Chapter 3: Anti-inflammatory Medications

Athletic trainers administer therapeutic modalities such as ultrasound, ice, and electrical stimulation on a daily basis. The goal of treatment is to bring about a rapid and complete resolution of injuries in order to expeditiously return athletes to competition. The treatment for each injury is typically devised and agreed on by the athletic trainer and the team physician, with each drawing on his or her past experience and knowledge of the current literature to develop the most beneficial rehabilitation plan. In recent years, that treatment plan has increasingly (and often reflexively) included prescription or over-the-counter (OTC) nonsteroidal anti-inflammatory medications (NSAIDs).

Electrical modalities, ultrasound, ice, heat, and therapeutic exercise all have accepted and valued roles in the rehabilitation of musculoskeletal injuries. Athletic trainers use these modalities regularly and are usually well aware of their effects, benefits, indications, and contraindications. However, the role of anti-inflammatory medications such as corticosteroids and NSAIDs in the rehabilitation process is not well defined or thoroughly understood.

The use of NSAIDs for the treatment of sports-related injuries, as well as other complaints (particularly osteoarthritis), continues to rise. In 2001, sales of NSAID prescriptions reached $10.9 billion in the United States alone.⁴⁷ This figure does not include sales of OTC drugs such as aspirin, ibuprofen, naproxen sodium, and ketoprofen. (Aspirin is technically an NSAID, but is not included in the generic term, which describes the newer agents.) It was recently estimated that more than 1 percent of the US population uses NSAIDs (other than aspirin) daily.⁶²

Although NSAIDs are considered relatively safe medications, such widespread use means that a significant number of individuals who take them are unable to tolerate certain side effects. Although gastrointestinal (GI) toxicity has been estimated to occur in only about 2 cases per 10,000 NSAID prescriptions dispensed,³⁴ this extrapolates to the rather startling figure of 14,000 yearly cases of serious GI complications, based on the over 70 million NSAID prescriptions filled in 1991.⁶ Such complications have led to the continued search for "safer" agents such as the cyclooxygenase-2(COX-2) inhibitors that have been introduced in recent years.

Considering that athletic trainers cannot prescribe or dispense prescription or OTC medications, why is this an important topic?¹⁰¹ If the athletic trainer understands the actions, indications, and side effects of corticosteroid and NSAID use, he or she can continue to play a pivotal role in all aspects of an athlete's treatment and rehabilitation plan. A thorough understanding of drug actions, interactions, and effects also enables the athletic trainer to educate athletes about the treatment plan and any symptoms resulting from anti-inflammatory drug therapy.

In the high school and college setting, athletic trainers may be particularly influential regarding the use of OTC NSAIDs by young athletes. A recent study of high school football players revealed that 75 percent of those surveyed had used NSAIDs in the previous 3 months and 15 percent of the respondents were daily NSAID users.⁹⁷ The daily users often used the drugs prophylactically before practices and games.

There are two basic injury categories seen in sports. Macrotrauma results from a single, high-force traumatic event. Examples include compound and comminuted fractures, joint dislocations, and tendon ruptures. Microtrauma is the result of chronic, repetitive stresses to local tissues (most often tendons). Often classified as overuse injuries, microtraumas typically involve repetitive activities such as throwing, swimming, or distance running. A variety of intrinsic and extrinsic factors contribute to the initial insult and may perpetuate the subsequent inflammatory response (Box 3–1).

Inflammation is the response of vascular tissue to physiological damage and can be divided into three components: acute inflammation, the immune response, and chronic inflammation (Fig. 3–1). The acute inflammatory cascade is set into motion by the initial tissue insult. Grossly, acute inflammation is recognized by the classic and familiar signs of pain (dolor), heat (calor), erythema (rubor), swelling (tumor), and loss of function (functio laesa).

Inflammation signals the initiation of the healing process and is one facet of the three phases of human tissue response, which include (1) the acute vascular inflammatory phase, (2) the repair-regeneration phase, and (3) the maturation phase.⁶⁰ Typically, within 48 hours of the initial trauma, fibroblasts begin the process of wound repair and collagen synthesis. The response prevents the extensive spread of injury-causing agents to nearby tissues, disposes of cellular debris, and sets the stage for the repair process.

Cellular injury signals the release of chemical mediators, such as histamine, serotonin, anaphylatoxins, bradykinin, thromboxane, leukotrienes, and prostaglandins, after a short period of vasoconstriction. These chemical mediators increase cellular and capillary permeability and stimulate capillary vasodilation and blood flow. The changes in vascular permeability directly result in edema, caused by the flow of proteins and fluid into the interstitial space. There is also activation of the immune system and humoral response mechanisms. The increased blood flow and vessel permeability allow neutrophils to migrate to the site of injury. Once the leukocytes arrive at the site of inflammation, evidence suggests that they are drawn to "adhesion factors" on the walls of certain vessels and cells. The expression of such adhesion factors increases at times of inflammation and allows the leukocytes to target specific areas.

