Are COX-2 Inhibitors Better NSAIDs?
November 15, 1999
Are COX-2 Inhibitors Better NSAIDs?
Authors: Keith K. Colburn, MD, Chief, Rheumatology, Pettis Veterans Medical Center and Loma Linda University Medical Center, Loma Linda, Calif; Raymond Flores, MD, Fellow of Rheumatology, Loma Linda, Calif; and John Rambharose, MD, Assistant Professor of Medicine, Loma Linda, Calif.
Peer Reviewer: Steen Mortensen, MD, Chief of Rheumatology, Wichita Clinic, Wichita, Kan.
Editor’s Note—This article is designed to inform the physician about how NSAIDs work pharmacologically, their potential side effects, and their use in a clinical setting. Traditional NSAIDs are compared with the new COX-2 selective NSAIDs as to their efficacy, mechanism of action, and relative toxicities. After reading this article, the physician should have an understanding of the current place of COX-2 selective NSAIDs in treatment programs requiring their use.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are taken by approximately 17 million Americans every day.1 NSAIDs account for about 4.5% of all prescriptions written in the United States.2 Worldwide, approximately 100 million prescriptions are written annually, amounting to more than $2 billion in sales, not including over-the-counter purchases.3 These figures reflect a large segment of the population suffering from rheumatic conditions. Individuals with arthritis and nonarticular rheumatism are often treated with NSAIDs to control inflammation and provide relief of pain and stiffness.
More than 50% of NSAID prescriptions are written for individuals older than 60 years of age for the management of osteoarthritis (OA).2,4 The use of NSAIDs is growing for non-rheumatic indications, such as acute and chronic pain from biliary or ureteral colic and dysmenorrhea.
NSAIDs exhibit analgesic, anti-inflammatory, antipyretic, and platelet inhibitory properties.1 Analgesic effects are obtained at lower doses than those required for anti-inflammatory activity. All NSAIDs, when prescribed at equipotent doses, are purported to show similar clinical efficacy. Clinical responses, however, vary among individuals in all populations.5 Unfortunately, complications from NSAID use in the United States result in approximately 100,000 hospitalizations a year at a cost of $4 billion and 10,000-20,000 deaths.6 Among the elderly alone, an estimated 41,000 hospitalizations and 3300 deaths are secondary to patients taking NSAIDs.7 Studies comparing diclofenac, naproxen, and acetaminophen showed that NSAID use in the elderly increased gastrointestinal (GI) complications three- to five-fold compared with non-NSAID users.8-13 As the geriatric population grows, the incidence of OA increases. This group with the highest risk of NSAID toxicity is most likely to be given NSAID prescriptions. Therefore, the search is ongoing for an NSAID, without side effects, that specifically targets molecules causing pain and inflammation. (See Table 1.)
| 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 |
There are no apparent differences in complication rates between the sexes. Other possible risk factors include smoking and alcohol use.14 It appears that complications from ingesting NSAIDs are noticeably greater in the first month of therapy and with higher doses.15,16
Historical Background of NSAIDs
Dating back to ancient Greece and Egypt, salicylic acid and salicylates extracted from myrtle leaves and willow bark were used as medications to treat fever, pain, and swelling. In 1860, salicylic acid was chemically synthesized in Germany. It was used as an external antiseptic, antipyretic, and a treatment for "rheumatism."
In 1899, Felix Hoffman, a chemist who worked for the Bayer Company, 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, phenylbutazone (introduced in 1949), and indomethacin (introduced in 1967). Due to their similar therapeutic action, they were grouped under the "aspirin-like" drug category. Since these drugs are clearly distinct from glucocorticoids, they were also called nonsteroidal anti-inflammatory drugs or NSAIDs.
