The Role of COX-2 Inhibitors in Emergency and Acute Care Medicine
The Role of COX-2 Inhibitors in Emergency and Acute Care Medicine
High Benefit-Low Risk Therapy for Outcome-Effective Management of Inflammatory Arthritis and Common Pain Syndromes
Authors: Keith K. Colburn, MD, Chief, Rheumatology, Pettis Veterans Medical Center and Loma Linda University Medical Center, Loma Linda, CA; Raymond Flores, MD, Fellow of Rheumatology, Loma Linda, CA; and John Rambharose, MD, Assistant Professor of Medicine, Loma Linda, CA.
Peer Reviewer: Steen Mortensen, MD, Chief of Rheumatology, Wichita Clinic, Wichita, KS.
Editors: Gregory R. Wise, MD, FACP, Associate Professor of Medicine, Wright State University, Dayton, OH; Vice President, Medical Integration, Kettering Medical Center, Kettering, OH; Gideon Bosker, MD, FACEP, Assistant Clinical Professor, Section of Emergency Services, Yale University School of Medicine; Associate Clinical Professor, Oregon Health Sciences University.
Despite their well-documented renal and gastrointestinal side effects, nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely prescribed medications in emergency practice. Gastrointestinal (GI) toxicities represent some of the most serious side effects of this drug class, and common complications include gastric mucosal ulceration, hemorrhage, or perforation. The analgesic and anti-inflammatory mechanism of action of NSAIDs has been attributed to their capacity for inhibiting the enzyme cyclooxygenase (COX). Recently, two isoforms of cyclooxygenase have been identified. COX-1 is believed to have a gastroprotective effect, while COX-2 inhibition is responsible for the production of proinflammatory mediators.
Pharmacological differences among NSAIDs are playing an increasingly important role in drug selection, and clinicians must be aware of the potential advantages and disadvantages of drugs that comprise this large and potentially problematic therapeutic class. For example, generally speaking, older NSAIDs such as ibuprofen and ketoprofen are relatively more potent inhibitors of COX-1 than COX-2, whereas newer NSAIDs, such as nabumatone and etodolac, have more balanced inhibition. A new and recently approved class of selective COX-2 inhibitors—represented by celecoxib (Celebrex®) and rofecoxib (Vioxx®)—offer new opportunities for high benefit/low risk therapy in appropriately selected and risk-stratified patients previously requiring conventional NSAID therapy.
It is estimated that NSAIDs currently are taken by approximately 17 million Americans every day.1 Overall, NSAIDs account for about 4.5% of all prescriptions written in the United States and approximately 22-31% of prescriptions written in the outpatient and/or emergency department.2 Worldwide, it has been estimated that 100 million prescriptions are written annually, accounting for more than $2 billion in sales, excluding over-the-counter (OTC) purchases.3 These usage patterns reflect a large segment of the population suffering from such conditions as osteoarthritis (OA) and rheumatoid arthritis (RA), in whom NSAIDs represent initial therapy for control of inflammation and relief of pain and stiffness.
Not surprisingly, more than 50% of NSAID prescriptions are written for individuals older than 60 years of age for the management of OA.2,4 However, in the acute, outpatient, and emergency practice environment, NSAIDs have become a bulwark of defense against pain syndromes linked to non-rheumatic conditions, among them migraine headache, muscle tension, ureteral and biliary colic, dysmenorrhea, and trauma.
As a therapeutic class, NSAIDs exhibit analgesic, anti-inflammatory, antipyretic, and platelet inhibitory properties.1 Generally speaking, analgesic effects are obtained at lower doses than those required for anti-inflammatory activity. Although there is some controversy surrounding the issues of relative effectiveness, most experts agree—and clinical experience supports the observation—that when prescribed at equipotent doses, NSAIDs are purported to show similar clinical efficacy. Clinical responses, however, may vary among individuals.5
Unfortunately, complications associated with NSAID use in the United States result in approximately 100,000 hospitalizations a year at a cost of $4 billion; moreover, it is estimated that NSAIDs are directly linked to about 10,000-20,000 deaths each year.6 Among the elderly alone, an estimated 41,000 hospitalizations and 3300 deaths annually are thought to be secondary to NSAID therapy.7 Studies comparing diclofenac, naproxen, and acetaminophen showed that NSAID use in the elderly increased GI complications three- to five-fold as compared with non-NSAID users.8-13 As the geriatric population has grown, the incidence of OA has increased. As might be expected, elderly patients with OA and RA have been identified as being at high risk for NSAID toxicity. As a result, the search has been ongoing for NSAIDs that specifically target molecules that generate pain and inflammation, but without compromising the cytoprotective effects of prostaglandins. (See Table 1.) NSAID toxicity is greater during the first month of therapy and is potentiated by higher doses.15,16
| Table 1. Risk Factors for NSAID-Induced Ulcers |
| Definite |
| • Age older than 65 |
| • Previous ulcer or GI bleeding |
| • Concomitant corticosteroid therapy |
| • High-dose or multiple NSAID therapy |
| • Duration of therapy |
| Possible |
| • Smoking |
| • Alcohol |
| • Helicobacter pylori |
| • Comorbid conditions |
Given the frequency with which NSAIDs are used in acute outpatient and emergency practice, a thorough understanding of the benefit-to-risk ratio associated with specific agents is essential for outcome-effective, toxicity-minimizing therapy. With these issues in clear focus, the purpose of this detailed review is to outline the current status of NSAIDs (i.e., clinical options, risks, pearls, pitfalls, and solutions) in emergency and acute outpatient practice. To this end, the authors discuss the pharmacological properties of NSAIDs, their potential side effects, and drug interactions, as well as their risks and benefits in specific clinical settings and for well-established indications. Because the NSAID landscape is undergoing a rapid shift toward COX-2 inhibiting agents, "traditional" NSAIDs are compared with currently available COX-2, selective NSAIDs with respect to efficacy, mechanism of action, and relative toxicities.
