Chapter 3 Anti-inflammatory Medications

NSAIDs
The use of NSAIDs for the treatment of sports-related injuries, as well as other maladies, (namely osteoarthritis) continues to rise. In 2001, sales of NSAID prescriptions accounted for $10.9 billion in the United States.
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NSAIDs (cont.)
A thorough understanding of drug actions, interactions, and effects allows the athletic trainer to educate athletes on treatment plans and symptoms resulting from NSAIDs

NSAIDs (cont.)
A recent study of high school football players revealed that 75% of those surveyed had used NSAIDs in the previous 3 months and 15% of the respondents were daily NSAID users. The daily users often used the drugs prophylactically prior to practices and games.
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The Inflammatory Response

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).
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Figure 3-1: The Inflammatory Response

Inflammatory Response (cont.)

Following a short period of vasoconstriction - cellular injury signals the release of chemical mediators, such as histamine, serotonin, anaphylatoxins, bradykinin, thromboxane, leukotrienes, and prostaglandins.

Box 3-2 page 36

Major actions of the Eicosanoids
Prostaglandins Thromboxane Leukotrienes

Anti-inflammatory Medications
Aspirin (acetylsalicylic acid) - a derivative of salicylic acid.
Salicylic acid, in turn, was created from salicin, which is found in the bark of willow trees. 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 9 marketplace in the spring of 1899.

 In 1971, Sir John Vane discovered that the aspirin molecule transfers a functional group onto the cyclooxygenase enzyme. Until this time the actual mechanism of action for aspirin was unknown.

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Cyclooxygenase Enzyme (COX)

This enzyme is irreversibly inhibited and unable to bind arachidonic acid, therefore, the enzyme can no longer convert arachidonic acid to prostaglandins and thromboxane. The Leukotriene pathway, however, is unaffected
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Effects of Aspirin
Analgesic Antipyretic Anticoagulant Anti-inflammatory

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Effects of Aspirin
3000 6000 mg per day for antiinflammatory action; a series of chemical events results from the blockage of cyclooxygenase
325 mg aspirin = 12 to 18 aspirin per day to reach an anti-inflammatory effect
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Effects of Aspirin
The decrease in prostaglandin production leads to a corresponding reduction in inflammation and edema.

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Effects of Aspirin
Blocks prostaglandin production, even the cytoprotection. In the GI tract, aspirin can cause gastric upset, bleeding, and even ulcers.
Various studies have shown GI disturbance incidence of anywhere from 2 percent to 40 percent.

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Effects of Aspirin
The mechanism of gastric irritation appears related to the direct effect of aspirin upon the lining of the stomach.
Mild gastrointestinal upset can often be avoided if aspirin is taken with a meal, due to the "buffering" action of the food.
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Effects of Aspirin
Aspirin use may also result in complications, such as prolonged bleeding and tinnitus.
Decreased platelet function lasts from 4 to 6 days (used for blood thinning in heart patients). Tinnitus may be an indication of aspirin toxicity.
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Reyes Syndrome
Reyes syndrome is a rare and potentially devastating, acute illness that usually strikes children following a viral infection when they are given aspirin to lower fever. This syndrome is now suspected in teens and young adults with viral infections who take aspirin.
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Table 3-1: The Five Clinical Stages of Reyes Syndrome

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Aspirin Sensitive Asthma

Upon exposure to even small quantities of aspirin, those affected may develop nasal congestion and acute, often severe bronchospasm. There is an almost universal crossreactivity with other NSAIDs. Patients can be desensitized over time with daily administration of aspirin and cross-tolerance to other NSAIDs usually occurs.
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Acetaminophen
Acetaminophen (Tylenol) is not an antiinflammatory agent, it has antipyretic and analgesic properties. Will be discussed with the analgesics (Chapter 10).