In 1971, Vane demonstrated that inhibition of prostaglandin synthesis is the primary mechanism of action for NSAIDs.18 Miyamoto et al purified cyclooxegenase (COX) in 1976, identifying the key pathway in prostanoid synthesis inhibited by NSAIDs.19 In 1989, Simmons et al identified a second enzyme with COX activity. Upon this new discovery, 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 Reverend 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 |
With the major pathway of NSAID action identified, new medications are being developed to inhibit the activity of specifically COX-2 enzymes. These developments may lead to safer and better tolerated NSAIDs and maybe even prevention of Alzheimer’s disease and cancer.
Mechanism of Action of the NSAIDs
NSAIDs are cyclooxygenase inhibitors. The side effects of these medications may be, in part, attributable to the inhibition of prostaglandin production.21,22 The two forms, 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. 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 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 | ||
| 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 cytoprotection, 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, constitutively expressed in the brain and kidney, is found elsewhere in significant quantities only in regions of active inflammation23,24 and is undetectable under basal conditions in other tissues.25,26 Both isoforms share a 60% amino acid sequence homology and differ in their tertiary structures. The COX-2, unlike the COX-1 enzyme, 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
COX-1 and COX-2 have distinct patterns of expression. COX-1 is a "constitutive" enzyme, meaning that it is always present, found in most tissues, and is involved in physiologic homeostasis maintaining the integrity of gastric and duodenal lining and 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.
The COX-1 enzyme does not appear to be involved in the mediation of the inflammatory response and 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 Smith et al 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
The COX-2 isoform is an "inducible" enzyme, meaning that it is normally undetected unless stimulated or, if expressed, is found in low levels. Anderson and colleagues 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, were elevated in the affected paws. Also, serum IL-6 was increased. 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 patients with OA or healthy individuals, it is found at low levels or not at all.32 An NSAID selective for COX-2 inhibition has the potential of being an "ideal" anti-inflammatory drug, since it spares COX-1, consequently avoiding GI damage and possibly renal toxicity.
In a study of human synovial tissue from patients with RA, ankylosing spondylitis, and psoriatic arthritis compared with patients with OA, there was increased expression of COX-2 enzyme but not COX-1, further confirming the importance of this enzyme in inflammatory diseases.33
The different NSAIDs vary in their COX-1 and COX-2 selectivity. 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 a greater COX-2 inhibition than a ratio greater than 1, while an IC50 of 1 reflects equal selectivity. 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. These NSAIDs have been referred to as COX-2 "preferential." Drugs that show 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 prior to the introduction of the COX-2 inhibitors.36 NSAIDs introduced prior to celecoxib are capable of GI mucosal prostaglandin depletion at customary therapeutic doses. Early studies showed no prostaglandin inhibition with NS-398, an experimental COX-2 inhibitor, and nonacetylated salicylic acid.36 To completely inhibit COX-2 without affecting the COX-1, the ideal NSAID should be 100 times more potent against COX-2 than COX-1 and 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. Celecoxib demonstrated a 375-fold selectivity for COX-2, while rofecoxib had an 800-fold selectivity for COX-2 in human enzyme systems.34,37 The clinical significance of the difference in COX-2 selectivity between these drugs remains undetermined. Celecoxib was introduced onto the market in February 1999. Rofecoxib was released in June 1999.
| 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. | ||
A recent review comparing celecoxib, meloxicam, and nabumetone in dogs demonstrated GI and renal injury in all the subjects given nabumetone, some given meloxicam, and none in the celecoxib group.38
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 acid. CYP2C also has subfamilies including CYP2C9.
CYP2C9 inhibitors, such as zarfilukast, fluconazole, and fluvastatin, may increase the serum concentration of celecoxib. Celecoxib also inhibits CYP2D6. Drugs metabolized by this enzyme, including beta-blockers, antidepressants, and antipsychotics, need to be appropriately adjusted.39
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
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 FDA approval for RA treatment but was expected to within 12 months.41 Oral doses of rofecoxib 12.5-50 mg daily were found to be as effective for the treatment of OA as diclofenac (Voltaren) 50 mg PO three times a day.42 Details of this study are discussed under the heading, "Safety and Efficacy of COX-2 Inhibitors."