Activation of neutrophils at the injury site by lysosomal enzymes results in the generation of high concentrations of oxygen free radicals.⁸⁹ These free radicals are quite unstable and extremely reactive, attacking the phospholipid structure of cell membranes and resulting in the formation of arachidonic acid metabolites. Once this process is set in place, chemotactic factors are produced, resulting in further migration and activation of leukocytes and potentiating the inflammatory response. It is this continued potentiation that likely plays a role in the development of chronic inflammation.

Chronic inflammation is usually the product of either vascular disruption (in acute injuries) or intermittent tissue hypoxia (Fig. 3–2).⁵⁹ Theoretically, such tissue hypoxia might result from the typical cyclic loading of athletic activity and stimulate the release of oxygen free radicals.⁵⁷ Leadbetter terms this "sports-induced inflammation" and defines it as "a localized tissue response, initiated by injury or disruption of vascularized tissues exposed to excessive mechanical load or use."⁶⁰ Sports-induced inflammation may resolve spontaneously or become a significant limitation to activity. The factors that contribute to its evolution into a chronic injury are poorly understood, but may involve the continued release of local chemotactic factors and a "failed healing response," which leads to the formation of granulation tissue or tissue degeneration.⁵⁸

Two other important substances in the inflammatory process are tumor necrosis factor (TNF) and interleukin-1 (IL-1). Produced predominantly by mononuclear cells and macrophages, they are potent contributors to inflammation and are the principal mediators of the immune response to endotoxins produced by bacterial infections. When released because of musculoskeletal injury, they activate and mobilize leukocytes, increase the expression of adhesion molecules, and induce production of the enzymes cyclooxygenase and lipoxygenase, which catalyze the creation of prostaglandins and leukotrienes. Also, TNF and IL-1 likely contribute to the fibrosis and tissue degeneration of chronic inflammation.

There is accumulating evidence that the immune system plays a role in both the acute and chronic inflammatory responses.⁵⁹ The immune system is activated when the inflammatory response liberates antigenic substances.³⁰ These antigenic substances are recognized as foreign tissue by the immune system and eliminated. A complete discussion of the immune response is beyond the scope of this review; however, the immune response certainly results in further amplification and potential propagation of the inflammatory response.

By definition, the inflammatory response is essential to the resolution of the injury. Even so, excessive edema coupled with vascular damage can disrupt the flow of oxygen to the healthy tissue surrounding the injury site. The resultant hypoxia can lead to further tissue damage, appropriately referred to as secondary hypoxic injury.⁵³ The following discussion will shed light on the specific roles played by various chemical mediators in the inflammatory response and how anti-inflammatory medications may affect that process.

Eicosanoids

As noted earlier, the prostaglandins, thromboxane, and the leukotrienes all play a role in the inflammatory response. They are members of the eicosanoid family, derivatives of the 20-carbon fatty acid molecule arachidonic acid (Fig. 3–3). Arachidonic acid is a component of cell membranes and must be released from the membrane before it is synthesized into an eicosanoid. Once freed from the membrane, arachidonic acid can be converted through an enzymatic process to either a leukotriene or a common prostaglandin precursor. That precursor may then be converted to thromboxane or to one of a variety of prostaglandins (Box 3–2).

Leukotrienes

Leukotrienes are synthesized from arachidonic acid by the action of the enzyme lipoxygenase. The leukotrienes consist of a family of chemicals that function to mediate chemotaxis, increase vascular permeability, and activate leukocytes.³³ Several different lipoxygenase enzymes have been discovered; however, 5-lipoxygenase appears to have the most clinical relevance as it catalyzes the production of leukotriene B4 (LTB4), leukotriene C4 (LTC4), leukotriene D4 (LTD4), and leukotriene E4 (LTE4). LTB4 is a potent chemoattractant for leukocytes and promotes the migration of neutrophils into the extravascular space.⁶⁸ LTC4, LTD4, and LTE4 make up the slow-reacting substances of anaphylaxis (SRS-A), which induce smooth-muscle constriction, particularly in bronchial tissue.

Early attempts at producing pharmacologic agents that block leukotriene production proved too nonspecific or toxic for therapeutic use.³³ The past decade has seen great strides in the development of safe and effective leukotriene inhibitors. Zileuton (Zyflo) acts as a direct 5-lipoxygenase inhibitor; zafirlukast (Accolate) and montelukast (Singulair) are leukotriene-receptor inhibitors. These drugs are indicated for the treatment of asthma and currently have no role as systemic anti-inflammatory medications.

