the less expensive, less selective agents, they have apparently fulfilled their promise of limiting GI toxicity. One early study found rofecoxib to have a lower ulcer-producing rate than either ibuprofen or placebo.56 Other large double-blind studies found similar results with both rofecoxib and celecoxib.13,85,87 The COX-2 inhibitors probably have renal adverse effects similar to those of the nonselective NSAIDs, but data are limited.
Missouri Arthritis Rehabilitation Research and Training Center has good information on their Website concerning the use of anti-inflammatory medications. http://www.hsc.missouri.edu
Additional uses for these drugs may be indicated pending future research. Celecoxib is currently approved for the reduction of adenomatous colorectal polyps in familial adenomatous polyposis.12 The expression of COX-2 has been found to be upgraded by tumor promoters as well as inflammatory mediators.83 Therefore, there may be a role for COX-2 inhibitors in the prevention or suppression of colon cancer, which is often characterized by COX-2 expression.49 Epidemiologic data also suggest delayed expression or progression of Alzheimer's disease with NSAID use; studies show increased COX-2 expression and inflammation in the brain related to Alzheimer's.64,73
Benefiting from positive early studies and aggressive marketing campaigns, celecoxib and rofecoxib have become quite popular. In 2001, 24.5 million prescriptions were filled for celecoxib and 23.7 million for rofecoxib, making them the 10th and 13th best-selling drugs in the United States, and generating $3.1 billion and $2.6 billion, respectively.78 However, recent reports in both the medical literature and lay press have not been complimentary. In 2002, a scathing editorial in the British Medical Journal48 and an article in the Washington Post78 both echoed questions that had already been raised regarding the veracity of a celecoxib trial known as the CLASS study.85 The editorial termed the study "overoptimistic short-term data" and called the authors' data "misleading," alleging that the authors omitted disappointing long-term data.
Today there continues to be much debate in the medical community regarding the COX-2 inhibitors. Rofecoxib use was found to increase the risk for myocardial infarction by 300 percent in one large comparison study13 and has recently been associated with aseptic meningitis.14 Apart from these apparent concerns, many are troubled by the high cost of these medications as compared to that of generic NSAIDs (Table 3–2). Only further research and longer-term use will sort out many of these confusing implications of COX-2 use. For the time being, their use should be restricted to those who have failed to achieve good results with multiple other NSAID classes, or who are at high risk for GI complications (Box 3–3).
Table 3–2Comparative Costs of a 15-Day Course for a Few Selected Drugs ||Download (.pdf) Table 3–2 Comparative Costs of a 15-Day Course for a Few Selected Drugs
|Drug ||Dosage* ||Cost ($)† |
|Celebrex (celecoxib) ||200 mg twice per day ||76.95 |
|Daypro (oxaprozin) ||1200 mg once per day ||128.99 |
|Ibuprofen ||800 mg four times per day ||9.49 |
|Indomethacin ||50 mg three times per day ||15.99 |
|Naprosyn ||500 mg twice per day ||53.50 |
|Relafen (nabumetone) ||1500 mg once per day ||55.99 |
|Vioxx (rofecoxib) ||50 mg once per day ||60.50 |
BOX 3–3 Possible Adverse Reactions to NSAIDs
Nausea, vomiting, dyspepsia
Gastric mucosal irritation, superficial erosions, peptic ulceration
Increased fecal blood wasting
Major GI hemorrhage
Small-bowel erosions, "diaphragm" development in small bowel
Hepatotoxicity, hepatitis, fulminant hepatic failure
Alterations in renal plasma flow leading to fall in glomerular filtration rates
Interference with diuretic-induced natriuresis
Inhibition of renin release
Central Nervous System
Confusion, hallucinations, depersonalization reactions, depression
Aseptic meningitis, tinnitus, vertigo
Anemia, bone marrow depression, Coombs-positive anemia, decreased platelet aggregation
Asthma, asthma/urticaria syndrome, urticaria, rashes
Photosensitivity, Stevens-Johnson syndrome
Adapted from Polisson, R: Nonsteroidal anti-inflammatory drugs: Practical and theoretical considerations in their selection. Am J Med. 100 (Suppl2A): 31S–36S, 1996.
