Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
NSAIDs are frequently prescribed to athletes by sports medicine providers as a way to limit inflammation and pain and to subsequently facilitate return to play. Research regarding effects of these widely used medications has brought into question the role of these drugs in treating athletic injuries.
Prevalence
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NSAIDs are one of the most commonly used medications. In the United States (US) population, >29 million adults are estimated to be regular users of NSAIDs.
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In addition, an estimated 16% of the US population aged >50 years use an NSAID at least 3 times a week for at least 3 consecutive months.
Mechanism of Action
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NSAIDs work by primarily inhibiting the cyclooxygenase (COX) pathway and, to a lesser extent, the lipoxygenase pathway, thereby blocking the conversion of arachidonic acid to prostacyclins, prostaglandins, and thromboxanes.
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Through this mechanism, NSAIDs exert antipyretic, analgesic, and anti-inflammatory actions.
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Moreover, blocking the production of certain prostaglandins causes NSAIDs to exert an inhibitory effect on neutrophil aggregation and lysosomal enzyme release.
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NSAIDs are also thought to have nonprostaglandin effects on limiting leukotriene synthesis via inhibition of membrane-related processes.
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The two main forms of COX, COX-1 and COX-2, are thought to have different functions ( Fig. 7.1 ).
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COX-1 is presumably a constitutive enzyme involved in the synthesis of prostaglandins that regulate physiologic processes; it plays an important role in the function of the gastric mucosa, kidneys, vascular endothelium, and platelets.
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COX-2, on the other hand, is primarily considered as an inducible isoform (although data show that it may have a role in certain constitutive processes): involved in the synthesis of prostaglandins that mediate inflammation, pain, and fever in response to tissue injury.
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The concept behind the development of COX-2-specific inhibitors was to preserve the physiologic function of COX-1 while limiting the effects of COX-2 on tissue injury.
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Nonselective NSAIDs block both isoforms and subsequently have a significant side-effect profile.
Figure 7.1
Nonopioids: NSAIDs, selective cyclooxygenase-2 inhibitors, and acetaminophen.
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Alternate Mode of Delivery
Topical
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Pharmaceutical compounding of NSAIDs is readily available in the US. These formulations are prescribed in the form of a gel, foam, spray, cream, or patch.
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Purported benefits of topical delivery of NSAIDs lie in the decrease in adverse systemic effects on the gastric mucosa, kidneys, and vascular endothelium.
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Serum concentrations of topical NSAIDs appear to be considerably lower than the levels measured after oral intake or intramuscular administration; this may result in fewer drug–drug interactions.
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Older adults report a higher incidence of adverse effects than younger individuals.
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The most common side effect is local irritation at the application site, although this is uncommon.
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Several trials have demonstrated efficacy of topical NSAIDs with improvement in subjective pain symptoms. A Cochrane review showed that for all topical NSAIDs compared with placebo, the number needed to treat to benefit (NNT) for clinical success, equivalent to 50% pain relief, was 4.5 (3.9–5.3) for a treatment period of 6–14 days.
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Topical NSAID compounding appears to provide an alternative mode of use in the setting of acute superficial soft tissue injury with limited side effects.
Injectable
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There are few NSAIDs available for use as intramuscular (IM) injections, and their use is controversial.
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Intramuscular ketorolac (Toradol) is widely used before athletic competitions in college and professional sports; however, there are limited data, and actual prevalence of use remains unknown.
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Ketorolac reaches its peak plasma concentration within 45 minutes when administered via an IM route compared to 20 minutes via the oral route.
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In general, it is recommended that ketorolac should not be used prophylactically as a means of reducing anticipated pain during practices or games.
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It should be given in the lowest effective therapeutic dose and should not be used in any form for >5 days as the side-effect profile is nearly equivalent to oral administration.
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General caution and discussion of risks and benefits with the athlete should be considered before administration of an IM NSAID such as ketorolac.
Types
Within the NSAIDs family, there are several subclasses that may provide subtle differences in metabolism and therapeutic effects ( Box 7.1 ).
Salicylic Acid Derivatives
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ASA
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Salicyl salicylate
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Diflunisal
Heteroaryl Acetic Acids
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Diclofenac
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Ketorolac
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Tolmetin
Fenamates
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Mefenamic acid
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Meclofenamic acid
Alkanones
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Nabumetone
Indole Acetic Acids
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Indomethacin
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Sulindac
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Etodolac
Arylpropionic Acids
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Ibuprofen
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Naproxen
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Ketoprofen
Enolic Acids
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Piroxicam
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Phenylbutazone
COX-2 Inhibitors
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Celecoxib
Adverse Reactions
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Considering the significant side-effect profile of NSAIDs, physicians should be cautious when prescribing them.
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Long-term use of NSAIDs may increase the risk of stroke, myocardial infarction, and thrombotic events.
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Previously, COX-2 inhibitors have been linked to increased risk of myocardial infarction, but recent studies have suggested an increased risk of myocardial infarction with nonselective NSAIDs as well.
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Shown to have a negative impact on blood pressure, increasing both systolic and diastolic pressures.
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The most common side effect associated with NSAID use is gastrointestinal (GI) bleeding:
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Development of COX-2 inhibitors was supposed to ameliorate this problem, but data regarding an overall decrease in GI side effects are conflicting.
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Use of prophylactic medications such as H 2 -receptor antagonists and proton-pump inhibitors is common, but outcomes addressing risk reduction of stomach ulceration and GI bleeding are variable.
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H. pylori eradication is recommended if long-term use of NSAIDs is being considered.
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Increased risk of GI bleed, ulceration, and stomach or intestinal perforation may occur at any time without warning symptoms with both acute and chronic use.
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Dosing for shorter intervals and consumption with food may reduce side effects.
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Effects of NSAID use on various musculoskeletal variables have also been studied:
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Animal studies have demonstrated that NSAID use slows fracture healing and may contribute to malunion and/or nonunion.
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Studies on NSAID use for ligament sprains and muscle strains have reported early improvement in symptoms and subsequent return to activity, but effects of long-term use on soft tissue healing remain unknown.
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NSAIDs block constitutive prostaglandins necessary for optimal kidney function.
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Decrease sodium excretion and increase free water retention, particularly with long-term use
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Avoidance with endurance events safest owing to potential renal morbidity
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May also cause interstitial nephritis, regardless of duration of use
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Pharmacokinetics
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Rapidly and completely absorbed in the GI tract
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Although most NSAIDs are metabolized via the cytochrome P450 system through the enterohepatic circulation, excretion occurs through the kidneys.
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Half-lives of different NSAIDs vary considerably, ranging from a few to several hours.
Therapeutic Recommendations
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Despite their significant side-effect profiles, judicious short-term use of NSAIDs in the athletic arena is justifiable. In settings of sprains, acute muscle strains, eccentric load injury to muscle, and acute tenosynovitis or tendonitis, a 3–5 day course may help decrease pain and facilitate quicker return to activity.
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Caution should be exercised regarding use of NSAIDs with acute fractures or stress fractures of areas at a high risk for of nonunion.
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