—The Editor
Therapeutic History of NSAIDs: An Overview
Dating as far back as ancient Greece and Egypt, salicylic acid and salicylates extracted from myrtle leaves and willow bark were used as therapeutic agents to treat fever, pain, and swelling. In 1860, salicylic acid was chemically synthesized in Germany, where it was used as an external antiseptic and antipyretic, and as a treatment for "rheumatism." In 1899, Felix Hoffman, a chemist who worked for Bayer, synthesized acetyl salicylic acid, or aspirin (a palatable form of salicylic acid), which was introduced for public consumption by its research director, Herman Dresser.17
Other early, anti-rheumatism drugs included antipyrene, phenacetin, phenyl-butazone (introduced in 1949), and indomethacin (introduced in 1967). Because these drugs had similar therapeutic effects, they were grouped under the "aspirin-like" drug category. And because these medications were clearly distinct from glucocorticoids, they were categorized as nonsteroidal anti-inflammatory drugs or NSAIDs. In 1971, it was demonstrated that inhibition of prostaglandin synthesis is the primary mechanism of action for NSAIDs.18 Cyclooxygenase was synthesized in 1976, identifying the key pathway in prostanoid synthesis inhibited by NSAIDs.19 In 1989, a second enzyme with COX activity was identified, and the two isoforms were designated as "COX-1" and "COX-2."20 (See Table 2.)
| Table 2. History |
| • Ancient Egyptians, Greeks, and Romans used salicylate extracts derived from myrtle leaves, poplar tree juices, and willow leaves as analgesics and antipyretics. |
| • Medicinal herb gardens in the Middle Ages and Renaissance featured salicylate containing wintergreen and meadowsweet plants. |
| • 1763: The Rev. Edward Stone reported on use of willow bark powder as an antipyretic. |
| • 1853: Charles Frederic Von Gerhardt synthesized acetylsalicyclic acid. |
| • 1860: Felix Hoffman, using a modified Von Gerhardt method, synthesized acetylsalicyclic acid. |
| • 1949: Phenylbutazone introduced. |
| • 1963: Indomethacin introduced. |
| • 1971: Vane and Piper demonstrated NSAIDs inhibit prostaglandin production. |
| • 1974: Ibuprofen introduced. |
| • 1976: Miyamoto et al purified the COX enzyme. |
| • 1982: Piroxicam introduced. |
| • 1989: Simmons et al identified the COX-2 enzyme. |
| • 1999: Celecoxib introduced. |
| • 1999: Rofecoxib introduced. |
NSAIDs: Mechanism of Action
First and foremost, NSAIDs are COX inhibitors. Accordingly, the majority of NSAID-related side effects, in large part, can be attributed to inhibition of prostaglandin production.21,22 The actions, properties, and tissue characteristics of two forms of cyclooxygenase, COX-1 and COX-2, are described in Table 3. The COX-1 isoform is located in all tissues, except red blood cells, and is constitutively expressed in the stomach, kidneys, platelets, and endothelial cells under normal physiologic conditions. In contrast, COX-2 production is induced by proinflammatory substances (see Table 4), such as lipopolysaccharides, tumor necrosis factor alpha (TNF-a), interleukin-1 (IL-1), platelet-derived growth factor (PDGF), and other growth factors.21,23,24 In addition, COX-2 production is decreased by glucocorticoids, interleukin-4 (IL-4), and interleukin-13 (IL-13).24
| Table 3. Comparison of COX-1 and COX-2 | ||
| COX-1 | COX-2 | |
| Tissue Localization | Most tissues except RBCs | CNS, kidney, and areas of inflammation |
| Gene | Chromosome 9 | Chromosome 1 |
| Stimuli | Basal expression under physiologic conditions may have increased expression in response to some hormones or growth factor | Basal expression in kidney and brain-mitogens, growth factors, proinflammatory cytokines, and tissue injury |
| Function | Prostaglandin production, renal blood flow, platelet aggregation, gastric cyto-protection, vascular tone, and fetal development | Ovulation, parturition, renal development, salt and blood pressure regulation, response to tissue injury, colon cancer pathogenesis, and defense against GI pathogens |
| Inhibitors | Aspirin, NSAIDs | Glucocorticoids, aspirin, NSAIDs |
| Homology | 60% sequence homology for both enzymes | |
COX-2, which is constitutively expressed in the brain and kidney, is found in significant quantities in other tissues only in areas undergoing active inflammation, and is undetectable under basal conditions in other tissues.23-26 Both COX isoforms share a 60% amino acid sequence homology and differ in their tertiary structures. For example, unlike the COX-1 enzyme, COX-2 has valine at position 523 instead of isoleucine. This substitution allows COX-2 inhibitors access to the secondary internal side pocket of the molecule that is obstructed by isoleucine in the COX-1 isoform.21,26-29
Tissue Activity. Clinical effects produced by COX-1 and COX-2 differ because each has a distinctive pattern of expression. In this regard, COX-1 is a "constitutive" enzyme, which means that it is always present, it is found in most tissues, and it is involved in physiologic, homeostatic functions (i.e., maintaining the integrity of gastric and duodenal lining, as well as playing an integral, vasoactive role in the renal and vascular systems). COX-1 activation leads to the production of prostacyclin, which is cytoprotective when released by the gastric mucosa. Hence, the inhibition of COX-1 can lead to GI ulcerations and erosions.
Moreover, the COX-1 enzyme does not appear to be involved in the mediation of the inflammatory response and associated pain. Studies using a rat air pouch model of lipopolysaccharide-induced inflammation revealed that the COX-1 specific inhibitor investigational drug, SC-560, did not significantly inhibit the production of prostaglandin E2 (PGE 2) in the air pouch, while COX-1 derived PGE 2 production in the gastric mucosa was significantly diminished.30 This study also demonstrated that SC-560 had no significant effect on pain or edema in a carrageenan-inflamed rat foot pad model, while celecoxib, a COX-2 specific inhibitor, significantly reduced both pain response and paw edema, indicating that COX-2 was the primary enzyme mediating inflammation.30 When human synovial tissue from patients with RA, ankylosing spondylitis, and psoriatic arthritis was compared with patients with OA, there was increased expression of COX-2 enzyme but not COX-1, providing additional confirmation of the importance of this enzyme in inflammatory diseases.33
Anti-Inflammatory Effects. The COX-2 isoform is an "inducible" enzyme, meaning that it is normally not detected unless stimulated or, if it is expressed, it is found in low levels. One study demonstrated up-regulation of COX-2 mRNA and increased PGE 2 production using mycobacterial adjuvant-induced arthritis and inflamed rat foot pad models.31 Conversely, there was no increase in COX-1 mRNA. Like COX-2 mRNA, the mRNAs of the proinflammatory cytokines, IL-6 and TNF-a, also were elevated in the affected paws. In this experimental model, treatment with either celecoxib or indomethacin resulted in reversal of paw edema and a reduction of PGE 2 levels to the baseline. The expression of paw COX-2 mRNA was decreased in animals treated with celecoxib. The inhibition of COX-2 activity was associated with a decline in PGE 2 levels along with a decrease in paw and serum IL-6, suggesting that COX-2 derived prostaglandins provide a partial stimulus for the local and systemic production of proinflammatory cytokines.31 (See Table 4.)