As previously mentioned, the focus of COX-2 inhibitor development has been to improve or maintain NSAID efficacy while limiting potentially harmful or intolerable side effects. Topical application of NSAIDs is an alternative method of administration. It delivers the drug to the desired location while avoiding high systemic concentrations and drug interactions. Drug blood levels are less than 10 percent of those achieved after oral administration, but are present in muscle and subcutaneous tissue.24 The most commonly encountered adverse effect is a local rash.41 Data also suggest that there are fewer renal and GI effects.24,25,41
Many studies have found objective and subjective improvements in patient symptoms with topical NSAID use.1,2,31,80,90 The majority of these investigations have compared a single agent with a placebo.1,31,80,90 Interestingly, a number of researchers have found that, although patients subjectively report improved symptoms, physician evaluations of their responses showed no significant change. These findings imply that there may be some benefit to the use of topical NSAIDs during the rehabilitation process because the injured individual perceives less pain and disability.
In a quantitative systemic review, Moore et al.67 concluded that topical NSAIDs are effective in alleviating acute soft-tissue injury pain with adverse effects similar to those of placebo. Currently, there are no commercially marketed formulations of topical NSAIDs available for retail sale. However, a number of agents have been studied and may be compounded by a licensed pharmacist. Studies have looked at the use of topical formulations of naproxen, piroxicam, ketoprofen, indomethacin, diclofenac, and ibuprofen.
The initial research appears promising, and more data will certainly follow. The limited adverse effect profile of these agents is certainly appealing. However, their effects on the initial stages of healing, and their efficacy in certain conditions (bursitis versus tendinitis, acute versus chronic injury) need to be further delineated. The next several years will likely see an explosion in the research and marketing of topical NSAIDs.
Overview of Selected NSAIDs
Dozens of NSAIDs from several different chemical classifications are currently available by prescription in the United States (Table 3–3). Even more are marketed in Europe and Asia. New agents from well-established classifications, reformulations of older drugs, and completely new classes of NSAIDs enter the market on a regular basis. The constant innovation and development of new products seen in NSAID research are a testament to the popularity of the medications and demonstrate that those agents currently available are far from perfect in efficacy and potential adverse effects.
Table 3–3Currently Available NSAIDs, Excluding Aspirin Derivatives ||Download (.pdf) Table 3–3 Currently Available NSAIDs, Excluding Aspirin Derivatives
|Propionic Acid Derivatives |
|Fenoprofen calcium (Nalfon) |
|Flurbiprofen (Ansaid) |
|Ibuprofen (Motrin, Advil, others) |
|Ketoprofen (Orudis, Oruvail) |
|Naproxen (Naprelan, Naprosyn) |
|Naproxen sodium (Aleve, Anaprox, Anaprox DS) |
|Oxaprozin (Daypro) |
|Indomethacin (Indocin, Indocin SR) |
|Sulindac (Clinoril) |
|Tolmetin sodium (Tolectin, Tolectin DS) |
|Phenylacetic Acids |
|Diclofenac sodium (Voltaren, Voltaren XR) |
|Diclofenac potassium (Cataflam) |
|Diclofenac sodium/misoprostol (Arthrotec) |
|Nabumetone (Relafen) |
|Piroxicam (Feldene) |
|Meloxicam (Mobic) |
|Ketorolac tromethamine (Toradol) |
|Pyranocarboxylic Acid |
|Etodolac (Lodine, Lodine XL) |
|Selective COX-2 Inhibitors |
|Celecoxib (Celebrex) |
|Rofecoxib (Vioxx) |
|Valdecoxib (Bextra) |
|Mefenamic acid (Ponstel) |
|Meclofenamate sodium (Meclomen) |
The following section provides a brief overview of a handful of OTC and prescription NSAIDs. These agents have been chosen for discussion based on historical relevance, widespread use, unique clinical aspects, or a combination of all three. There are a number of factors the physician must consider when choosing an NSAID for use by the athlete. An overview of the major factors to consider is listed in Box 3–4. For an exhaustive review of all available NSAIDs the reader is referred to any current pharmacology textbook.