Rofecoxib is contraindicated in patients who exhibit an allergic reaction to aspirin and NSAIDs. Unlike Celebrex, 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
Adverse Drug Reactions of NSAIDs
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 in the treatment of the inflammatory arthritides, supplementing disease-modifying antirheumatic drugs (DMARDs) to reduce pain and inflammation. Unlike DMARDs, NSAIDs do not slow the progression of the disease process. They are often beneficial for pain relief but also may be responsible for significant, and even fatal, side effects (see Table 5).44
| 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 | |
Recent studies using "knock out" mice (genetically engineered to delete the COX-2 gene from the genome) produced no gastric ulcers. However, the mice developed renal dysplasia, cardiac fibrosis, and were susceptible to developing peritonitis.45,46 These abnormalities may have occurred as a result of the lack of fetal or adult expression of the COX-2 gene. In several standard models of inflammation in mice, the normal inflammatory response was unexpectedly preserved.47 These findings suggest that genes other than COX-2 may also be involved in the inflammatory response.
Gastrointestinal Effects. GI side effects from 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 pro-drugs like sulindac (Clinoril). Unfortunately, GI mucosal damage and ulcers still occurred with all of these formulations.48,51,52
Another commonly used strategy is the ingestion of NSAIDs with food. A study of healthy volunteers failed to support this approach.53 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 Baskin and colleagues 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
Hawkey and colleagues 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
Controversy exists 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 MacDonald et al concluded that the risk for any upper GI event was "constant during continuous exposure." In this study, the risk of any GI event increased 5-10-fold while the subjects were on NSAIDs vs. the period prior to NSAID therapy. Risks were initially high but decreased to baseline up to one year after discontinuation of the drug. The constant risk theory was countered by Singh in two reviews on NSAID-induced bleeding.62,63 He 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 Singh cited a 10-15-year study following 1600 subjects from the inception of NSAID therapy that 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 is 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 Sheng et al studied two human colon cancer cell lines.67 One cell line, HCA-7, expressed COX-2, while the other, HCT-116, did not. Nude mice implanted with HCA-7, when treated with the selective COX-2 inhibitor, SC-58125, showed reduced tumor formation by 85-90%.
SC-58125 had no effect on tumorigenesis in the nude mice HCT-116 implanted with cell cultures.67 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. Most nonaspirin NSAIDs 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 the endothelial and smooth muscle cells of the renal vasculature and in the podocytes of the glomerulus. Unlike in the rat, COX isoforms were not detected in the macula densa of humans.73 COX-1 was found to be 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 vasocontrictive effects of angiotensin II and norepinephrine. NSAID use is 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
Short-term studies of patients with RA and OA taking celecoxib 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 Furst and Hillson, 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 U.S.) 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 seen with naproxen.83 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 known 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 was reported, suggesting a COX-2 role in the pathogenesis of asthma.91 COX-2 blockade may be therapeutic in asthma, contrary to older NSAIDs, which can cause bronchoconstriction and edema, especially in aspirin-sensitive patients. However, we are not aware of studies using COX-2 inhibitors for asthma treatment.