| Table 4. Cytokines that Interact with COX-2 | ||
| Cytokines | Source | Action of Cytokines |
| IL-1 | Macrophages, monocytes | T- and B-cell activation increases body temperature, bone resorption, neutrophil mobilization, and early inflammatory response |
| IL-4 | T-cells and mast cells | B-cell activation |
| IgE isotype switching | ||
| IL-6 | T-cell, macrophages | Early inflammatory response |
| T- and B-cell growth factor | ||
| Pyrogen | ||
| IL-13 | T-cells | B-cell growth and differentiation |
In human synovium, the generation of COX-2 occurs at inflammatory sites in the presence of macrophages and endothelial cells up-regulated by cytokines and in the presence of bacterial products such as lipopolysaccharide. COX-2 is found in the synovial membrane of patients with RA; however, in healthy patients as well as those individuals with OA, COX-2 is found at low levels or is not detectable.32 Accordingly, an NSAID selective for COX-2 inhibition has the potential of being an "ideal" anti-inflammatory drug, since it spares COX-1 activity, and therefore, has the potential to minimize or prevent GI , and possibly renal, toxicity.
NSAIDs and COX Selectivity. Different NSAIDs vary in their relative COX-1 and COX-2 selectivity, a pharmacological property that has important clinical implications. The capacity of any NSAID to inhibit prostanoid production by these enzymes is expressed as the inhibitory concentration of 50% of an enzyme (IC50). The ratio of the IC50 of COX-2 to COX-1 defines COX-2 selectivity. Therefore, the smaller the ratio, the more COX-2 selective the drug.34 For example, a ratio of less than 1 would signify greater COX-2 inhibition than a ratio greater than 1, while an IC50 of 1 reflects equal selectivity.
Interestingly, the IC50 results depend on the assay that is being used. Salicylates do not significantly inhibit either COX isoform in pure cell free recombinant enzyme systems, but they demonstrate significant inhibition of both enzymes in a cell membrane system.21,35 Most NSAIDs inhibit the COX-1 isoform and exhibit a variable ability to inhibit the COX-2 enzyme.21,34 NSAIDs such as etodolac (Lodine®) and nambumetone (Relafen®) demonstrate some COX-2 selectivity at lower doses and are more COX-1 selective at higher anti-inflammatory doses. As a result, these NSAIDs have been referred to as COX-2 "preferential."
Drugs that demonstrate consistent COX-2 inhibition throughout their dose ranges are called COX-2 "selective."22,26 Table 6 ranks NSAIDs at usual therapeutic doses from the least to the most COX-2 selectivity; this ranking reflects NSAIDs that were available prior to the introduction of the COX-2 inhibitors.36 From a clinical perspective, it should be noted that NSAIDs introduced prior to celecoxib are capable of GI mucosal prostaglandin depletion at recommended therapeutic doses. In contrast, early studies showed no prostaglandin inhibition with NS-398, an experimental COX-2 inhibitor, and nonacetylated salicylic acid.36
In order to completely inhibit COX-2 without affecting the COX-1, an NSAID should be about 100 times more potent against COX-2 than COX-1 and it should have an IC50 COX-2/IC50 COX-1 ratio of 0.01 or lower. Celecoxib and rofecoxib far exceed this standard for a selective COX-2 inhibitor. Specifically, celecoxib demonstrates a 375-fold selectivity for COX-2, while rofecoxib has approximately an 800-fold selectivity for COX-2 in human enzyme systems.34,37 The clinical significance of the differences in COX-2 selectivity between these drugs has not been determined. Celecoxib was introduced into the market in February 1999. Rofecoxib was released in June 1999. A recent review comparing celecoxib, meloxicam, and nabumetone in dogs demonstrated GI and renal injury in all the subjects given nabumetone, in some given meloxicam, and in none of the subject in the celecoxib group.38
Celecoxib
Celecoxib is rapidly absorbed, reaching a maximum serum concentration in three hours with a half life of 11 hours. The drug is metabolized in the liver by the cytochrome P450 enzyme, CYP2C9, and excreted in feces and urine. Cytochrome P450 is a liver enzyme involved in biotransformation with 12 families subdivided by their gene protein sequence. CYP1, CYP2, and CYP3 encode the enzymes involved in drug metabolism, while the gene products of the remaining CYP 450 families are important in the metabolism of endogenous compounds such as steroids and fatty acids. CYP2C also has subfamilies including CYP2C9. CYP2C9 inhibitors, such as zarfilukast, fluconazole, and fluvastatin, may increase serum concentration of celecoxib. Celecoxib also inhibits CYP2D6. Drugs metabolized by this enzyme, including beta-blockers, antidepressants, and antipsychotics, may need to be appropriately adjusted.39
Celecoxib is indicated for the relief of the signs and symptoms of OA and RA in adults. For the relief of the signs and symptoms of osteoarthritis, the recommended dose is 200 mg daily administered as a single dose or as 100 mg twice daily. For the relief of the signs and symptoms of rheumatoid arthritis, the recommended dose is 100-200 mg twice daily.