Prostaglandins

The enzyme cyclooxygenase is responsible for the biosynthesis of arachidonic acid to prostaglandin H (PGH). From that point, PGH can be converted into numerous different prostaglandins, which are responsible for a variety of actions in almost every tissue of the body, playing various roles in a multitude of physiological processes. Thromboxane is also a product of PGH through the action of the enzyme thromboxane synthase. The relevant actions of these chemicals are examined in the following discussion.

A thorough review of the actions of the prostaglandins can be quite confusing because there are numerous subsets, many of which have antagonistic actions. These natural substances serve as a good reminder of the delicate balance in which the human body functions. As discussed later in this chapter, this delicate balance can be greatly affected by the administration of medications that block the production of these substances. The following discussion is focused on the important physiological properties of prostaglandins in the context of NSAID and corticosteroid use.

Mediation of Inflammatory Process

The term "mediation" is important in describing the inflammatory activities of prostaglandins. By themselves, prostaglandins do not appear to be capable of increasing vascular permeability, but prostaglandin E₂ (PGE₂) and prostaglandin I₂ (PGI₂) may increase edema and leukocyte migration through local capillary vasodilation. In addition, prostaglandins act synergistically with bradykinin and other autacoids to sensitize pain receptors to mechanical and chemical stimulation. Interestingly, PGE also exerts an anti-inflammatory effect by inhibiting the release of hydrolases and lysosomal enzymes from neutrophils.

Fever Mediation

Body temperature set point is regulated by the hypothalamus and can be influenced by a variety of conditions, including fever, inflammation, malignancy, and exercise. Prostaglandins have been implicated in the role of fever mediation. Cytokines increase the synthesis of PGE₂, which, through increases in cyclic adenosine monophosphate, triggers the hypothalamus to elevate body temperature. Supportive evidence for this action is found in animal studies, which have shown that injection of specific prostaglandins into the cerebral ventricles causes an increase in body temperature.⁸⁴

Gastric Protection

Prostaglandins interact in a number of ways to protect the delicate lining of the gastrointestinal system. PGE and PGI inhibit gastric acid secretion and may have an anti-ulcer effect. Prostaglandins also appear to have the property of cytoprotection, defined as the ability to protect the gastric mucosa from exposure to harmful substances. This cytoprotection likely results when PGE stimulates gastric mucus formation. The PGE₁ analog misoprostol (Cytotec) suppresses gastric acid secretion and has been found to be effective in the prophylaxis of gastric ulcers in patients on NSAID regimens.⁶⁸ Arthrotec is a formulation of misoprostol (200 μg) combined with the NSAID diclofenac sodium (50 mg and 75 mg).

Reproductive System

In the uterus, prostaglandins act to stimulate the contraction of the smooth muscle layer, known as the myometrium. This smooth muscle contraction serves two important purposes. During childbirth, prostaglandin-stimulated contractions of the myometrium aid in propelling the baby through the birth canal. They are also released at the end of the menstrual cycle to facilitate the shedding of the uterine lining through the stimulation of muscular contractions. These continuous contractions can result in ischemic pain, referred to as dysmenorrhea. Prostaglandins are also employed in "ripening" the cervix for the induction of delivery at term and as abortifacients that act to expel the fetus from the uterus for elective termination of pregnancy.

Renal Blood Flow

During exercise, the autonomic nervous system releases chemicals into the bloodstream that act as potent vasoconstrictors in many peripheral tissues, including the kidneys. Prostaglandins serve to dilate renal blood vessels, counteracting those chemicals and thus maintaining a constant flow of blood to the kidneys.⁷² Through alterations in renal blood flow and direct effects on the renal tubules, prostaglandins also influence salt and water excretion. Prostaglandins likely also affect the release of renin, a substance released from the renal cortex in response to hypotension. The renal effects of the prostaglandins appear to be more significant in patients whose kidneys are functioning abnormally.⁵¹

Hemostasis

A specific prostaglandin, prostacyclin, is released by the internal lining of the blood vessels. This substance appears to inhibit the aggregation of platelets on blood vessel walls. Thromboxane, produced in platelets, functions as a powerful inducer of platelet aggregation to aid in the clotting mechanism.³³ Therefore, thromboxane and prostacyclin have an antagonistic relationship. This is a good example of how prostaglandins naturally attenuate the actions of other chemicals in a variety of tissues.

Pulmonary Effects

The smooth muscles of the bronchial tree are quite reactive to prostaglandins and leukotrienes. PGF and PGD₂ contract bronchial smooth muscle, whereas PGE causes it to relax. LTC4 and LTD4 are potent bronchoconstrictors and also stimulate mucus secretion and edema in the bronchi. These inflammatory effects are best illustrated by the pathogenesis of bronchial asthma.