Central Nervous System Effects. NSAIDs can cause headaches, confusion, dizziness, and aggravate psychiatric illness, epilepsy, and parkisonism. The 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 was reported, implying 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 mechanism is unknown.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 needed in the normal oocyte development and probably in the 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 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
In a recent meta-analysis of 50 studies, NSAIDs increased the mean blood pressure by approximately 5 mmHg.102 The 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 congestive heart failure 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), received FDA approval this year. The potential for this new class of NSAIDs to profoundly affect the way physicians prescribe anti-inflammatory drugs should not be minimized. Early studies comparing side effects of the COX-2 inhibitors with other NSAIDs are impressive, especially in the GI system. The safety and efficacy of celecoxib in rheumatoid arthritis (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, or 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
Rofecoxib was studied in a double-blind, multicenter trial of 78 patients with OA. Patients with OA of the knee or hip were randomized to 12.5 mg or 25 mg qd of rofecoxib vs. 50 mg tid of diclofenac over 26 weeks. Analgesia was measured by the VAS, patient assessment and investigator assessment, and the Western Ontario & McMaster Universities VA 3.0 Osteoarthritis Index (WOMAC),106 a self-administered questionnaire that measures joint pain, stiffness, and physical function. These combined testing methods found rofecoxib at both doses to be as effective as diclofenac.42 Withdrawals due to adverse events were greater in the diclofenac group than in either rofecoxib group (P < 0.05).42 These findings were confirmed in a similar study population of 736 patients with OA randomized to receive rofecoxib 12.5 mg or 25 mg qd, ibuprofen 800 mg tid, or placebo.107 At the end of the six-week trial, all treatment groups were found to be superior to placebo and demonstrated comparable efficacy using the WOMAC scale. Withdrawals from the active treatment groups were also comparable. The only case of gastric ulcer with GI bleeding occurred in the ibuprofen group.107
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 and 38.1 seconds for placebo.83
Both celecoxib and the S-enantiomer of warfarin are metabolized in the liver by the P450 cytochrome enzyme, isoform CYP2C9. In order to investigate the possibility of celecoxib-warfarin drug interaction, 24 healthy volunteers were given warfarin 2-5 mg qd for three consecutive days to achieve a stable prothrombin time of 1.2-1.7 times the pretreatment values. The patients were then randomized to receive celecoxib 200 mg bid or placebo in addition to their maintenance dose of warfarin for seven days. The pharmacokinetics of either the R- or S-enantiomer of warfarin was unaffected when used in combination with the placebo or celecoxib.84
The effect of celecoxib 200 mg bid on 14 female RA patients on a stable dose of methotrexate 5-20 mg per week for at least three months was examined. Celecoxib had no clinically significant effect on the bioavailability or renal clearance of methotrexate.39 Rofecoxib, however, appears to enhance the effect of methotrexate, according to the manufacturer’s early releases.
The COX-2 selective inhibitors show a decreased rate of gastroduodenal ulcers. The incidence of gastroduodenal ulcers found on endoscopy in a study of patients with RA was 26% for the naproxen group, 6% for both the 400 and 100 mg bid celecoxib groups, and 4% in both the 200 mg bid celecoxib and placebo groups.105 Further safety was demonstrated in a six-month study of celecoxib 200 mg bid compared to diclofenac 75 mg in 655 RA patients.105 The rate of endoscopically proven gastroduodenal ulceration at 24 weeks or early termination was 4% for the celecoxib group and 15% for the diclofenac group.105
It appears that ideal candidates for the use of the new COX-2 selective NSAIDs include those patients with a history of side effects from standard NSAIDs, a history of peptic ulcer disease, the elderly, patients on anticoagulants needing an NSAID, and maybe those with renal insufficiency (although not yet confirmed).
Summary
The new COX-2 selective drugs provide hope that the high incidence of side effects from traditional NSAIDs may decrease. The selectivity and efficacy of celecoxib and rofecoxib are both promising and encouraging. It is too early to know if these drugs will be superior to the traditional NSAIDs, thus justifying their use. Those of us in the practice of medicine need to be observant for possible complications and adverse reactions not seen in previous controlled studies. However, barring the emergence of unexpected side effects, COX-2 inhibitors are likely to change the way we treat patients with pain and inflammation, especially the elderly, those at risk for GI bleeding and renal insufficiency, and patients using warfarin. COX-2 inhibitors, if they indeed have fewer toxic side effects than traditional NSAIDs, may dominate the NSAID market, becoming a prominent treatment modality in the management of pain and inflammation if the price is right!
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CME Questions
56. 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.
57. 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 even 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.
58. 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
59. Who discovered the COX-2 enzyme?
a. Vane
b. Miyamoto
c. Simmons
d. Hoffman
e. Dresser
60. 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.
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