In elderly patients (> 65 years of age), consideration should be given to starting celecoxib at a lower dose, as higher peak plasma levels (40% greater) and greater total absorption (50% greater) have been reported. Celecoxib can be taken without regard to meals. However, a high-fat meal delays the absorption by about 1-2 hours, with an increase in total absorption of 10-20%. Coadministration with an aluminum and magnesium containing antacid reduces the peak plasma level by 37% and total absorption by 10%. Celecoxib is supplied as 100 mg and 200 mg capsules. Celecoxib should not be taken by patients who have demonstrated allergic-type reactions to sulfonamides.
The GI safety of celecoxib has been evaluated in several excellent studies. In comparative trials between celecoxib and ibuprofen or naproxen, celecoxib was associated with a statistically significant lower incidence of endoscopic ulcers evaluated at 12 weeks. The incidences were 9.9%-17.6% with naproxen (500 mg bid) and 9.6% for ibuprofen (800 mg tid), compared to 1.5-4% and 1.5-5.9% for celecoxib at 100 mg bid and 200 mg bid, respectively. Moreover, among 5285 patients studied who received celecoxib over a 1-6 month period, only two patients (0.04%) experienced significant upper GI bleeding, at 14 and 22 days after initiation of therapy. The discontinuation rate for celecoxib (7.1%) was similar to that for placebo (6.1%). Higher than recommended doses of celecoxib (600 mg bid for 7 days) had no effect on platelet aggregation and bleeding time. A single dose of 800 mg of celecoxib did not inhibit platelet COX-1 dependent aggregation. Celecoxib does not appear to affect the anticoagulant effect of warfarin, although caution should be exercised if coadministration is considered.
The occurrence rate of dyspepsia and abdominal pain with celecoxib appears to be lower than that of naproxen, ibuprofen, and diclofenac but slightly higher than placebo. The occurrence rates were 8.8% for dyspepsia and 4.1% for abdominal pain compared to 6.2%/2.8%, 12.2%/7.7%, 10.9%/9%, 12.8%/9% for placebo, naproxen, ibuprofen, and diclofenac, respectively. Dyspepsia and abdominal pain were the most common side effects of celecoxib which led to discontinuation in clinical trials. Borderline elevation of one or more liver tests may occur in up to 15% of patients. Significant elevation (> 3 times the upper limits of normal) has been reported in only 1% of patients in clinical trials. Celecoxib is contraindicated in patients with a known allergy to aspirin or to other NSAIDs. Because celecoxib is a 4 benzenesulfonomide, it is also contraindicated in patients with documented sulfonamide allergy.39
The correlation between endoscopic findings or symptoms and serious GI side effects has not been established. Although this method has been widely used in clinical studies, endoscopically observed ulcers may not be reliable predictors of severe GI events. Endoscopic ulcers tend to be smaller, superficial, and predominately gastric, while serious events tend to be both gastric and duodenal. Despite the present lack of conclusive, prospective studies confirming the gastrointestinal-sparing effects and safety advantages of COX-2 inhibitors, the available endoscopic data showing reduction in ulcers—as well as the reduction in dyspepsia and abdominal pain—are sufficiently compelling to recommend COX-2 inhibitors such as celecoxib as initial therapy for pain management in patients with OA. Celecoxib is priced similar to branded NSAIDs. The average wholesale price is $2.42 for the 200 mg capsules and $1.43 for the 100 mg capsules. These prices are similar to nabumetone (1000 mg/d) and oxaprozin (1200 mg/d).
Rofecoxib
Rofecoxib inhibits COX-2 without evidence of COX-1 inhibition, even at oral doses of up to 1000 mg.40 This COX-2 inhibitor is approved for treatment of OA pain in adults and conditions such as pain from postoperative dental and orthopedic surgical procedures and primary dysmenorrhea. At the time this manuscript was prepared, rofecoxib had not received approval for RA treatment.41 Oral doses of rofecoxib 12.5-50 mg daily have been found to be as effective for the treatment of OA as diclofenac (Voltaren) 50 mg PO three times a day.42
Rofecoxib is contraindicated in patients who exhibit an allergic reaction to aspirin and NSAIDs. Unlike celecoxib, rofecoxib can be given to patients with sulfa allergy. Because rofecoxib does not inhibit the cytochrome P450 enzyme, CYP2D6, it can be taken with fuconazole and lithium. Adverse effects experienced by patients on rofecoxib include diarrhea, headache, insomnia, and edema.43
Rofecoxib is available as 12.5 mg or 25 mg tablets and as an oral suspension containing 12.5 mg or 25 mg per 5 mL. The recommended initial dose for osteoarthritis is 12.5 mg once daily. Some patients may achieve added benefit at a dose of 25 mg once daily, which is considered the maximal dose for this indication. It may be taken without regard to meals. Rofecoxib should not be taken by patients who have experienced allergic-type reactions to aspirin or other NSAIDs.
Rofecoxib, 25 mg or 50 mg daily, has been reported to produce a lower percentage of endoscopic gastroduodenal ulcers than ibuprofen 2400 mg daily. Difference was statistically significant at 12- and 24-week assessments. Rofecoxib also appears to be well tolerated in terms of GI adverse events. In a clinical trial, the percent of patients experiencing diarrhea was 6.8% vs. 6.5% for placebo, 3.5% vs. 2.7% for dyspepsia, 3.8% vs. 2.8% for epigastric discomfort, and 4.2% vs. 3.6% for heartburn. A general enzyme inducer, rifampin, has been reported to produce a 50% decrease in the plasma concentration of rofecoxib. Rofecoxib has no effect on platelet function. Dosages up to 375 mg given daily for up to 12 days did not affect bleeding time relative to placebo.
Rofecoxib is approved for OA but not for RA. The renal effects of rofecoxib are similar to those of other NSAIDs. The use of rofecoxib for the relief of pain at the 50 mg dose is not recommended beyond five days. Coadministration of rofecoxib and warfarin have resulted in an increase of 8-11% in INR. Therefore, monitoring of INR is recommended with coadministration.