Ever since the bark of willow trees was boiled to cure ague (fever) centuries ago, the power of anti-inflammatory medications has been appreciated. However, that power has long included a variety of adverse effects, with GI toxicity chief among them. From the creation of phenylbutazone in that late 1940s, through the synthesis of indomethacin in the 1960s, to the recent introduction of the selective COX-2 inhibitors, the goal has been to improve efficacy while limiting toxicity.

In the latter half of the 20th century, chemists used aspirin as a prototype to develop the group of drugs now known as NSAIDs. The main goal of this research was to produce agents that do not present aspirin's sometimes severe adverse effects, yet maintain its potent anti-inflammatory properties. Although there are differences in potency, specificity, and specific mechanisms of action, all NSAIDs inhibit the activity of cyclooxygenase in some manner.³⁰ This inhibition is not an irreversible reaction like that caused by aspirin, but is instead dependent on drug concentration.⁷⁴

Along with blocking cyclooxygenase, NSAIDs are thought to have additional properties, including modulation of T-cell function, inhibition of inflammatory cell chemotaxis, lysosomal membrane stabilization, and free radical scavenging.^5,74 Although some NSAIDs offer theoretical pharmacologic advantages, no single agent appears to be superior to another in diseases such as rheumatoid arthritis or osteoarthritis.^37,94,98 However, efficacy can vary greatly among individuals. Therefore, if an individual does not respond to a specific NSAID within 1 to 2 weeks of initiating therapy, another agent should be started. Nonresponsiveness to one particular NSAID does not preclude response to another agent within the same class.

Aspirin

Aspirin (acetylsalicylic acid) is a derivative of salicylic acid. Salicylic acid, in turn, is created from salicin, a substance found in the bark of willow trees. Both the medicinal benefits and adverse effects of willow bark have been known for more than 2000 years. Aspirin was first synthesized by a Bayer Company chemist in the late 19th century. It proved to be far less of a gastric irritant than salicylic acid and was introduced to the marketplace in the spring of 1899. Heralded as a wonder drug, it quickly became one of the most widely used pharmaceutical products in the world. Aspirin use has declined in recent years since the introduction of a number of newer anti-inflammatory agents. However, aspirin remains the standard against which these new medications are judged.

Surprisingly, aspirin's mechanism of action has only been known since 1971, when John Vane discovered that the aspirin molecule transfers a functional group onto the cyclooxygenase enzyme.⁹⁶ As a result, the enzyme is irreversibly inhibited and is unable to bind arachidonic acid. The enzyme can no longer convert arachidonic acid to prostaglandins and thromboxane. The leukotriene pathway, however, is unaffected.

Effects of Aspirin

After the ingestion of aspirin, typically 3000 to 6000 mg per day for anti-inflammatory action, a series of chemical events results from the blockage of cyclooxygenase. The decrease in prostaglandin production leads to a corresponding reduction in inflammation and edema. The inhibition of prostaglandin and thromboxane synthesis may not be the only effect that aspirin has on the tissues. In some systems aspirin may impinge on the formation of 12-HETE, a leukotriene derivative that acts as a chemotactic agent. Aspirin may also reduce inflammation and pain through its influence on the migration of chemical potentiators such as neutrophils and monocytes.⁵¹

Aspirin use may also produce negative consequences. In the gastrointestinal tract, aspirin can cause gastric upset, bleeding, and even ulcers. Various studies have shown an incidence of these symptoms in anywhere from 2 to 40 percent of patients, depending on the parameters of the investigation.⁵¹ It does not appear that these gastrointestinal side effects are caused by the inhibition of prostaglandin synthesis alone, although this area is not without controversy.^51,74

The mechanism of gastric irritation appears related to the direct effect of aspirin on the lining of the stomach.⁶¹ Unbuffered aspirin lowers the electrical potential of the gastric membrane, which then affects the flow of hydrogen ions. Davenport's theory contends that this disruption of hydrogen ions triggers a series of events that leads to gastric erosion and bleeding.⁵¹ Studies have shown that enteric-coated aspirin does not cause as many abnormalities in the stomach lining because of its buffering action.⁵¹ Mild gastrointestinal upset can often be avoided if aspirin is taken with a meal because of the "buffering" action of the food.

Aspirin use may also result in complications such as prolonged bleeding time and tinnitus. Prolonged bleeding time results from the inhibition of thromboxane. Because aspirin irreversibly binds to cyclooxygenase, the decreased platelet function lasts from 4 to 6 days (the platelet life span) after aspirin intake.⁷⁴ In addition, many people taking high doses of aspirin develop a ringing in their ears. This condition, referred to as tinnitus, is probably caused by an effect on the inner ear rather than the central nervous system (CNS), and may be an indication of aspirin toxicity.

