ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Overview of COX-2 selective NSAIDs

Overview of COX-2 selective NSAIDs
Literature review current through: Jan 2024.
This topic last updated: Nov 15, 2023.

INTRODUCTION — Nonsteroidal antiinflammatory drugs (NSAIDs) exert analgesic, antipyretic, and antiinflammatory effects and cause a range of adverse effects, largely through the inhibition of cyclooxygenase (COX; prostaglandin synthase [PGHS]), which impairs the ultimate transformation of arachidonic acid to prostaglandins, prostacyclin, and thromboxanes (figure 1) [1].

There are two related isoforms of the COX enzyme, COX-1 and COX-2, with important differences in the regulation and expression of these enzymes in various tissues [2,3]. The extent of enzyme inhibition varies among the different NSAIDs [4,5], and the degree to which a particular NSAID inhibits an isoform of COX may affect both the activity and toxicity of that NSAID.

Most NSAIDs, until the discovery of the COX-2 isoform in the early 1990s, were effective inhibitors of both forms of COX; subsequent to those observations, there was an effort to develop NSAIDs that preferentially inhibited COX-2, the isoform that is upregulated in inflammatory states and involved in the production of inflammatory mediators, while sparing COX-1, which is important for gastric cytoprotection. These newer drugs were termed COX-2 selective NSAIDs and also referred to as COX-2 inhibitors, selective COX-2 inhibitors, and coxibs.

An overview of the COX-2 selective NSAIDs, particularly of those characteristics that distinguish them from COX nonselective NSAIDs, is presented here. The uses of COX-2 selective NSAIDs in specific disorders are also discussed elsewhere (see appropriate topic reviews). The therapeutic and pharmacologic effects of NSAIDs overall and an overview of the adverse effects of nonselective NSAIDs are presented separately. (See "NSAIDs: Therapeutic use and variability of response in adults" and "NSAIDs (including aspirin): Pharmacology and mechanism of action" and "Nonselective NSAIDs: Overview of adverse effects".)

MECHANISM OF ACTION

Cyclooxygenase biology — The primary effect of nonsteroidal antiinflammatory drugs (NSAIDs) is to inhibit cyclooxygenase (COX, or prostaglandin synthase [PGHS]); as a result, NSAIDs impair the ultimate transformation of arachidonic acid to its metabolites, including prostaglandins, prostacyclin, and thromboxanes (figure 1) [1]. The extent of enzyme inhibition varies among the different NSAIDs [6], although there are no studies relating the degree of COX inhibition to antiinflammatory efficacy in individual patients [4,5]. (See "NSAIDs (including aspirin): Pharmacology and mechanism of action".)

Two related isoforms of the COX enzyme have been described [2,3]: COX-1 (PGHS-1) and COX-2 (PGHS-2). They possess 60 percent homology in those amino acid sequences apparently conserved for catalysis of arachidonic acid [7-11]. The most important differences between the two isoforms are the regulation and expression of the enzymes in various tissues:

COX-1 is expressed in most tissues, but variably. It is described as a "housekeeping" enzyme, regulating normal cellular processes (such as gastric cytoprotection, vascular homeostasis, platelet aggregation, and kidney function), and it is stimulated by hormones or growth factors.

COX-2 is constitutively expressed in the brain, in the kidney, in bone, and probably in the female reproductive system [12]. Its expression at other sites is increased during states of inflammation or, experimentally, in response to mitogenic stimuli. As an example, growth factors, phorbol esters, and interleukin (IL)-1 stimulate the expression of COX-2 in fibroblasts, while endotoxin serves the same function in monocytes/macrophages [3,13].

Both COX isoforms are regulated by physiologic stimuli, including shear stress in the vasculature [14] and ovulation and implantation in the female reproductive tract of rodents [15]. Increased expression of COX-2 messenger RNA (mRNA) and protein has been described in the human kidney in nonphysiologic states such as diabetic nephropathy, hypertension, bone fracture, and heart failure (HF) [16]. The clinical relevance of this is not yet clear.

COX-2 selective NSAIDs (coxibs) — COX-2 selective NSAIDs (variably termed COX-2 selective NSAIDs, COX-2 inhibitors, selective COX-2 inhibitors, or coxibs) were developed in an attempt to inhibit the inducible COX-2 isoform without having a substantial effect on the constitutive COX-1 isoform. The hope was that this formulation could decrease inflammation, improve effectiveness, and also minimize toxicities including gastrointestinal adverse effects. (See "NSAIDs (including aspirin): Pathogenesis and risk factors for gastroduodenal toxicity", section on 'COX-1 mediated NSAID injury'.)

COX-2 selective NSAIDs demonstrate at least a 200- to 300-fold selectivity for inhibition of COX-2 over COX-1 at the defined therapeutic doses (figure 2). They are more effective at inhibiting COX-2 and less effective at inhibiting COX-1 compared with nonselective NSAIDs. COX-2 selectivity is a dose-related phenomenon, with decreased selectivity with higher doses within the recommended ranges and particularly above the usual recommended doses. In the doses used clinically, COX-2 selective NSAIDs provide comparable analgesia to the nonselective NSAIDs among patients with rheumatoid arthritis and osteoarthritis and several other potential benefits, particularly a reduction in gastroduodenal toxicity (since COX-1 is involved in gastric cytoprotection). (See 'Therapeutic effects and usage' below.)