BOX 3–4 Factors to Consider in Choosing an NSAID
Age of Patient
Patients over 60 years of age at increased risk for GI toxicity.
Few studies have been conducted on NSAID safety in children. Ibuprofen and naproxen are most often used in this population. There has been some use of indomethacin and sulindac in juvenile rheumatoid arthritis.
Duration of Treatment
If long-term use is planned, safety and cost must be balanced and dosing schedule must be considered.
Duration of treatment longer than 3 months increases risk of GI toxicity, therefore, medications with superior safety profiles must be considered.
Time of Onset
Drugs with shorter half-lives, such as ibuprofen, reach peak plasma levels much sooner than long-acting agents. Therefore, if quick pain-relief is desired, short-acting agents should be used.
General Health of the Patient
Cost of Treatment
Table 3–4NSAID Drug-Drug Interactions ||Download (.pdf) Table 3–4 NSAID Drug-Drug Interactions
|Drug ||Common Use ||Interaction |
|ACE inhibitors ||Treatment of hypertension ||Decreased renal perfusion |
|Aminoglycosides ||Antibiotics ||Decreased renal function |
|Antacids ||Treatment of dyspepsia ||Reduced NSAID absorption |
|Anticoagulants ||Prophylaxis/treatment of clotting disorders ||Effect prolonged, increased risk of GI bleeding |
|Barbiturates ||Sedation, anxiety disorders ||Accelerated NSAID metabolism |
|Beta-blockers ||Treatment of hypertension ||Diminished treatment effect |
|Hypoglycemic agents ||Treatment of Type 2 diabetes ||Increased hypoglycemic activity |
|Lithium ||Treatment of bipolar disorder ||Decreased renal excretion |
|Phenytoin and valproic acid ||Anti-epileptic drugs (AEDs) ||Diminished AED metabolism |
|Potassium-sparing diuretics ||Treatment of hypertension ||Increased risk of hyperkalemia |
Ibuprofen (Advil, Motrin, Nuprin)
A propionic acid derivative, ibuprofen is the most frequently used NSAID.6 Introduced to the OTC market in 1985, it is available in 200 to 800 mg tablets by prescription, and 200 mg tablets OTC. Chewable tablets and liquid formulations are also available. It boasts aspirin's potency for analgesic and anti-inflammatory action, but has a lower incidence of side effects. This reduced incidence may be a result of ibuprofen's decreased inhibition of platelet aggregation, which lessens possible gastric bleeding.84 Ibuprofen is among the most beneficial NSAIDs in easing the pain of primary dysmenorrhea, for which it is effective at doses of 400 mg every 6 hours. It is also frequently used as an antipyretic in adults and children because its longer duration of action makes it a popular alternative to acetaminophen.
Peak plasma levels are achieved within 15 to 30 minutes of ingestion.30 This rapid onset of action can be quite beneficial for quick relief of pain. However, with a half-life of about 2 hours, ibuprofen must be taken every 6 to 8 hours to maintain effect. An anti-inflammatory regimen requires 2400 to 3200 mg daily, taken in three separate doses. This dosing scheme allows it to be taken at mealtimes, lessening the likelihood of gastric irritation. Sufficient analgesia should be achieved by daily dosages of less than 2400 mg per day. Daily dosage should not exceed 3200 mg. Although ibuprofen is better tolerated than aspirin and indomethacin, approximately 10 to 15 percent of individuals must discontinue use because of GI symptoms.30 It should be noted that a large meta-analysis found ibuprofen to have the lowest risk of adverse effects among all nonselective NSAIDs.27 Additional adverse effects, which are quite rare, include headaches, rash, blurry vision, and thrombocytopenia.