Because of the high incidence of GI and other adverse effects and the availability of safer, efficacious OTC medications such as acetaminophen, ibuprofen, and naproxen, aspirin use continues to diminish. Although it is certainly not as "trendy" as modern alternatives, in those who tolerate it, aspirin remains a potent and effective anti-inflammatory and analgesic agent.

Reye's Syndrome

First described in 1963, Reye's syndrome is a rare and potentially devastating acute illness that usually strikes children after a viral infection. For several years, epidemiological data suggested a relationship between Reye's syndrome and aspirin use by children infected with either the influenza or chickenpox virus. Despite the lack of firm scientific evidence, for more than 20 years medical professionals have warned against using aspirin in children with probable viral illnesses. Thus, we have seen a great rise in the use of ibuprofen and acetaminophen as antipyretics.

The incidence of Reye's syndrome has diminished dramatically over the past decades, although it has been suggested that this decline began before the decrease in the use of aspirin.³⁰ Although no definitive cause-and-effect relationship has been established, it appears prudent to disallow the use of aspirin and other salicylates by anyone under 18 years old who may have a viral infection.

Although the cause of Reye's syndrome is unknown, it is known that the illness impairs mitochondrial function, resulting in liver and neurological damage.⁹⁹ In 1974, Lovejoy et al. proposed a five-stage system on which to chart the symptoms of Reye's syndrome (Table 3–1). Reye's syndrome is a potentially fatal condition and the symptoms must be treated as a medical emergency; however, a diagnosis can be made only through various laboratory tests.

Aspirin-Sensitive Asthma

An unusual complication of aspirin use, aspirin-sensitive asthma may be associated with the development of vasomotor rhinitis and nasal polyps. On exposure to even small quantities of aspirin, affected people may develop nasal congestion and acute, often severe bronchospasm. The prevalence of this disorder is unknown. There is an almost universal cross-reactivity with other NSAIDs, particularly ibuprofen, indomethacin, fenoprofen, naproxen, and mefenamic acid. As yet there are no reports of sensitivity to the selective COX-2 inhibitors. The mechanism for this reaction has not been elucidated, but it may be related to the preferential shunting of arachidonic acid into the lipoxygenase pathway, resulting in the production of bronchoconstricting leukotrienes. Patients can be desensitized over time with daily administration of aspirin. Cross-tolerance to other NSAIDs usually occurs as well.

Acetaminophen

Although not an anti-inflammatory agent, acetaminophen (Tylenol) is an important drug and deserves our attention because of its clinical usefulness. Discovered in 1877, it has analgesic and antipyretic properties through its actions on the CNS. Acetaminophen has no anti-inflammatory properties because it cannot inhibit cyclooxygenase in the peripheral tissues.⁷⁷ As a result, it also does not present complications such as gastrointestinal disturbance or prolonged bleeding time. Therefore acetaminophen is indicated for mild pain and fever in people for whom aspirin is contraindicated because of Reye's syndrome risk (see previous text) or who cannot tolerate aspirin or NSAIDs. The usual dosage of acetaminophen is 325 to 650 mg at 4-hour intervals.

Acetaminophen can be toxic if abused. The minimum toxic dose in adults is 5 to 15 g.²⁸ Overdoses or prolonged overuse (5–8 g per day for several days) may result in severe hepatic damage or death.⁵ The liver damage appears to be produced by a metabolite of acetaminophen. In therapeutic therapeutic doses, the toxic metabolite is detoxified by glutathione; however, with extreme intake, if the glutathione drops below 30 percent of normal values, tissue necrosis occurs.²⁸

COX-2 Inhibitors

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.

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).

Topical NSAIDs

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.

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.

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.

Indomethacin (Indocin)

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.

Phenylbutazone

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

Nabumetone (Relafen)

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.

Rofecoxib (Vioxx)

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.

Ketorolac (Toradol)

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

NSAID Indications

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.

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.

Adverse Effects

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

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.

Drug Interactions

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.