Subsequent to the description and characterization of COX-2, several COX-2 selective NSAIDs were approved by the US Food and Drug Administration (FDA) for use in rheumatoid arthritis and osteoarthritis, including celecoxib, rofecoxib, and valdecoxib, and rofecoxib and celecoxib were also approved for use in acute pain. However, rofecoxib was withdrawn worldwide by the manufacturer in 2004 because of an increased risk of adverse cardiovascular events, and valdecoxib was withdrawn from the United States and European Union markets in 2005. Parecoxib, a water soluble prodrug of valdecoxib, is administered intravenously and available in Europe but not in the United States. Etoricoxib is another coxib that is available in Europe and some non-European countries, but it has never been available for use in the United States. The one remaining agent in this class in the United States, celecoxib, never received approval from the FDA to be marketed as safer than nonselective NSAIDs on the gastrointestinal system. (See "NSAIDs: Adverse cardiovascular effects".)

THERAPEUTIC EFFECTS AND USAGE — Nonselective and cyclooxygenase 2 (COX-2) selective NSAIDs have similar overall efficacy as analgesic, antiinflammatory, and antipyretic agents in the doses used clinically, although responses to particular agents can vary among individuals (see "NSAIDs: Therapeutic use and variability of response in adults"). These benefits have been shown in multiple conditions, including osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and other disorders; and with a number of COX-2 selective agents [17-30]. The clinical use of NSAIDs in these and other conditions is described separately (see appropriate topic reviews).

The choice to use a COX-2 selective NSAID rather than a nonselective NSAID is sometimes based upon its reduced risk of gastroduodenal toxicity compared with nonselective NSAIDs. The use of these agents for primary and secondary prevention of gastroduodenal toxicity and the adverse effects and benefits, respectively, of concomitant therapy with aspirin and proton pump inhibitors in these settings are described in detail separately. (See 'Reduction in gastroduodenal toxicity' below and "NSAIDs (including aspirin): Treatment and secondary prevention of gastroduodenal toxicity".)

COX-2 selective NSAIDs may also be used in selected patients in whom their reduced capacity for platelet inhibition and low risk for triggering aspirin-exacerbated respiratory disease have advantages. (See 'Lack of platelet inhibition and use during anticoagulation' below and 'Lack of bronchoconstriction' below.)

A number of studies have documented an association between the use of aspirin and other NSAIDs, including the COX-2 selective NSAID celecoxib, and a reduced risk of colorectal adenomas; this reduction in risk extends to colorectal cancer. The evidence supporting these associations and the mechanisms proposed to explain these observations are described elsewhere. (See "NSAIDs (including aspirin): Role in prevention of colorectal cancer".)

REDUCTION IN TOXICITIES WITH COX-2 SELECTIVE NSAIDS (COXIBS) — Several toxicities associated with nonsteroidal antiinflammatory drug (NSAID) use occur less frequently or to a lesser degree with the cyclooxygenase 2 (COX-2) selective inhibitors than with most nonselective NSAIDs, when used at the approved doses. There is reduced gastroduodenal toxicity, minimal to no effect upon platelet function, and reduced bleeding risk (see 'Reduction in gastroduodenal toxicity' below and 'Lack of platelet inhibition and use during anticoagulation' below). In addition, the COX-2 selective NSAIDs appear to have little risk of precipitating bronchospasm in patients with aspirin-induced asthma. (See 'Lack of bronchoconstriction' below.)

Reduction in gastroduodenal toxicity — Many clinical trials have confirmed the relative reduction in gastroduodenal toxicity of all of the selective COX-2 inhibitors when compared with nonselective NSAIDs in comparably therapeutic doses. Detailed information regarding these trials is presented elsewhere. (See "COX-2 inhibitors and gastroduodenal toxicity: Major clinical trials" and "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity" and "NSAIDs (including aspirin): Treatment and secondary prevention of gastroduodenal toxicity".)

A possible concern regarding selective COX-2 inhibition is the potential to delay healing of gastric erosions or ulcers, an effect that has been observed in mouse models [31]. Although neither a clinically significant nor statistically significant delay in healing of ulcers was observed in the clinical trials of celecoxib, approximately 40 percent of the patients included in the trials were required to be free of ulcers prior to study entry. In addition, studies on rofecoxib excluded patients with active peptic ulcer disease. Thus, it is still unclear whether the COX-2 selective inhibitors may induce damage to the gastrointestinal tract, even though there may be no effects on COX-1 activity in vivo at any therapeutic dose. Instead, the observed gastrointestinal effects of the COX-2 selective inhibitors may be due to the drug effect on healing of ulcers induced through other pathologic effects. (See "NSAIDs (including aspirin): Pathogenesis and risk factors for gastroduodenal toxicity".)