In OA, rofecoxib (12.5-25 mg) has been reported to be similar in effectiveness as ibuprofen 800 mg tid over six weeks or diclofenac 50 mg tid over six months. Study patients included patients with OA of the hip or knee. Ninety percent had an increase in pain following withdrawal of NSAIDs and 10% had moderate symptoms while taking acetaminophen. Rofecoxib, ibuprofen, and diclofenac all showed about a 50% reduction in the WOMAC (Western Ontario and McMaster Universities OA index) visual analog scale walking on a flat surface. This is a composite of pain, stiffness, and functional measures in OA. Like celecoxib, rofecoxib (25 mg-50 mg) has been associated with fewer endoscopic ulcers than ibuprofen (2400 mg daily) (4.1-8.8% vs 27.7-29.2%). This compares favorably to placebo (5.1-9.9%). (VX1) Rofecoxib (12.5-25 mg daily) is priced competitively with celecoxib when used for OA.
Toxicity of Traditional NSAIDs vs. COX-2 Inhibitors: Incentives for Risk Management Upgrades
The therapeutic shift—or risk management upgrade—from traditional NSAIDs to selective COX-2 inhibitors is justified by the relative benefit-to-risk advantage that appears to be associated with the newly introduced agents. Currently, NSAIDs play an important role in the management of various types of arthritis and are often the primary treatment used for patients with OA. These drugs are used for a variety of inflammatory arthritides, supplementing disease-modifying antirheumatic drugs (DMARDs) to reduce pain and inflammation. Unlike DMARDs, however, NSAIDs do not slow the progression of the disease process. Their primary benefits frequently are related to pain relief but, on the downside, NSAIDs also may be responsible for significant, and even fatal, side effects.44 (See Table 5.)
| Table 5. Adverse Effects of NSAID Therapy | |
| GI | Gastroduodenal ulcers, strictures, esophagitis, gastritis, colitis, small and large bowel erosions |
| Renal | Acute and/or chronic renal failure, fluid and electrolyte imbalances, hyperkalemia, hematuria, nephrotic syndrome with interstitial nephritis, papillary necrosis |
| Cardiovascular | Exacerbation of hypertension, exacerbation of congestive heart failure, arrhythmia |
| Hepatic | Elevated transaminases, choleostasis, hepatic failure (rare) |
| CNS | Headache, tinnitus, vertigo, tremor, depression, somnalence, altered mental status, aseptic meningitis |
| Hematologic | Thrombocytopenia, hemolytic anemia, agranulocytosis, leukopenia, eosinophilia, aplastic anemia |
| Pulmonary | Exacerbation of asthma, cough, respiratory depression, laryngeal and pharyngeal edema |
| Dermatologic | Skin rash, photosensitivity, Stevens Johnson syndrome, pemphigoid reaction, erythema multiform, urticaria, angioedema |
| Bone/Cartilage | Joint erosions, decreased repair of cartilage damage |
Adverse Gastrointestinal Effects. GI side effects associated with NSAID therapy are common. Approximately 30-60% of NSAID users experience some abdominal discomfort, or dyspepsia.48,49 These symptoms do not necessarily correlate with endoscopic findings. Approximately 40% of persons with erosive gastritis are asymptomatic, while almost 50% of patients with dyspepsia have no evidence of mucosal damage on endoscopy.48
Endoscopic studies of arthritic patients receiving chronic NSAID therapy revealed that 50-75% of subjects have gastroduodenal lesions ranging from small subepithelial hemorrhages and mucosal erosions to ulcers.48 The majority of these lesions are of little clinical significance.49,50 Studies showed the prevalence of peptic ulcers in patients on chronic NSAIDs to be about 25%.45 Gastric ulcers were seen in 15% of patients, while duodenal ulcers were present in 10%.49
Strategies used to avoid GI mucosal injury from NSAIDs included the use of enteric-coated NSAIDs, rectal suppositories, injectable NSAIDs, and the use of pro-drugs such as sulindac. Unfortunately, GI mucosal damage and ulcers still occurred with all of these formulations.48,51,52
Another commonly used strategy is to recommend ingestion of NSAIDs with food. A study of healthy volunteers failed to support the outcome-effectiveness of this approach.53 In one study, the participants, who took ranitidine and aspirin with meals, had significantly more gastric erosions than those who ingested these medications two hours before meals.53 Misoprostol, a synthetic PGE1 analog with antisecretory and cytoprotective effects, was shown to prevent both gastric and duodenal ulcers in chronic NSAID users.54 One trial found that misoprostol 200 mg qid decreased upper GI tract NSAID complications such as perforated ulcers, obstruction, and bleeding ulcers by 40%; however, 42% of study patients had to withdraw because of side effects from misoprostol including diarrhea and abdominal discomfort.55
The ability of the proton pump inhibitor, omeprazole, to decrease the incidence of gastroduodenal ulcers in NSAID users was demonstrated in four recent large, randomized, controlled trials.56-59 Omeprazole 20 mg/d was superior to ranitidine 150 mg bid in the treatment and prevention of gastroduodenal ulcers.56 At the end of the eight-week healing phase in this six-month trial, 80% of patients in the omeprazole group had been successfully treated compared to 63% of patients in the ranitidine group. Upon completion of the trial, 72% of subjects taking omeprazole remained in remission vs. 59% of those given ranitidine.56
Another study showed that omeprazole 20 mg daily exhibits greater efficacy in gastroduodenal ulcer prevention than placebo or misoprostol 200 mg bid.57 Healing rates at eight weeks were 87% for gastric ulcers and 93% for duodenal ulcers in the omeprazole group, while healing rates for the misoprostol subjects were approximately 73% for gastric ulcers and almost 77% for duodenal ulcers. Sixty-one percent of patients remained in remission in the omeprazole group vs. 48% receiving misoprostol and 27% on placebo.57
| Table 6. COX-1/COX-2 Ratios for a Variety of NSAIDs | ||
| Rank | Drug | Ratio* |
| 1 | Flubiprofen | 10.17 |
| 2 | Ketoprofen | 8.16 |
| 3 | Fenoprofen | 5.14 |
| 4 | Aspirin | 3.12 |
| 5 | Oxaprofin | 2.52 |
| 6 | Tolmetin | 2.09 |
| 7 | Indomethacin | 1.78 |
| 8 | Ibuprofen | 1.69 |
| 9 | Naproxen | 0.88 |
| 10 | Piroxicam | 0.79 |
| 11 | Ketorolac | 0.68 |
| 12 | 6-MNA | 0.64 |
| 13 | Nabumetone | 0.62 |
| 14 | Sulindac | 0.61 |
| 15 | Bismuth (subsalicylate) | 0.50 |
| 16 | Salsalate | 0.29 |
| 17 | Acetaminophen | 0.25 |
| 18 | Salicylic acid | 0.13 |
| 19 | Etodolac | 0.12 |
| 20 | Mefenamic acid | 0.08 |
| 21 | Diclofenac | 0.05 |
| 22 | NS-398 | 0.042 |
| 23 | Nimesulide | 0.017 |
| 24 | Dexamethasone | 0.002 |
| 25 | Valeryl salicylate | 0.001 |
| * Ratios more than 1 indicate drug is more COX-1 selective; ratios less than 1 indicate drug is more COX-2 selective. | ||
| Since actual IC50 for COX-1 in blood was more than 100 mM, a value of 100 mM was used in calculation of ratio; therefore, these ratios represent a maximum possible ratio of IC50 COX-2/ IC50 COX-1 in blood. | ||
Adaptation. Controversy still exists as to whether continuous NSAID therapy results in adaptation of the GI tract to drug-induced damage or if the risk of GI events remains constant.49,60 Evidence for a constant risk may be found in a Scottish study of 52,293 NSAID users and 72,792 controls followed over a two-year period.61 These investigators concluded that the risk for any upper GI event was "constant during continuous exposure." In this study, the risk of any GI event increased 5- to 10-fold while the subjects were on NSAIDs vs. the period prior to NSAID therapy. Risks were initially high, but then decreased to baseline up to one year after discontinuation of the drug.