Naproxen (Naprosyn, Aleve)
Also a propionic acid derivative, naproxen is chemically similar to ibuprofen.30 In one comparison study with ibuprofen, naproxen was found to be marginally superior in decreasing joint inflammation.71 The sodium salt of naproxen is available as the OTC preparation Aleve, and as Anaprox by prescription. Naproxen sodium is more readily concentrated in the synovium than naproxen, and therefore may be more efficacious for joint pain and inflammation.3
Because of naproxen's long half-life (approximately 12 hours), the daily recommended dosage of 750 to 1000 mg can be taken on a twice-daily schedule. This tends to reduce gastric upset caused by the lesser number of exposures and improves compliance. Peak plasma levels are achieved within 2 to 4 hours.30 An extended-release formulation (Naprelan) is now available for once daily dosing and is also effective for migraine headache prophylaxis in some individuals.
Naproxen is 20 percent more potent than aspirin with an adverse-effect profile similar to ibuprofen's.84 Although naproxen is better tolerated from a GI standpoint than indomethacin, the incidence of upper GI bleeding in OTC use is double that of OTC ibuprofen.30 A dose effect may be the cause of this aberration. Naproxen is eliminated from the body mainly by way of the kidneys. Therefore, like all NSAIDS, it should be used with caution in persons with renal complications.
Introduced in 1963, indomethacin (an indole derivative) was one of the first NSAIDs developed and continues to be among the most powerful inhibitors of cyclooxygenase.54 It may also owe its potency to the additional activities of phospholipase A inhibition, reduced migration of PMNs, and decreased proliferation of T and B cells.30 Although particularly effective in maladies such as rheumatoid arthritis, ankylosing spondylitis, and gout, indomethacin is typically not recommended for use as a simple analgesic or antipyretic because of potentially severe adverse effects.5 Up to half of people using indomethacin may experience some adverse effects, and almost one-third will discontinue use. Common adverse effects include gastrointestinal symptoms (ulceration, nausea, abdominal pain) and headaches (15 to 25% of patients).5
Peak concentrations can be achieved in 1 to 2 hours (in fasting subjects, onset is delayed by food intake) with a half-life of approximately 2.5 hours.30 Daily dosage ranges from 75 to 100 mg taken in 3 or 4 doses. Prolonged-release formulations are available (75 mg 1 to 2 times per day); however, gastrointestinal and other adverse effects appear to be similar to those seen with the regular formulation.5
Indomethacin's use has declined as newer agents with a lower side effect profile have emerged. However, with almost 40 years of evidence-based efficacy in the clinical setting, it remains a popular choice in certain situations. Nonorthopedic uses of indomethacin include suppression of uterine contractions to prevent delivery during preterm labor and intravenous administration in neonates to induce closure of a patent ductus arteriosus.
The significance of phenylbutazone, formerly marketed under the trade name Butazolidin, is now historical rather than clinical. Introduced in 1949, it was widely used for decades, but decreased in popularity with the development of less toxic NSAIDs. Long-term use of phenylbutazone increased the incidence of various blood dyscrasias, including aplastic anemia, and severe hepatic reactions.74
The only nonacid NSAID currently available, nabumetone is converted to an active acetic acid derivative in the liver. The prodrug resembles naproxen in structure. It can be given once a day because the half-life is more than 24 hours. Dosage varies from 1000 mg to 2000 mg per day. The incidence of GI ulceration does appear to be lower with nabumetone than with the other nonselective NSAIDs.69 As a nonacid prodrug, it produces no local irritation of the gastric mucosa. It also does not undergo enterohepatic recirculation, which may improve its GI profile. Adverse effects may include diarrhea, rash, and heartburn.
A furanose derivative, rofecoxib was introduced in 1999 and is one of only three potent and highly selective COX-2 inhibitors available. It does not inhibit COX-1 and has no effect on platelet function. It is FDA approved for the treatment of osteoarthritis, dysmenorrhea, and acute pain at dosages ranging from 12.5 mg to 50 mg. It is administered once daily because of its nearly 17-hour half-life. Long-term toxic effects, including GI and renal effects, are not yet known because of the drug's relatively recent introduction. Please see the section on COX-2 inhibitors for further discussion on rofecoxib and similar agents.