Coadministration with low-dose aspirin — The potential gastroduodenal sparing effect with COX-2 selective agents may be counterbalanced by toxicity from concurrent low-dose aspirin therapy for primary or secondary prevention of cardiovascular or cerebrovascular disease, although this effect can be mitigated substantially by use of a proton pump inhibitor. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity" and "Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'Bleeding'.)

Lack of platelet inhibition and use during anticoagulation — COX-2 selective NSAIDs have little to no inhibitory effect upon platelet function. Generation of prostanoids by activated platelets plays an important role in platelet function and in promoting vasoconstriction (see "Platelet biology and mechanism of anti-platelet drugs", section on 'Cyclooxygenase (COX)-1'). Production of the potent prostanoid, thromboxane A2, is dependent upon COX-1, and inhibition of COX-2 alone produces little or no effect upon platelet function, including platelet aggregation and adhesion [32]. This property results in reduced bleeding risk in warfarin-treated patients being treated concurrently with a COX-2 selective NSAID compared with those receiving a nonselective NSAID [33].

The lack of platelet inhibition has been shown in a study in which doses of celecoxib much larger than those used in clinical practice were given to normal subjects for 10 days; platelet function was assessed with in vitro measures as well as measurement of bleeding time [32]. Neither celecoxib at 600 mg twice daily (which is greater than the usual maximum dose of 200 mg twice daily) nor placebo had any measurable effect on platelet function, while naproxen 500 mg twice daily produced significant prolongation of the bleeding time and decreases in platelet aggregation and adhesion.

The lack of an inhibitory effect on platelet function of the COX-2 selective inhibitors may be valuable when an NSAID is needed in a patient receiving ongoing anticoagulation. This was illustrated by a case-control study of 1491 reported episodes of bleeding in patients who were on anticoagulation therapy with a coumarin-related coumarin derivative (phenprocoumon or acenocoumarol) [33]. Cases were patients who bled who reported use of an NSAID (COX-2 selective or nonselective), and controls were coumarin derivative-treated patients who reported NSAID use but who did not bleed. Cases more often used a nonselective NSAID than controls (96 versus 88 percent, respectively). The bleeding risk was approximately threefold higher for those using nonselective agents compared with use of COX-2 selective inhibitors (adjusted odds ratio [OR] 3.07, 95% CI 1.18-8.03). Use of highly selective COX-2 inhibitors was infrequent, with most patients using somewhat selective agents (nabumetone and meloxicam) (see 'Other relatively selective COX-2 inhibitors' below). A subsequent meta-analysis supported the relative safety of selective COX-2 inhibitor (celecoxib, parecoxib, or etoricoxib) use during the perioperative period, compared with nonselective NSAIDs, analgesics, or placebo, with no increased risk of bleeding observed with the COX-2 selective agents [34].

Lack of bronchoconstriction — Unlike aspirin and some NSAIDs, COX-2 selective inhibitors appear to have little risk of precipitating bronchospasm in patients with aspirin-induced asthma (see "NSAIDs (including aspirin): Allergic and pseudoallergic reactions", section on 'Highly selective COX-2 inhibitors' and "Aspirin-exacerbated respiratory disease"). However, despite the reassuring data from clinical trials, it should be noted that the manufacturers' labeling for the coxibs in the United States includes a warning that they should not be given to patients who have experienced asthma, urticaria, or allergic reactions after taking aspirin or other NSAIDs.

Lack of high blood pressure — In contrast to non-selective NSAIDs, COX-2 selective NSAIDs do not appear to be associated with hypertension. A multicenter, double-blind trial examined the effects of different types of NSAIDs on 24-hour blood pressure measurements in patients with osteoarthritis or rheumatoid arthritis who had or were at risk for coronary artery disease [35]. At four months, the change in 24-hour mean systolic blood pressure was -0.3 mmHg (95% CI, -2.25 to 1.74) in patients randomly assigned to the COX-2 selective NSAID compared with 3.7 mmHg (95% CI, 1.72-5.58) in patients assigned to the nonselective NSAID ibuprofen. In addition, the incidence of new-onset hypertension was lower in the celecoxib group (10 versus 23 percent).

TOXICITIES AND POSSIBLE TOXICITIES — The cyclooxygenase 2 (COX-2) selective nonsteroidal antiinflammatory drugs (NSAIDs) share a number of potential risks for adverse events with other NSAIDs, including increased risk of cardiovascular adverse events, renal compromise, and others, despite their potential for reducing the likelihood of gastroduodenal and other selected toxicities. (See 'Reduction in toxicities with COX-2 selective NSAIDs (coxibs)' above.)

Cardiovascular disease — In patients with and without cardiovascular disease, the use of most NSAIDs, including nonselective NSAIDs and coxibs, is associated with an increased risk of adverse cardiovascular events, including death, myocardial infarction (MI), heart failure (HF), and stroke. The increase in absolute risk varies depending upon the baseline cardiovascular risk of the patient, the NSAID chosen, and its dose. To minimize the risk for an adverse cardiovascular event in patients treated with an NSAID, it should be prescribed at the lowest effective dose for the shortest duration possible. A discussion of the adverse cardiovascular effects that may occur with COX-2 selective and nonselective NSAIDs is presented in detail separately. (See "NSAIDs: Adverse cardiovascular effects".)