The constant risk theory was countered by two reviews on NSAID-induced bleeding.62,63 One observed that chronic NSAID therapy does not appear to result in GI adaptation to the effects of NSAIDs and the most important risk factor for GI bleeding in chronic NSAID users is the duration of therapy.62 A 10- to 15-year study following 1600 subjects from the inception of NSAID therapy revealed the risk of GI bleeding after three months’ treatment to be 25% following one year of therapy.63 Patients taking NSAIDs for five years were subject to a five-fold increased risk of GI bleeding when compared to patients receiving one year of NSAID therapy.62
Lower GI complications, while not as common as those seen in the upper GI tract, are potentially serious. NSAID use can be associated with colonic ulceration, perforation, inflammation, strictures, and diarrhea.51 Patients with quiescent inflammatory bowel disease could suffer an exacerbation of their disease by taking NSAIDs.64
Recent reports suggest that NSAIDs suppress the development of colon polyps and may even reduce the incidence of colorectal cancer.65,66 COX-2 inhibitors may be helpful only in preventing tumors that have increased expression of COX-2 enzymes. Two separate reports found that the expression of COX-2 increases during the formation of colorectal adenomas and adenocarcinomas.68,69 A recent, large population-based study reported that chronic NSAID use reduced the risk of colon cancer by approximately half. Celecoxib has been approved for prevention of colon cancer in individuals with familial polyposis of the colon. Most non-aspirin NSAIDs have demonstrated the ability to prevent colon cancer.70 COX-2 generation was mapped to chromosome No. 1 at one of the loci associated with colon cancer.68 COX-2 is present in pancreatic islet cells under both basal and cytokine stimulated conditions.71,72 The effects of the new COX-2 selective drugs on the GI system will be addressed under the heading, "Safety and Efficacy of COX-2 Inhibitors."
Renal Effects. As previously alluded to, the COX-2 enzyme is constitutively expressed in endothelial and smooth muscle cells of the renal vasculature and in the podocytes of the glomerulus. COX-1 is present in the podocytes of the fetal kidney but absent in adult glomeruli.73 Prostacyclin and PGE2 maintain renal blood flow in states of effective volume depletion such as congestive heart failure (CHF), liver cirrhosis, and true volume depletion seen with chronic diuretic therapy.74 Prostacyclin and PGE2 preserve renal blood flow by antagonizing the vasoconstrictive effects of angiotensin II and norepinephrine.
Because of these properties, NSAID use maybe associated with peripheral edema, hyperkalemia, acute renal failure in patients with hypovolemia, altered intrarenal plasma flow, nephrotic syndrome with interstitial nephritis, and papillary necrosis.75 Apart from peripheral edema, there are no studies implicating COX-2 inhibitors with the aforementioned adverse renal complications from NSAID use. Animal models demonstrated that high doses of celecoxib do not impair renal prostaglandin synthesis.76 Future studies will clarify the potential renal-sparing effects of COX-2 inhibitors.
For now, short-term studies of patients with RA and OA taking celecoxib have reported no renal dysfunction. Peripheral edema was minimally higher in the celecoxib group of patients than in the placebo group, implying a role for COX-2 in maintaining fluid and electrolyte balance.25,77 Interstitial nephritis caused by NSAIDs was extremely rare and, most likely, idiosyncratic in nature.78,79 Mice deficient in COX-2 enzymes developed kidney abnormalities including inflammation, fibrosis, and papillary mineralization.47
Hepatic Effects. Liver injury from NSAIDs ranges from asymptomatic transaminase elevation to clinical hepatitis.80 Fatal liver damage may rarely occur. Liver function tests are advised at the beginning of treatment and three months later, since side effects frequently appear during the initial three months of therapy.80 NSAIDs should be discontinued when alanine transferase (ALT) and asparate transferase (AST) are elevated 2-3 times normal levels. A recent review identified three NSAIDs most commonly associated with hepatic toxicity as sulindac, diclofenac, and aspirin.81
Differences in the IC50 of these NSAIDs do not appear to directly correlate with increased risk of liver injury.37 According to one group of investigators, the risk of liver toxicity ascribed to certain NSAIDs may be biased because estimates are based on spontaneous reports from physicians or patients.38
Hematologic Effects. Adverse hematologic side effects from NSAIDs are rare. Agranulocytosis and aplastic anemia are the most serious.38 Phenylbutazone (not available in the United States) and indomethacin are the NSAIDs most commonly associated with agranulocytosis. The potential for hematologic side effects with COX-2 inhibiting drugs is not yet clear.