Although it is not typically employed for its anti-inflammatory properties, ketorolac, an acetic acid derivative, deserves special mention. It is the only NSAID available for intramuscular or intravenous injection as well as oral administration. Although it also has anti-inflammatory and antipyretic properties, it is most commonly marketed and used as an analgesic, particularly in postoperative patients. As an analgesic, ketorolac offers great promise because it avoids the most common shortcomings of opioids, (i.e., tolerance, withdrawal effects, and respiratory depression). Interestingly, Tokish et al92 recently reported that 28 of 30 National Football League team medical staffs commonly use ketorolac intramuscular injections on game days for pain relief.
Studies have shown ketorolac to be equal to, or more effective than, opioids in the treatment of postoperative pain.6,8 Dosages range from 15 to 60 mg and peak plasma concentrations are reached within 30 to 50 minutes. Ketorolac may also be used as a therapeutic adjunct to opioids, allowing for a decrease in opioid requirement. When ketorolac ketorolac is administered intramuscularly, damage to the gastrointestinal mucosa may still occur. However, doses of 10 to 30 mg given 5 times per day produced less mucosal injury than 650 mg of aspirin given on the same dosage schedule.5
Ketorolac use has been linked to acute renal failure in a small number of published reports,92 but few large studies have been conducted on ketorolac's renal effects. Feldman et al. found a similar incidence (1.1%) of acute renal failure in patients treated with either ketorolac or opioids. However, ketorolac treatment longer than 5 days in duration did show an increased risk of renal failure.29 Thus, in clinical practice, duration of ketorolac treatment is typically held to less than 5 days. An additional study found ketorolac users to have a higher rate of upper GI bleeding than users of other NSAIDs.32
NSAIDs are commonly used in the treatment of many afflictions, including but not limited to rheumatoid arthritis, spondyloarthropathies, juvenile rheumatoid arthritis, osteoarthritis, gout, and a variety of acute and chronic musculoskeletal injuries (sprains, strains, tendonitis, bursitis). Although our discussion has centered on sports-related use, the majority of research regarding the efficacy of NSAIDs has been conducted on patients with rheumatoid arthritis or osteoarthritis. As mentioned previously, no single NSAID has been found to be superior in the treatment of either condition.37,94,98
Given that no one agent has been found superior in a large number of clinical trials involving rheumatoid arthritis or osteoarthritis, we can be assured that no data exist guiding specific NSAID therapy in acute or chronic musculoskeletal conditions. In fact, as we will discuss further, little evidence supports the use of any NSAID for any injury. Because no one agent is superior to another, the criteria listed in Box 3–4 must be considered when deciding on appropriate NSAID therapy. Cost must also be considered because there is a tenfold difference in price between some agents (see Table 3–2).
Despite decades of widespread use of NSAIDs, some research over the past decade has cast uncertainty on the empiric use of NSAIDs in sports medicine practice. Several studies have concluded that NSAIDs may have the effect of slowing the healing process. In a study conducted by culturing rabbit articular cartilage chondrocytes in the presence of certain NSAIDs, diclofenac and indomethacin (and piroxicam to a lesser degree) inhibited the secretion of proteoglycans.20 Proteoglycans are extracellular molecules involved in the formation of cartilage, tendons, and ligaments, and are vital to the process of tissue repair. Other studies have shown that indomethacin and aspirin can interfere with the synthesis or transport of connective tissues components.9,22,39 One recent animal study suggests that the new COX-2 inhibitors may actually delay fracture healing.86
A review of studies conducted in the clinical setting is largely inconclusive when looking for direction in NSAID use. Reynolds found worse outcomes at 7 days after injury in patients treated with NSAIDs.79 DuPont et al. found some positive subjective trends, but no significant efficacy in the treatment of ankle sprains.26 These results are similar to those of many other studies, including LaBelle et al., which found no evidence to support the use of NSAIDs or corticosteroids in the treatment of lateral epicondylitis.55 A paucity of randomized studies exist regarding NSAID treatment of chronic conditions such as tendonitis and bursitis. However, few studies point to significant delays in healing or return to competition in NSAID-treated groups.