Kidney disease — NSAIDs, including the COX-2 selective agents, can induce several different forms of kidney injury (table 1). COX-2 selective NSAIDs as well as nonselective NSAIDs may cause acute kidney injury (AKI) by the attenuation of renal vasodilation in patients in whom the secretion of vasodilator prostaglandins is increased to counteract the effect of increased renal vasoconstrictors such as angiotensin II. Risk factors for NSAID-induced AKI include chronic kidney disease (CKD); volume depletion from aggressive diuresis, vomiting or diarrhea, or effective arterial volume depletion due to HF, nephrotic syndrome, or cirrhosis; and severe hypercalcemia. Medications including diuretics, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), and calcineurin inhibitors (CNIs) also can increase the risk of NSAID-induced AKI. Higher doses of NSAIDs are associated with a greater risk of AKI. Hemodynamically mediated acute renal failure due to NSAIDs is discussed in detail separately. (See "NSAIDs: Acute kidney injury".)

The role of nonselective and of COX-2 selective NSAIDs in other forms of kidney disease, including electrolyte and acid-base disorders; acute interstitial nephritis (AIN), which may be accompanied by the nephrotic syndrome; and papillary necrosis and CKD, are discussed separately. (See "NSAIDs: Electrolyte complications" and "Clinical manifestations and diagnosis of acute interstitial nephritis" and "Epidemiology and pathogenesis of analgesic-related chronic kidney disease".)

There are relatively few data directly comparing the risk of kidney injury with COX-2 selective and nonselective NSAIDs.

However, there is evidence from the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION) trial that celecoxib may be associated with fewer clinically significant kidney events than ibuprofen [36,37]. There were nearly 40 percent fewer kidney events in adults using celecoxib compared with ibuprofen (hazard ratio [HR] 0.61, 95% CI 0.44-0.85). The trend was similar when comparing celecoxib with naproxen, but did not reach statistical significance (HR 0.79, 95% CI 0.56-1.12).

Multiple studies in vitro and in animals suggest that the COX-2 enzyme has a significant role in kidney development and function [38-42]. In mice, for example, deletion of the COX-2 gene is associated with aberrant kidney development after birth, resulting in marked diffuse tubular cysts, glomerular hypoplasia, interstitial fibrosis, and kidney failure [38,43]. The enzyme is also constitutively expressed and occasionally upregulated in the macula densa, cortical thick ascending limb, and cortical collecting duct [39]. In rabbits, the functional effects of selective COX-2 inhibition include an enhanced pressor effect of angiotensin-2 and decreased renal medullary blood flow, urine output, and sodium excretion [44].

Sulfonamide allergy — The molecular structures of celecoxib and valdecoxib include a sulfonamide moiety, whereas rofecoxib contained a sulfone. The sulfur components are necessary for receptor binding, but their varying structures have different potentials for causing allergic reactions.

Celecoxib — Cross-reactivity between antimicrobial sulfonamides (such as trimethoprim-sulfamethoxazole) and celecoxib (a non-arylamine sulfonamide) has not been adequately analyzed, although some studies suggest it is unlikely. The risk of allergic reactions to celecoxib, potential cross-reactivity with antimicrobial sulfonamides, and the use of celecoxib in patients with a history of possible antimicrobial sulfonamide hypersensitivity are discussed in more detail separately. (See "Sulfonamide allergy in HIV-uninfected patients", section on 'Celecoxib'.)

The COX-2 selective agents, including celecoxib, are associated with higher rates of Stevens-Johnson syndrome and toxic epidermal necrolysis. (See "Sulfonamide allergy in HIV-uninfected patients", section on 'Celecoxib' and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

Valdecoxib — Initial clinical trials of valdecoxib included patients with a history of sulfonamide allergy, and there was no higher incidence of allergic reactions noted. As a result, sulfonamide allergy was initially not considered a contraindication to the use of valdecoxib. However, postmarketing reports of serious anaphylactoid reactions in sulfonamide-allergic patients who received valdecoxib led to relabeling with a caution against use of this agent in patients with an allergy to sulfonamide-containing antibiotics [45].

In 2005, the US Food and Drug Administration (FDA) recommended and the manufacturer agreed to a withdrawal of valdecoxib from the United States and European Union markets. Parecoxib, a water soluble prodrug of valdecoxib, is administered intravenously and is available in Europe but not in the United States.

Anaphylactoid reaction — Patients who have had anaphylactoid reactions to aspirin or nonselective NSAIDs may be at risk for similar effects when challenged with COX-2 selective agents. This was illustrated by one patient with well-documented anaphylactoid reactions to diclofenac-misoprostol who had a similar reaction (shaking, flushing, and hypotension) when given rofecoxib [46]. Rapid resolution of symptoms and hypotension followed subcutaneous epinephrine and intravenous administration of saline, diphenhydramine, and methylprednisolone. (See "Anaphylaxis: Emergency treatment".)