Coagulation Effects. There are several mechanisms by which NSAIDs increase the risk and severity of bleeding, especially in a patient already taking warfarin. A direct hypoprothrombinemic effect occurs by depressing the vitamin K-dependent synthesis of clotting factors VII, IX, and X. Second, NSAIDs displace warfarin from plasma albumin, which is a transient effect, since there is an increase in the clearance of unbound warfarin until the previous concentration is again reached.38
Because platelets contain COX-1 but not COX-2, non-COX-2 selective NSAIDs demonstrate antiplatelet effects by inhibiting COX-1. COX-2 selective agents do not interfere with platelet activity.38,82 Celecoxib administered at doses of 600 mg bid does not interfere with serum thromboxane, bleeding time, or platelet aggregation as is seen with naproxen.83 Moreover, celecoxib, when combined with 2-5 mg per day of warfarin, does not prolong the prothrombin time.84 A role for celecoxib as prophylaxis for myocardial infarction and stroke is not likely, due to its lack of antiplatelet activity.
Cartilage Effect. Prostaglandins are well-documented modulators of articular cartilage metabolism and bone resorption.85 According to some reports, NSAIDs can exacerbate cartilage erosion, produce bony destruction of the femoral head in OA patients, and accelerate the progression of joint damage.86-88 COX-2 was recently shown to play a part in the bone loss induced by interleukin-1. (See Table 7.) Interleukin-1 functions to stimulate osteoclast formation.89 However, an increase in COX-2 production in cartilage explants suggests it may have a role in cartilage repair.90
| Table 7. ACR-20 Responder Index | |
| Patient must show a 20% improvement in: | |
| • Number of tender/painful joints | |
| • Number of swollen joints | |
| And in three more of the following: | |
| • Physician's global assessment of arthritic condition | |
| • Patient's global assessment of arthritic condition | |
| • Visual analog scale | |
| • Health assessment questionnaire of patient activities of daily living | |
| • C-reactive protein | |
Pulmonary Effects. A four- to 14-fold increase in COX-2 levels in asthmatic subjects has been reported, suggesting a possible COX-2 role in the pathogenesis of asthma.91 As might be expected, COX-2 blockade may be therapeutic in asthma, whereas older NSAIDs can cause bronchoconstriction and edema, especially in aspirin-sensitive patients. The authors, however, are not aware of studies evaluating COX-2 inhibitors for asthma treatment.
Central Nervous System Effects. NSAIDs can cause headaches, confusion, dizziness, and aggravate psychiatric illness, epilepsy, and parkinsonism. Ingestion of indomethacin is associated with the highest incidence of NSAID-associated CNS symptoms. There are anecdotal reports of aseptic meningitis in SLE patients using ibuprofen.92
The presence of the COX-2 protein in neuronal and glial cells following ischemic injury has been reported, suggesting a possible pathologic role for COX-2.92 Epidemiologic studies suggest that COX-2 inhibition delays the development of Alzheimer's disease, possibly by blocking neuro-inflammation; however, the precise mechanism is not known.74,93 COX-2 is reported to be the predominant isoform in the neocortex and hippocampus areas of the brain, the same areas affected by Alzheimer’s disease.94 No consistent association is found between COX-2 expression and neurologic abnormalities.
Reproductive Tract Effects. The COX-2 enzyme is apparently induced in ovulation. Mice deficient in COX-2 are noted to be infertile.95 COX-2 expression is prominent in the human amnion at term by 100-fold compared with earlier in gestation, suggesting a possible role for COX-2 inhibiting preterm labor.38 COX-2 inhibitors are contraindicated at or near term. Recent data showed that the fetus produces PGF2a-inducing luteolysis, leading to uterine contractions. This process reduces maternal progesterone levels and induction of oxytocin receptors in the myometrium, leading to parturition.96 COX-2 also influences fertilization and implantation. This enzyme is required for normal oocyte development and probably for generation of the enzymes necessary to rupture the follicle.97 Following fertilization, COX-1 prepares the wall for interaction with the embryo, while COX-2 and prostaglandin receptors mediate implantation.98-100
Cardiovascular Effects. Cardiovascular side effects of NSAIDs occur more frequently than previously recognized. NSAIDs have increased the blood pressure of subjects in several trials. By inhibiting prostaglandin synthesis, NSAIDs interfere with systemic and renal vasodilation, glomerulo-filtration, tubular secretion of fluids and electrolytes, adrenergic neurotransmission, and the renin-angiotensin-aldosterone system, leading to hypertension.101
A recent meta-analysis of 50 studies reported that NSAIDs increased the mean blood pressure by approximately 5 mmHg.102 Investigators also found that hypertensive patients taking blood pressure-lowering drugs were more severely affected by NSAID use than normotensive volunteers given antihypertensives. The hypertensive effect of NSAIDs appears to be most pronounced in patients taking angiotensin-converting enzyme inhibitors, diuretics, and beta-blockers.103 However, the anti-hypertensive effect of calcium channel blockers does not appear to be affected by NSAIDs.103
The American College of Rheumatology (ACR) recommends that for patients taking NSAIDs, a baseline CBC, creatinine, AST, and ALT should be done and repeated yearly.104 It is also advisable to check a patient’s blood pressure within a few weeks of initiating NSAID therapy and 2-3 times a year, as indicated, thereafter.103 Other cardiovascular effects of NSAIDs include exacerbation of CHF and isolated peripheral edema.103 NSAIDs are beneficial in relieving the pain of post-pericardectomy syndrome and pericarditis.103 The extent to which COX-2 selective drugs affect the cardiovascular system requires further study.
Safety and Efficacy of COX-2 Inhibitors
In the United States, two COX-2 selective agents, celecoxib (Celebrex®) and rofecoxib (Vioxx®), have received FDA approval. The potential for this new class of NSAIDs to affect prescribing of anti-inflammatory drugs by emergency physicians should not be minimized. Early studies comparing side effects safety of the COX-2 inhibitors with other NSAIDs are impressive, especially in the GI system.