The decision to use NSAIDs should not be a reflexive one. Although their lack of proven scientific efficacy may discourage some clinicians, NSAIDs are still widely prescribed in sports medicine practice. On an individual basis, they may have positive effects in "cooling down" chronic inflammation, diminishing pain and inflammation associated with chronic injury, or potentially aiding in the rehabilitation of acute injuries through the same means. In reviewing the mechanism of chronic, or "sports-induced," inflammation, one can postulate that NSAIDs (or corticosteroids) may diminish the inflammatory process enough to allow for the resolution of the normal tissue healing process.
Implications for Activity
The athletic trainer should not use NSAIDs impulsively for all athletic injuries. The efficacy of NSAIDs remains a topic of research, and the athletic trainer should remember that there are valid arguments on both sides of the research question. However, NSAIDs are still widely prescribed in sports medicine practice. It may be that the use of NSAIDs provides a period of time during which the body can rest and recuperate while maintaining some movement, which allows the injured tissues to be remodeled in the appropriate fashion. The athletic trainer must be concerned if an athlete continues to use NSAIDs after the healing process should have been complete.
It is unlikely that definitive data will ever emerge on the exact effect of NSAIDs in musculoskeletal injuries. Variations in type and degree of tissue trauma, individual responses, and study outcomes are all difficult to quantify. More importantly, long-term outcome data may be quite misleading because nearly all musculoskeletal injuries eventually resolve without treatment. In fact, one argument against the use of NSAIDs is the self-limiting nature of such injuries. However, for competitive athletes, a difference of 1 or 2 days in return from an injury may be crucial.
Controversy also exists regarding when an NSAID regimen should begin after an acute injury. Some clinicians initiate drug therapy immediately, along with rest, ice, compression, and elevation (RICE), in an attempt to arrest the inflammatory process. Others believe that NSAID therapy should begin no sooner than 48 hours after injury and implementation of RICE.91 Experts advising against NSAID treatment are concerned that the inhibition of thromboxane production will promote additional bleeding and that early NSAID use may diminish the inflammatory response and delay healing. Evidence on either side of the argument is largely anecdotal and based on clinical experience.
Certainly the inflammatory process is important to the resolution of any injury because it represents the first phase of tissue healing. Thus, NSAIDs must be used judiciously and only in situations in which the presumed benefits outweigh potential risks. This author's current practice is to recommend against the use of NSAIDs in the first 48 hours after acute injury. After that, they are prescribed for use only on an as-needed basis for minor pain and discomfort. Depending on the degree of pain, acetaminophen or prescription- strength analgesics may be helpful. Ibuprofen is typically recommended because it is relatively inexpensive, efficacious, and safe and has a rapid onset of action. In chronic inflammatory conditions, naproxen sodium is recommended twice daily for 10 to 14 days to alleviate pain and break the inflammatory cycle.
A number of complications and adverse effects of NSAID therapy have been alluded to throughout this chapter, particularly in the section on the new COX-2 inhibitors. Numerous NSAID adverse effects have been reported (see Box 3–3). However, the majority of complications arise in the GI tract and the renal parenchyma. NSAID use may occasionally result in elevation of liver enzymes, but hepatotoxicity is rare. Please refer to the discussion of aspirin-sensitive asthma for pulmonary complications.