Anaphylactoid reactions and angioedema have been reported in association with valdecoxib; serious skin reactions have also been noted, including exfoliative dermatitis, toxic epidermal necrolysis, and Stevens-Johnson syndrome [47].

Aseptic meningitis — Postmarketing surveillance has identified rare cases of aseptic meningitis with celecoxib [48], as well as at least five cases in patients treated with rofecoxib [49]. This uncommon side effect also occurs in patients treated with nonselective NSAIDs. (See "Nonselective NSAIDs: Overview of adverse effects", section on 'Neurologic' and "Aseptic meningitis in adults".)

Healing of musculoskeletal injury

Possible effect on fracture healing — A small increased risk of nonunion in patients with bone fractures has been reported with the use of nonselective NSAIDs or COX-2 selective agents. However, a causal relationship has not been proven, and the effect of these drugs on fracture healing in humans is uncertain. At present, we would not avoid the use of these agents in patients with fractures, given the very small absolute risk. This is discussed in more detail elsewhere. (See "Nonselective NSAIDs: Overview of adverse effects", section on 'Possible effect on fracture healing'.)

Possible effect on tendon injury — Possible effects on tendon and ligament injury are discussed elsewhere. (See "Nonselective NSAIDs: Overview of adverse effects", section on 'Possible effect on tendon injury'.)

Effects on vision — Irreversible blindness, temporary loss of vision, chromatopsia, and other visual abnormalities have occurred in patients taking selective COX-2 inhibitors. A postmarketing surveillance program in New Zealand identified seven cases of visual disturbances in patients taking celecoxib or rofecoxib; in the six cases where the outcome was known, vision recovered after the selective COX-2 inhibitor was stopped [50]. As of May 2003, reports to the World Health Organization's Collaborating Center for International Drug Monitoring included 37 cases of blindness and 14 cases of temporary blindness associated with use of selective COX-2 inhibitors. However, a possible association with temporary or permanent visual loss was also noted with nonselective NSAIDs.

It is difficult, from postmarketing reports, to conclude that there is a clear causal relationship between use of COX-2 inhibitors or other NSAIDs and vision problems. Although the issue of causality deserves further study, occurrence of otherwise unexplained loss of vision, blurred vision, color vision changes, or scotomata should lead to discontinuation of a COX-2 selective or nonselective NSAID.

Pregnancy and lactation — The safety of NSAIDs during pregnancy and lactation is discussed separately. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'NSAIDs'.)

OTHER RELATIVELY SELECTIVE COX-2 INHIBITORS — Some older nonsteroidal antiinflammatory drug (NSAIDs), including nabumetone, meloxicam, and etodolac, are also relatively selective for cyclooxygenase 2 (COX-2) at lower doses. Diclofenac also exhibits some evidence of COX-2 selectivity. (See 'Nabumetone' below and 'Meloxicam and etodolac' below and 'Diclofenac' below.)

Nabumetone — Nabumetone appears to be a more effective inhibitor of COX-2 than COX-1 in some experimental systems [51]. Limited clinical data suggest that nabumetone may be less likely to induce gastric ulcers than other NSAIDs. However, relative inhibition of COX-2 decreases and the risk of ulcer disease increases when higher doses of nabumetone are used. In one report, for example, the administration of nabumetone to healthy human volunteers at an adequate antiinflammatory dose inhibited COX-2 and COX-1 to the same degree [51]. Use of an in vitro model showed that 6-MNA (the active metabolite of nabumetone) also equally inhibited both COX isoforms in a whole blood system consisting of inducible mononuclear cells. These results were supported by a second study that found that most NSAIDs did not spare COX-1 activity at therapeutic concentrations [52]. Thus, rather than a selective effect on COX-2, the relative gastric protection observed with nabumetone may be due to the neutral state of its prodrug formulation and the fact that 6-MNA is not a powerful inhibitor of COX at low doses.

Meloxicam and etodolac — Meloxicam and etodolac also inhibit the COX-2 isoform more than COX-1 (10 to 1 ratio) [53,54]. Meloxicam, an NSAID with similar properties to etodolac, is available in the United States, Europe, and elsewhere at doses of 7.5 and 15 mg once per day. Meloxicam and etodolac were shown to principally inhibit the activity of COX-2 at low doses, while there is greater effect upon COX-1 at higher doses. This loss of COX-2 selectivity with higher approved doses is reflected by an increase in the rate of serious gastrointestinal adverse events when a meloxicam dose of 15 mg per day is compared with 7.5 mg per day [55]. In general, meloxicam has similar effects when used clinically to those of the other NSAIDs [56,57].

Diclofenac — Diclofenac is another NSAID with relative COX-2 selectivity at recommended doses. It is approved by the US Food and Drug Administration (FDA) for osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis and has been one of the most commonly used NSAIDs worldwide for a variety of conditions. Its major dose forms are oral and topical. In the United States and many other countries, both dose forms carry warnings for cardiovascular and gastrointestinal risks, similar to all other NSAIDs. While several studies have suggested an increase in cardiovascular risk associated with diclofenac similar to the now-withdrawn rofecoxib, this has not been a consistent finding [58-60]. The cardiovascular risks of diclofenac are described in more detail separately. (See "NSAIDs: Adverse cardiovascular effects".)