History

In 1849, Addison first described the importance of the adrenal glands, detailing fatal outcomes in patients with adrenal destruction. Over the next century, Brown-Sequard, Cushing, and others further elucidated the importance of the adrenal glands, their products, and their interactions with the pituitary gland and hypothalamus. With the synthesis of cortisone (compound E) in the late 1940s, the stage was set for the use of corticosteroids as therapeutic agents. Hench and colleagues showed dramatic effects in the treatment of rheumatoid arthritis in 1949.³⁸

The practice of injecting anti-inflammatory medications directly into inflamed joints began in 1951 when hydrocortisone acetate crystal suspension became available for trials.⁵⁷ In the early 1950s Hollander^44–46 reported in multiple publications his experience of nearly 8000 intra-articular injections. Over the past 50 years the use of many synthetic analogs of adrenal corticosteroids has become essential. However, the role for corticosteroids in the treatment of sports-related musculoskeletal injuries remains unclear.

Physiology of Adrenal Corticosteroids

The adrenal glands lie above the kidneys in the retroperitoneum and are essential to the normal function of the human body. The production of adrenal corticosteroids is influenced by the pituitary gland and the hypothalamus. Many of these hormones are released cyclically throughout the day, and times of emotional or physical stress may trigger increased production and release. Each gland consists of two areas: the medulla and the cortex. Epinephrine (adrenaline) and norepinephrine are the main products of the medulla. The cortex is further subdivided into three zones, each producing distinct steroidal hormones. Mineralocorticoids are produced in the zona glomerulosa. Their primary function is to maintain the proper balance of electrolytes (chiefly sodium) in the body. The zona reticularis is the site of androgen production. Androgens are the precursors of male and female sex hormones and the analogs of anabolic steroids.

Glucocorticoids are products of the zona fasciculata and have a multiplicity of actions, because receptor proteins for these hormones are found throughout the body. Although glucocorticoids influence glucose concentration, protein metabolism, epinephrine release, gastric acid secretion, and kidney function, among other actions, our discussion centers on their anti-inflammatory actions. The exact mechanisms are not completely understood, but the anti-inflammatory effects of glucocorticoids are thought to result from a variety of intracellular actions (Box 3–6).

Phospholipase is directly inhibited, limiting the availability of inflammatory substrates for both the cyclooxygenase and lipoxygenase enzyme pathways. Evidence also supports the hypothesis that glucocorticosteroids regulate the expression of the COX-2 isoenzyme, thus limiting the production of prostaglandins at two distinct steps in the pathway. Many studies have shown that glucocorticosteroids greatly inhibit the migration of white blood cells to areas of injury, thus greatly limiting the migration of other proinflammatory substances to the area. The expression of cytokines such as IL-1 and TNF is also greatly limited. Finally, the enhanced stabilization of cell membranes diminishes capillary permeability and prevents the release of lysosomal enzymes. This effect includes the stabilization of neutrophil membranes, inhibiting their release of inflammatory mediators.

In an animal study by Beiner et al., the potent anti-inflammatory actions of glucocorticosteroids and their subsequent effects on healing were confirmed. They found that, when used to treat muscle contusions, glucocorticosteroids induced an early, transient recovery of the force-generating capacity of the affected muscle. However, long-term findings revealed irreversible damage to the healing muscle, including atrophy and diminished force-generating capacity. It is speculated that such damage results from the initial inhibition of a typical inflammatory response to injury. The attenuated inflammatory response was confirmed by a relative paucity of inflammatory cells seen in the tissue. This study underscores the importance of the inflammatory response in tissue healing.¹⁰

Current Use of Corticosteroids in Sports Medicine

Despite a half-century of use, the efficacy of corticosteroids in the treatment of acute and chronic musculoskeletal injuries is not truly known. In their 1998 review article, Stanley and Weaver state that "inconsistency in the studies on glucocorticosteroid use does not lend adequate support or direction to the sports medicine clinician in their use."⁸⁹ A more accurate observation could not have been made. A review of the available literature on corticosteroid use certainly leaves one a bit confused regarding their overall role in the treatment of sports injuries.

Why is there not a better body of literature to give us better insight into the use of these powerful medicines? There are actually several reasons for the lack of good, consistent data. There is no reproducible animal model for "overuse" musculoskeletal injuries. In most animal studies that have been conducted, the animals were relatively healthy. Even if good animal models existed, the application of these results to humans would not always be appropriate. Also, in human subjects, an exact diagnosis is not always possible. The degree to which bursitis, tendonitis, and tenosynovitis each contribute to pain in a certain area may be difficult to quantify without radiographic imaging or tissue diagnosis, thus making it difficult to determine which condition is actually being treated.