It has been estimated that 50 percent of patients on NSAID therapy experience some form of reaction, and 1 to 2 percent of these reactions may be serious.59 The first week of therapy with any new NSAID is quite important because most patients who do not tolerate a new agent will develop intolerance during this time frame. Age is also an important factor because only 10 percent of complications occur in patients under 40 years old.11
GI toxicity is the most frequently encountered NSAID complication. Up to 20 percent of patients have some GI symptoms and 1 to 2 percent may develop peptic ulcer disease. Shockingly, Hollander reported that 33 to 50 percent of all patients who die of ulcer-related complications have recently ingested NSAIDs.43 NSAID-related ulceration may be asymptomatic, particularly in older patients, which may increase their risk of serious complications once bleeding develops. Risk factors for GI complications are listed in Box 3–5. The pathogenesis of GI irritation and prophylaxis for NSAID gastropathy are discussed elsewhere in this chapter. Prophylactic use of H2 blockers such as Zantac, Pepcid, Axid, and Tagamet has not been shown to reduce NSAID-related GI ulceration.59
BOX 3-5 Patient Risk Factors that May Increase the Likelihood of GI Toxicity with NSAID Use
Age greater than 60 years
Higher NSAID dose, or use of more than one NSAID at a time
Concomitant use of a corticosteroid
NSAID use longer than 3 months
History of peptic ulcer disease
Patients with preexisting renal disease are at particular risk for renal toxicity related to NSAID use. Prostaglandins are more critical to the maintenance of renal blood flow in diseased kidneys. Therefore inhibition of prostaglandin production may have deleterious effects on renal blood flow and function. These effects may result in hypertension, edema, exacerbation of congestive heart failure, and reduced renal function. There are many case reports of acute and chronic renal failure, interstitial nephritis, papillary necrosis, proteinuria, and other renal effects.19 Avoidance of renal toxicity is best carried out by careful patient selection, by limiting dosages, and by carefully following blood pressure and renal function in at-risk individuals.
Implications for Activity
When an athlete is given an NSAID such as aspirin, the athletic trainer should remind the athlete of the possibility of gastrointestinal toxicity as a complication. Typically, athletes will try to play through the adverse effects that are sometimes produced by NSAID use. Signs and symptoms of GI toxicity can include severe stomachache (especially when the stomach is empty), diarrhea, nausea, vomiting, unexpected weight loss, and darkened stools. If the athlete is having problems with any of these signs and symptoms, he or she needs to speak to a physician. The physician may encourage the athlete to have food in the stomach before taking NSAIDs or may even change the type of medication being prescribed.
A number of drug interactions may occur in patients taking other medications in addition to NSAIDs (see Table 3–2). Fortunately, in a young, athletic population, multiple disease states are rare, and such interactions are typically not of concern. However, the practicing athletic trainer should be aware of such possibilities. Most NSAIDs are extensively bound to plasma proteins and compete for binding sites with other protein-bound medications, resulting in higher drug levels and increased risk of toxicity. Such drugs include the anticoagulant warfarin, oral hypoglycemic agents, digoxin, and antihypertensives.15,17,95
Specifically in the kidneys, NSAIDs may reduce the clearance of methotrexate and inhibit lithium excretion. As discussed previously, GI and renal toxicity are particular concerns in NSAID use. Concomitant use of anticoagulants, aspirin, high-dose corticosteroids, or alcohol increases the risk of serious GI pathology.40 Particular caution must be given to patients on antihypertensive therapy because NSAIDs may diminish their effectiveness. ACE inhibitors, which diminish renal perfusion, may also interact poorly with NSAIDs.
Potential risks of herbal anti-inflammatory medications is the subject of a bulletin by the American Academy of Orthopedic Surgeons.
What to Tell the Athlete
Some athletes will not understand which types of OTC drugs produce anti-inflammatory effects and will thus be using products that do not work but still produce adverse effects. It is important for the athletic trainer to be able to discuss with the athlete the types of OTC drugs the athlete may select to gain an anti-inflammatory effect.
The athletic trainer should make the following points when educating the athlete about these drugs:
Taking anti-inflammatories with meals can reduce adverse GI effects.
There appear to be differences in the potential for adverse effects between OTC and prescription anti-inflammatory medications. These adverse effects need to be communicated to the athlete.
To produce maximum effectiveness, anti-inflammatory medications must be taken as prescribed.
The overall effects of OTC and prescription anti-inflammatory medications on the inflammatory process are very similar.
For the athlete on a budget, a more expensive prescription drug may not be worth the extra cost in controlling a short-term inflammatory reaction.