Topical diclofenac seems to produce similar benefits in knee osteoarthritis with fewer gastrointestinal symptoms [61], and at least one study has found less cardiovascular toxicity with topical compared with oral use [62].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Beyond the Basics topic (see "Patient education: Nonsteroidal antiinflammatory drugs (NSAIDs) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Mechanism of action – Nonsteroidal antiinflammatory drugs (NSAIDs) act to inhibit cyclooxygenase (COX, or prostaglandin synthase [PGHS]); as a result, NSAIDs impair the transformation of arachidonic acid to its metabolites, including prostaglandins, prostacyclin, and thromboxanes (figure 1).

COX enzymes – Two related isoforms of the COX enzyme have been described. COX-1 is variably expressed in most tissues and regulates normal cellular processes (such as gastric cytoprotection, vascular homeostasis, platelet aggregation, and kidney function). COX-2 is constitutively expressed in just a few organs and is increasingly expressed at other sites in response to inflammation. (See 'Cyclooxygenase biology' above.)

COX-2 selective NSAIDs – NSAIDs that selectively inhibit COX-2 rather than both COX enzymes were developed in an effort to preserve antiinflammatory effects while reducing COX-1-dependent adverse effects, such as gastroduodenal toxicity. However, it is important to recognize that the COX-2 selectivity is a dose-related phenomenon, with decreased selectivity with higher doses within the recommended ranges and particularly above the usual recommended doses. (See 'COX-2 selective NSAIDs (coxibs)' above.)

Therapeutic effects and usage – COX-2 selective and nonselective NSAIDs have similar overall efficacy as analgesic, antiinflammatory, and antipyretic agents in the doses used clinically, although responses to particular agents can vary in different individuals. (See 'Therapeutic effects and usage' above.)

NSAID toxicities reduced with COX-2 selective NSAIDs – The choice to use a COX-2 selective NSAID rather than a nonselective NSAID is sometimes based upon its reduced risk of certain toxicities compared with nonselective NSAIDs, including gastroduodenal toxicity, platelet inhibition and bleeding, and worsening of aspirin-exacerbated respiratory disease. (See 'Reduction in toxicities with COX-2 selective NSAIDs (coxibs)' above and 'Reduction in gastroduodenal toxicity' above and 'Lack of platelet inhibition and use during anticoagulation' above and 'Lack of bronchoconstriction' above.)

Toxicities – The COX-2 selective NSAIDs share a number of potential risks for adverse events with other NSAIDs, which vary between agents and depend in part upon the clinical characteristics in individual patients. Potential toxicities include an increased risk of cardiovascular adverse events, including death, myocardial infarction (MI), heart failure (HF), and stroke; and kidney complications, including electrolyte and acid-base disorders, acute interstitial nephritis, and acute kidney injury (AKI), especially in patients at risk due to NSAID inhibition of compensatory secretion of vasodilator prostaglandins. Other potential adverse effects include sulfonamide allergy, which may be seen with celecoxib; rare anaphylactoid reactions; aseptic meningitis; and visual disturbances. (See 'Toxicities and possible toxicities' above.)

Other relatively selective COX-2 inhibitors – Some NSAIDs traditionally viewed as being COX nonselective have been found to have relative selectivity for COX-2 compared with other nonselective NSAIDs. These relatively selective agents include, at low doses, nabumetone, meloxicam, and etodolac. Additionally, diclofenac also exhibits some evidence of COX-2 selectivity. (See 'Other relatively selective COX-2 inhibitors' above.)