In this regard, the safety and efficacy of celecoxib in RA was reported in both phase II and phase III clinical trials. In a four-week phase II trial, 330 RA patients received celecoxib at doses of 40 mg bid, 200 mg bid, 400 mg bid, or a placebo. At the end of the trial, 18% of the patients had withdrawn from the placebo group due to lack of efficacy compared with 17% for the 40 mg group, 4% from the 200 mg group, and 6% from the 400 mg group. A statistically significant difference (P < 0.005) was seen in the higher dose celecoxib groups at weeks 1, 2, and 4 when compared with placebo.37
In a 12-week, double-blind, placebo-controlled trial, 1149 subjects with active RA received celecoxib at doses of 100 mg, 200 mg, or 400 mg bid, or naproxen 500 mg bid, or placebo.105 Celecoxib at 200 mg bid and 400 mg bid was as effective as the naproxen 500 mg bid. All were statistically better than placebo (P < 0.05) in demonstrating improvement of the ACR 20 responder.105 (See Table 7.)
Celecoxib demonstrated safety and efficacy in a two-week placebo-controlled study of 293 subjects with OA.37 Patients were randomized to receive celecoxib in doses of 40 mg, 100 mg, 200 mg bid, or placebo. Withdrawals due to lack of efficacy were greater in the placebo group (14%) vs. subjects in the 100 mg group (1%) and the 200 mg group (4%).37 Except for the group on 40 mg celecoxib bid, the patient assessment of pain using a visual analog scale (VAS) was statistically significant (P < 0.048) at both weeks 1 and 2 for the treatment groups compared to placebo.37
No effect on collagen-induced platelet aggregation was seen in a study of six healthy male subjects receiving celecoxib 400 mg bid. Results of pre- and post-treatment collagen-induced platelet aggregation were not statistically significant. This same group subsequently received a single dose of 650 mg aspirin. The post-dose values were significantly different from predose values (P = 0.031).83 In another study, bleeding time was affected slightly by celecoxib 600 mg qd when compared to naproxen 500 mg bid after 10 days. The mean increase in bleeding time for naproxen was 244.7 seconds vs. 60.5 seconds for celecoxib.
Summary
The decision to use NSAIDs for treatment of inflammatory arthritides and pain-producing conditions encountered in the emergency department or acute care clinic must weigh the potential clinic benefits of COX-2 inhibitors such as celecoxib against the potential short- and long-term adverse effects and/or discomfort that may be associated with "traditional" COX-1 inhibitors. Until the recent introduction of selective COX-2 inhibitors such as celecoxib, the risks of using traditional NSAIDs such as ibuprofen, naproxen, and ketoprofen frequently outweighed the possible benefits, especially in high-risk populations (i.e., the elderly; individuals with CHF and/or hypertension; patients with renal disease; patients on warfarin; and most importantly, patients at risk for gastric or duodenal ulceration).
The introduction of COX-2 inhibitors has dramatically changed the therapeutic landscape for anti-inflammatory treatment in the emergency department and acute care clinic. The mandate to use COX-2 inhibitors is now established, especially for the aforementioned high-risk subgroups, in whom the benefits of pain relief and inflammation management can now potentially be accomplished with a significant reduction in gastrointestinal complications, at least based on initial endoscopic surveillance studies and associated comparative data suggesting a 40- to 100-fold reduction in significant GI tract hemorrhage in patients taking selective COX-2 inhibitors.
Although both COX-2 inhibitors appear to be associated with a high benefit-to-risk ration, celecoxib appears to have features and flexibility that make it especially useful in the elderly patient with co-morbid conditions who is taking medications frequently prescribed in this age group: it has dual indications for both OA and RA, it can be administered safely in combination with aspirin or warfarin, and toleration is excellent. Based on evidence-based trial data, expert consensus, medico-legal considerations, and available post-marketing experience, the "risk management" upgrade from NSAIDs to COX-2 inhibitors makes excellent clinical sense. A "First, do no harm" medication that has "high benefit and low risk" should be considered a milestone in modern medicine. We’ve come a long way from aspirin.
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Physician CME Questions
17. To completely inhibit the COX-2 without affecting the COX-1, the COX-2 specific NSAID would need to be at least:
A. 20 × potent against COX-2 than COX-1.
B. 50 × potent against COX-2 than COX-1.
C. 80 × potent against COX-2 than COX-1.
D. 100 × potent against COX-2 than COX-1.
E. 150 × potent against COX-2 than COX-1.
18. COX-2 selective drugs may have the following advantages over traditional NSAIDs, except:
A. they inhibit mainly inducible COX-2 enzymes found at inflammatory sites and spare the constitutive COX-1 enzymes.
B. they can be given in patients taking warfarin.
C. they do not interfere with platelet activity, since platelets express only COX-1 enzymes and, thus, can be given during surgery.
D. they can theoretically be given in patients with asthma, since bronchial inflammatory cells produce cytokine-induced COX-2.
E. both celecoxib and rofecoxib can be given to patients with sulfa allergy.
19. Side effects of COX-2 selective NSAIDs are reported to be few but include which one of the following?
A. Peripheral edema
B. Increased risk of gastritis
C. Increased risk of renal insufficiency
D. Prolonged bleeding time
E. Exacerbation of asthma
20. Who discovered the COX-2 enzyme?
A. Vane
B. Miyamoto
C. Simmons
D. Hoffman
E. Dresser
21. NSAIDs most likely to cause liver toxicity include:
A. diclofenac, sulindac, and aspirin.
B. indomethacin, flubiprofen, and naproxen.
C. nabumetone, etodolac, and aspirin.
D. ketoprofen, sulindac, and ketorolac.
E. oxaprofin, diclofenac, and ibuprofen.
22. Approximately what percentage of NSAID prescriptions are written for patients 60 years of age or older?
A. 20%
B. 30%
C. 40%
D. 50%
23. Producion of the COX-2 isoform is induced by:
A. elevated PGE2 levels.
B. proinflammatory substances.
C. hyperkalemia.
D. hypertension.
24. Of 5285 patients studied who received celecoxib over a 1-6 month period, how many experienced significant upper GI bleeding?
A. .04%
B. .08%
C. .10%
D. 5%
Clarification
With reference to Table 1 in Vol. 20, No. 24, of Emergency Medicine Reports, it should be noted that the PORT scoring system includes age itself as point. Male patients receive the same number of points as their age, and female patients get the number of points equivalent to their age minus 10.
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