Much of the early successful experience with corticosteroids was in the treatment of rheumatoid arthritis. This success led to their use in a variety of other inflammatory conditions, as well as musculoskeletal injuries and osteoarthritis. These medications can be delivered to the desired tissue in a variety of ways. The oral administration of corticosteroids has been used to treat numerous systemic illnesses, such as asthma and juvenile rheumatoid arthritis. Although this route is effective at attenuating the inflammatory process, it also raises the risk of complications, which may include GI bleeding, fluid retention, adrenal insufficiency, and behavioral changes.⁸²

If a more direct route to the needed site of action exists, this is preferable because it avoids the more potent adverse effects. Thus, the development of inhaled anti-inflammatory medications in the treatment of asthma has been a major advance. Orally administered corticosteroids currently have no clinically proven role in the treatment of acute or chronic musculoskeletal injuries. Phonophoresis and iontophoresis are two novel approaches to the administration of anti-inflammatory medication. These involve the use of therapeutic ultrasound or electrical current, respectively, in an attempt to "drive" the medication into the underlying inflamed tissues. Although these modalities are often used by athletic trainers and physical therapists, there is a paucity of scientific evidence to validate them, and studies have failed to show greater delivery of medication to the target tissue than that found with topical application alone.⁹¹ Therefore the preferred method of delivery for corticosteroids is injection at the site of inflammation. Although this method limits systemic adverse effects, it is not without risk, as will be discussed in the following paragraphs.

The conflict between the lack of proven scientific efficacy of corticosteroids and their use in clinical practice can be no better illustrated than in the results of studies by LaBelle et al. and Hill et al. Since 1966, 185 articles have been published on the management of lateral epicondylitis ("tennis elbow"). LaBelle et al. carried out a meta-analysis of all of these articles and found that only 18 were randomized and controlled studies. None of these 18 studies met criteria for acceptance as a "valid clinical trial." Therefore the authors concluded that the evidence was insufficient to support the use of corticosteroid injection or NSAIDs for lateral epicondylitis treatment.⁵⁵ Three years before the publication of La Belle's findings, Hill (1989) and colleagues surveyed orthopedic surgeons regarding their use of corticosteroid injections. They found that 93 percent of those surveyed would inject a painful elbow epicondyle.⁴² Their findings underscore the fact that the use of corticosteroids in sports medicine practice is likely to depend more on personal experience, anecdotal reports, and local practice preferences than on scientific data.

An extensive review of the available literature is beyond the scope of this discussion; however, there are a handful of significant studies that may be used to guide the judicious use of these powerful medications. The primary indication for their use is a chronic inflammatory condition, such as that seen with bursitis and tendonitis (Box 3–7). The goal of the therapy, just as with NSAIDs, is to break the cycle of inflammation and allow proper healing. There is no indication for the use of corticosteroids in the treatment of acute injuries because some degree of inflammatory response is mandatory for tissue healing. Additionally, not all inflammatory tendonopathies are appropriately treated with corticosteroids. For example, injections in and around the Achilles and patellar tendons should be avoided.⁵⁹

In reviewing the literature regarding the use of corticosteroids, one may conclude that evidence, albeit anecdotal in many cases, does support the use of these medications in certain conditions. Many studies support the efficacy of corticosteroid injections in the treatment of stenosing tenovaginitis, trigger finger, and de Quervain's tenosynovitis.^4,35,37 Chronic olecranal bursitis was found to have a more rapid resolution with corticosteroid injection, but side effects included skin atrophy, infection, and chronic pain and were thought to outweigh the benefits of injection in a typically self-limiting condition.¹⁰⁰ An additional study found significantly less swelling at 1 week in injected patients.⁸⁸ Interestingly, these results have not been duplicated in treating prepatellar bursitis, in which injection therapy has resulted in frequent surgical removal and infection.⁷⁰ Corticosteroids are not indicated for the treatment of acute traumatic bursitis⁷⁰ and one may speculate that this is the explanation for the lack of efficacy for steroid injection in prepatellar bursitis.

Plantar fasciitis is also commonly treated with corticosteroid injection. Crawford et al. reported in 1999 that a group treated with corticosteroids showed improvement at one month, but no difference at 3 or 6 months after injection.²¹ Although steroid injection has been recommended for a variety of running maladies, including greater trochanteric bursitis, iliotibial band friction syndrome, and retrocalcaneal bursitis, as well as plantar fasciitis,¹⁶ upper extremity conditions are more commonly treated. Elbow epicondylitis, shoulder bursitis, and various tendon maladies of the hands are among the more frequent injuries treated by corticosteroid injection.⁵⁹

Among the reasons for the lack of good scientific evidence demonstrating the efficacy of steroid injections is the variety of regimens regarding the specifics of treatment. Apart from the actual injection site (and that may vary depending on the technique and the skill of the physician), multiple confounding variables may exist. Foremost among these is the proper diagnosis. The number of previous injections, the agent and dosage injected, and the postinjection rehabilitation are also variables.