  1. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol 1971; 231:232.
  2. Meade EA, Smith WL, DeWitt DL. Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs. J Biol Chem 1993; 268:6610.
  3. DeWitt DL, Meade EA, Smith WL. PGH synthase isoenzyme selectivity: the potential for safer nonsteroidal antiinflammatory drugs. Am J Med 1993; 95:40S.
  4. Brooks PM, Day RO. Nonsteroidal antiinflammatory drugs--differences and similarities. N Engl J Med 1991; 324:1716.
  5. Abramson SB, Weissmann G. The mechanisms of action of nonsteroidal antiinflammatory drugs. Arthritis Rheum 1989; 32:1.
  6. Warner TD, Giuliano F, Vojnovic I, et al. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci U S A 1999; 96:7563.
  7. DeWitt DL, el-Harith EA, Kraemer SA, et al. The aspirin and heme-binding sites of ovine and murine prostaglandin endoperoxide synthases. J Biol Chem 1990; 265:5192.
  8. Shimokawa T, Smith WL. Prostaglandin endoperoxide synthase. The aspirin acetylation region. J Biol Chem 1992; 267:12387.
  9. Shimokawa T, Smith WL. Essential histidines of prostaglandin endoperoxide synthase. His-309 is involved in heme binding. J Biol Chem 1991; 266:6168.
  10. Shimokawa T, Kulmacz RJ, DeWitt DL, Smith WL. Tyrosine 385 of prostaglandin endoperoxide synthase is required for cyclooxygenase catalysis. J Biol Chem 1990; 265:20073.
  11. Toh H. Prostaglandin endoperoxide synthase contains an EGF-like domain. FEBS Lett 1989; 258:317.
  12. Dubois RN, Abramson SB, Crofford L, et al. Cyclooxygenase in biology and disease. FASEB J 1998; 12:1063.
  13. Lee SH, Soyoola E, Chanmugam P, et al. Selective expression of mitogen-inducible cyclooxygenase in macrophages stimulated with lipopolysaccharide. J Biol Chem 1992; 267:25934.
  14. Doroudi R, Gan LM, Selin Sjögren L, Jern S. Effects of shear stress on eicosanoid gene expression and metabolite production in vascular endothelium as studied in a novel biomechanical perfusion model. Biochem Biophys Res Commun 2000; 269:257.
  15. Lim H, Paria BC, Das SK, et al. Multiple female reproductive failures in cyclooxygenase 2-deficient mice. Cell 1997; 91:197.
  16. Khan KN, Stanfield KM, Harris RK, Baron DA. Expression of cyclooxygenase-2 in the macula densa of human kidney in hypertension, congestive heart failure, and diabetic nephropathy. Ren Fail 2001; 23:321.
  17. Simon LS, Weaver AL, Graham DY, et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA 1999; 282:1921.
  18. Emery P, Zeidler H, Kvien TK, et al. Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomised double-blind comparison. Lancet 1999; 354:2106.
  19. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000; 284:1247.
  20. Bensen WG, Fiechtner JJ, McMillen JI, et al. Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized controlled trial. Mayo Clin Proc 1999; 74:1095.
  21. Saag K, van der Heijde D, Fisher C, et al. Rofecoxib, a new cyclooxygenase 2 inhibitor, shows sustained efficacy, comparable with other nonsteroidal anti-inflammatory drugs: a 6-week and a 1-year trial in patients with osteoarthritis. Osteoarthritis Studies Group. Arch Fam Med 2000; 9:1124.
  22. Cannon GW, Caldwell JR, Holt P, et al. Rofecoxib, a specific inhibitor of cyclooxygenase 2, with clinical efficacy comparable with that of diclofenac sodium: results of a one-year, randomized, clinical trial in patients with osteoarthritis of the knee and hip. Rofecoxib Phase III Protocol 035 Study Group. Arthritis Rheum 2000; 43:978.
  23. Day R, Morrison B, Luza A, et al. A randomized trial of the efficacy and tolerability of the COX-2 inhibitor rofecoxib vs ibuprofen in patients with osteoarthritis. Rofecoxib/Ibuprofen Comparator Study Group. Arch Intern Med 2000; 160:1781.
  24. Gibofsky A, Williams GW, McKenna F, Fort JG. Comparing the efficacy of cyclooxygenase 2-specific inhibitors in treating osteoarthritis: appropriate trial design considerations and results of a randomized, placebo-controlled trial. Arthritis Rheum 2003; 48:3102.
  25. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000; 343:1520.
  26. Bensen W, Weaver A, Espinoza L, et al. Efficacy and safety of valdecoxib in treating the signs and symptoms of rheumatoid arthritis: a randomized, controlled comparison with placebo and naproxen. Rheumatology (Oxford) 2002; 41:1008.
  27. Pavelka K, Recker DP, Verburg KM. Valdecoxib is as effective as diclofenac in the management of rheumatoid arthritis with a lower incidence of gastroduodenal ulcers: results of a 26-week trial. Rheumatology (Oxford) 2003; 42:1207.
  28. Tannenbaum H, Berenbaum F, Reginster JY, et al. Lumiracoxib is effective in the treatment of osteoarthritis of the knee: a 13 week, randomised, double blind study versus placebo and celecoxib. Ann Rheum Dis 2004; 63:1419.
  29. Schnitzer TJ, Beier J, Geusens P, et al. Efficacy and safety of four doses of lumiracoxib versus diclofenac in patients with knee or hip primary osteoarthritis: a phase II, four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2004; 51:549.
  30. Wiesenhutter CW, Boice JA, Ko A, et al. Evaluation of the comparative efficacy of etoricoxib and ibuprofen for treatment of patients with osteoarthritis: A randomized, double-blind, placebo-controlled trial. Mayo Clin Proc 2005; 80:470.