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NSAIDs
COX-2 Inhibitors
Primarily induced at sites of inflammation COX-2 inhibitor could block the production of proinflammatory prostaglandins without interfering with gastric protection or platelet activity Research is controversial and the drugs are expensive
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Overview of Selected NSAIDs

Box 3-4 Page 42 Factors to Consider in Choosing an NSAID
Age of Patient Duration of Treatment Time of Onset Compliance Other Medications General Health of Patient Cost of Treatment
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Ibuprofen
Advil, Motrin, Nuprin Most frequently used NSAID Introduced to the OTC market in 1985, it is available in 200 to 800 mg tablets by prescription, and 200 mg tablets OTC Frequently used as an antipyretic in adults and children, as its longer duration of action makes it a popular alternative to acetaminophen
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Ibuprofen
Peak plasma levels are achieved within 15 to 30 minutes of ingestion Rapid onset of action can be quite beneficial for quick relief of pain Half-life of about 2 hours, it must be taken every 6 to 8 hours to maintain effect An anti-inflammatory regimen requires 2400 3200 mg daily

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Ibuprofen
Taken in three separate doses, allowing it to be taken at meal times, lessening the likelihood of gastric irritation. Sufficient analgesia should be achieved by daily dosages of less than 2400 mg per day. Approximately 10 percent to 15 percent of individuals must discontinue use secondary to gastrointestinal symptoms.
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Naproxen
Naprosyn, Aleve. Chemically similar to ibuprofen. Naproxen is available as the OTC preparation Aleve, and as Anaprox by prescription. Due to naproxen's long half-life (approximately 12 hours), the daily recommended dosage of 750 1000 mg can be taken on a twice daily schedule, reducing gastric upset due to only two exposures and improving compliance.
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Naproxen
Peak plasma levels are achieved within 2 to 4 hours Incidence of upper gastrointestinal bleeding in OTC use is double that of OTC ibuprofen

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Indomethacin
Indocin. 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 due to potentially severe side-effects. Up to half of those using indomethacin may experience some side-effects and almost one-third will discontinue use.

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Indomethacin
Common side-effects include gastrointestinal symptoms (ulceration, nausea, abdominal pain) and headaches (15 percent to 25 percent of patients). Peak concentrations can be achieved in 1 to 2 hours (in fasting subjects, onset is delayed by food intake).
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Indomethacin
A half-life of about 2.5 hours. Daily dosage ranges from 75 mg 100 mg taken in two to three doses. Indomethacins use has declined as newer agents with a lower side-effect profile have emerged.

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Nabumetone (Relafen)
Only nonacid NSAID currently available Once-a-day treatment; half-life is 24 hours

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Rofecoxib
Vioxx 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.
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Rofecoxib
Dosages range from 12.5 mg 50 mg. It is administered once daily given its nearly 17-hour half-life. Long-term toxic effects, including gastrointestinal and renal effects, are not yet known given the drugs relatively recent introduction.
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Celecoxib
Celebrex COX-2 inhibitor
200 mg tablets Peak Plasma levels = 3 hours Half-life (approximate-effective) = 11 hours Problems include:
Liver and kidneys Heart ?
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Ketorolac
Toradol. Not typically employed for its antiinflammatory properties. It is the only NSAID available for intramuscular or intravenous injection as well as oral administration.

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Ketorolac
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 as it avoids the most common shortcomings of opioids, i.e., tolerance, withdrawal effects, and respiratory depression.

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Ketorolac
Interestingly, Tokish et al (1992) recently reported that 28 of 30 National Football League team medical staffs commonly use ketorolac intramuscular injections on game days for pain relief. Due to high risk of renal effects, duration of ketorolac treatment is typically held to less than 5 days.
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NSAID Indications

39

NSAID Adverse Effects

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NSAID Use

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Drug-Drug Interactions

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Glucocorticosteroids
Animal studies demonstrate:
Potent anti-inflammatory actions of glucocorticosteroids and their subsequent effects upon healing Glucocorticosteroids induced an early, transient recovery of the force-generating capacity of the effected muscle Long-term findings revealed irreversible damage to the healing muscle, including atrophy and diminished force-generating capacity

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Actions of Corticosteroids

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Corticosteroids in Sports Medicine

Stanley and Weaver (1989) state that inconsistency in the studies on glucocorticosteroid use does not lend adequate support or direction to the sports medicine clinician in their use. Extremely powerful anti-inflammatory medications but no good research to demonstrate their effectiveness in activity-related injury.
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Box 3-7: Most Common Indications for Injectable Corticosteroids

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Box 3-8: Potential Complications of Injectable Corticosteroids

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