Most authorities recommend a minimum of 2 weeks between injections and a maximum of 3 injections per site.^59,89 As has been the familiar refrain throughout this section, there are no controlled studies to validate these practices. Pettrone urged that injections be used sparingly because of the risk of collagen breakdown in athletes. Typically, a "relative rest" period of 10 to 14 days after the injection of a corticosteroid is prescribed.⁷⁵ This recommendation, in and of itself, raises questions. First, in the treatment of any overuse injury, any period of rest is beneficial to the condition and thus clouds the efficacy of the steroid itself. Second, few athletes are willing, or able, to take 2 weeks off from training or sports participation. The selection bias for steroid treatment singles out those who are more seriously injured, or who have exhausted all other nonsurgical options.

The agent and dosage are subject to the greatest variation among those who perform corticosteroid injections. The most important characteristics of a corticosteroid are its solubility and its duration of action.⁵⁹ A soluble, short-acting agent, such as betamethasone sodium phosphate (Celestone) is preferred for paratenonous injections. Intra-articular and bursal injections are appropriate for a less soluble, longer-acting drug such as triamcinolone diacetate. Little guidance is given in the literature regarding drug doses. An additional consideration is the avoidance of corticosteroid preparations that contain additives.^59,89 One additive, phenol, can be caustic to soft tissues and another, sodium bisulfate, has been implicated in anaphylactic reactions in sensitive patients.⁵⁹

Another common type of additive to corticosteroid injections is an anesthetic agent such as lidocaine. This combination of agents is both diagnostic and therapeutic. If effective, the so called "pain ablation test" assures the physician both that the diagnosis was correct and that the medication was delivered to the proper tissue. The patient is also reassured by immediate relief and encouraged that the appropriate therapy has been initiated.

Despite the lack of convincing scientific data, corticosteroids remain popular in the treatment of many chronic inflammatory conditions encountered by the sports medicine clinician. These agents are obviously effective in some conditions because anecdotal evidence keeps their use alive. Although they are probably not as widely used as they have been in the past, they do have a role in the treatment of a few specific conditions. The future should see more controlled, double-blind studies further assessing the role of corticosteroids. At this time, they must be used cautiously and only after more conservative treatment regimens (e.g., ice, activity modification, NSAIDs) have failed. The athlete should be fully aware of the risks and benefits of the treatment and of other treatment options.

Adverse Effects

Historically, the most feared complication of corticosteroid injection has been tendon rupture. Although there are no controlled studies regarding tendon rupture after corticosteroid injection, numerous anecdotal and case reports exist.^50,52 Such reports have led many experts to suggest avoiding direct tendon injection, as well as avoiding injection around the Achilles, patellar, or biceps tendons.⁵⁹

Although tendon rupture is the most devastating adverse consequence of corticosteroid injection, it was found to be the third most common complication encountered by practicing orthopedists. Bruno and Clark surveyed 52 orthopedic surgeons and found fat necrosis and skin depigmentation to be the most commonly encountered complications.¹⁸ Another survey found similar results, along with infection, peripheral nerve damage, and systemic reactions (vasovagal syncope and transient hypoglycemia).¹⁸ A wide range of potential local and systemic consequences of local corticosteroid injection are listed in Box 3–8.

There are multiple anecdotal reports regarding joint destruction after multiple intra-articular corticosteroid injections. Intra-articular injections are often used in both rheumatoid arthritis and osteoarthritis. Although they are often used for symptomatic pain relief in osteoarthritis, a systematic review failed to find any long-term benefit from steroid injections. Some short-term (1 to 2 weeks in duration) benefit was demonstrated.⁹³ Some animal models suggest that corticosteroids may have a detrimental effect on cartilage, but there is no pathological evidence in humans to support a diagnosis of steroid-induced arthropathy.

1. What is the role of eicosanoids in inflammation?

2. Arachidonic acid in the body is converted to which substance(s)?

3. What actions are prostaglandins responsible for in the various tissues of the body?

4. Which syndrome is attributed to a combination of aspirin and viral infection in children and young adults?

5. Acetaminophen produces what effects in the body?

6. What is the goal of the COX-2 inhibitors used in the inflammatory process?

7. Aspirin was derived from what product?

8. What is the most frequently reported complication of NSAIDs therapy?

9. The COX -2 inhibitors are targeted at which of the following?

   1. Central nervous system/neurotransmitters

   2. Blood-brain barrier

   3. Inflammation from arthritis

   4. Muscle spasms

10. With the recent advent of the use of over-the-counter NSAIDs for anti-inflammatory reasons, it is apparent that:

    1. They are superior to aspirin in their action within the body.

    2. There is no evidence that they are any better than aspirin in gaining a therapeutic effect on the system.

    3. There is a high incidence of abuse with these drugs.

    4. Acetaminophen is as good an anti-inflammatory without the side effects.