  31. Mizuno H, Sakamoto C, Matsuda K, et al. Induction of cyclooxygenase 2 in gastric mucosal lesions and its inhibition by the specific antagonist delays healing in mice. Gastroenterology 1997; 112:387.
  32. Leese PT, Hubbard RC, Karim A, et al. Effects of celecoxib, a novel cyclooxygenase-2 inhibitor, on platelet function in healthy adults: a randomized, controlled trial. J Clin Pharmacol 2000; 40:124.
  33. Knijff-Dutmer EA, Van der Palen J, Schut G, Van de Laar MA. The influence of cyclo-oxygenase specificity of non-steroidal anti-inflammatory drugs on bleeding complications in concomitant coumarine users. QJM 2003; 96:513.
  34. Teerawattananon C, Tantayakom P, Suwanawiboon B, Katchamart W. Risk of perioperative bleeding related to highly selective cyclooxygenase-2 inhibitors: A systematic review and meta-analysis. Semin Arthritis Rheum 2017; 46:520.
  35. Ruschitzka F, Borer JS, Krum H, et al. Differential blood pressure effects of ibuprofen, naproxen, and celecoxib in patients with arthritis: the PRECISION-ABPM (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen Ambulatory Blood Pressure Measurement) Trial. Eur Heart J 2017; 38:3282.
  36. Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med 2016; 375:2519.
  37. Yeomans ND, Graham DY, Husni ME, et al. Randomised clinical trial: gastrointestinal events in arthritis patients treated with celecoxib, ibuprofen or naproxen in the PRECISION trial. Aliment Pharmacol Ther 2018; 47:1453.
  38. Morham SG, Langenbach R, Loftin CD, et al. Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse. Cell 1995; 83:473.
  39. Ferguson S, Hébert RL, Laneuville O. NS-398 upregulates constitutive cyclooxygenase-2 expression in the M-1 cortical collecting duct cell line. J Am Soc Nephrol 1999; 10:2261.
  40. Kömhoff M, Wang JL, Cheng HF, et al. Cyclooxygenase-2-selective inhibitors impair glomerulogenesis and renal cortical development. Kidney Int 2000; 57:414.
  41. Harris RC. Cyclooxygenase-2 in the kidney. J Am Soc Nephrol 2000; 11:2387.
  42. Khan KN, Paulson SK, Verburg KM, et al. Pharmacology of cyclooxygenase-2 inhibition in the kidney. Kidney Int 2002; 61:1210.
  43. Norwood VF, Morham SG, Smithies O. Postnatal development and progression of renal dysplasia in cyclooxygenase-2 null mice. Kidney Int 2000; 58:2291.
  44. Qi Z, Hao CM, Langenbach RI, et al. Opposite effects of cyclooxygenase-1 and -2 activity on the pressor response to angiotensin II. J Clin Invest 2002; 110:61.
  45. New treatment for hemophilia. FDA Consum 2003; 37:5.
  46. Schellenberg RR, Isserow SH. Anaphylactoid reaction to a cyclooxygenase-2 inhibitor in a patient who had a reaction to a cyclooxygenase-1 inhibitor. N Engl J Med 2001; 345:1856.
  47. "The Pink Sheet" FDC Reports. Chevy Chase, MD 2002; 64(45):19.
  48. Morís G, Garcia-Monco JC. The challenge of drug-induced aseptic meningitis revisited. JAMA Intern Med 2014; 174:1511.
  49. Bonnel RA, Villalba ML, Karwoski CB, Beitz J. Aseptic meningitis associated with rofecoxib. Arch Intern Med 2002; 162:713.
  50. Coulter DM, Clark DW, Savage RL. Celecoxib, rofecoxib, and acute temporary visual impairment. BMJ 2003; 327:1214.
  51. Roth SH. NSAID gastropathy. A new understanding. Arch Intern Med 1996; 156:1623.
  52. Cryer B, Feldman M. Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs. Am J Med 1998; 104:413.
  53. Patrignani P, Panara MR, Greco A, et al. Biochemical and pharmacological characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthases. J Pharmacol Exp Ther 1994; 271:1705.
  54. Glaser K, Sung ML, O'Neill K, et al. Etodolac selectively inhibits human prostaglandin G/H synthase 2 (PGHS-2) versus human PGHS-1. Eur J Pharmacol 1995; 281:107.
  55. Singh G, Lanes S, Triadafilopoulos G. Risk of serious upper gastrointestinal and cardiovascular thromboembolic complications with meloxicam. Am J Med 2004; 117:100.
  56. Yocum D, Fleischmann R, Dalgin P, et al. Safety and efficacy of meloxicam in the treatment of osteoarthritis: a 12-week, double-blind, multiple-dose, placebo-controlled trial. The Meloxicam Osteoarthritis Investigators. Arch Intern Med 2000; 160:2947.
  57. Furst DE, Kolba KS, Fleischmann R, et al. Dose response and safety study of meloxicam up to 22.5 mg daily in rheumatoid arthritis: a 12 week multicenter, double blind, dose response study versus placebo and diclofenac. J Rheumatol 2002; 29:436.
  58. McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med 2011; 8:e1001098.
  59. Fosbøl EL, Folke F, Jacobsen S, et al. Cause-specific cardiovascular risk associated with nonsteroidal antiinflammatory drugs among healthy individuals. Circ Cardiovasc Qual Outcomes 2010; 3:395.
  60. Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ 2011; 342:c7086.
  61. Tugwell PS, Wells GA, Shainhouse JZ. Equivalence study of a topical diclofenac solution (pennsaid) compared with oral diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial. J Rheumatol 2004; 31:2002.
  62. Lin TC, Solomon DH, Tedeschi SK, et al. Comparative Risk of Cardiovascular Outcomes Between Topical and Oral Nonselective NSAIDs in Taiwanese Patients With Rheumatoid Arthritis. J Am Heart Assoc 2017; 6.
Topic 7992 Version 29.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