Use of NSAIDs in treating patients with arthritis

Patients with rheumatic diseases, including rheumatoid arthritis and osteoarthritis, almost universally describe pain and stiffness as important contributors to reduced health-related quality of life. Of the treatment options available, NSAIDs are the most widely used agents for symptomatic treatment. NSAIDs are effective anti-inflammatory and analgesic drugs by virtue of their ability to inhibit biosynthesis of prostaglandins at the level of the cyclooxygenase enzyme. However, many of the adverse effects of NSAIDs are also related to inhibition of prostaglandin production, making their use problematic in some patient populations. For the clinician, understanding the biology of prostaglandin as it relates to gastrointestinal, renal, and cardiovascular physiology and the pharmacologic properties of specific NSAIDs is key to using these drugs safely. Of particular importance is the recognition of co-morbid conditions and concomitant drugs that may increase the risk of NSAIDs in particular patients. In patients with risk factors for NSAID toxicity, using the lowest dose of a drug with a short half-life only when it is needed is likely to be the safest treatment option. For those patients whose symptoms cannot be managed with intermittent treatment, using protective strategies is essential.

drugs tend to accumulate in synovial fl uid, where the concentration of drug may remain more stable than in the plasma. Short half-life NSAIDs potentially could be given less frequently than indicated by their plasma halflife. NSAIDs exhibiting longer half-lives require more time to reach steady-state plasma levels. Drugs with halflife >12 hours can be given once or twice a day, and plasma levels increase for a few days to several weeks (depending on the specifi c half-life) but then tend to remain constant between doses. NSAIDs with longer half-lives also enable drug concentrations to equilibrate between the plasma and the synovial fl uid, although total bound and unbound drug levels are usually lower in synovial fl uid because there is less albumin in synovial fl uid than in plasma. However, NSAIDs with longer halflife or extended release formulation may be asso ciated with increased propensity to cause adverse eff ects [5]. COX-isozyme selectivity is likely to be a critically important factor in determining relative gastrointestinal and cardiovascular risk that should also be considered in addition to other pharmacologic properties for each NSAID [6].
Almost all NSAIDs are >90% bound to plasma proteins. If total drug concentrations are increased beyond the point at which the binding sites on albumin are saturated, biologically active free-drug concentrations increase dispro portionately to the increasing total drug concen tration. Th e clearance of NSAIDs is usually by hepatic metabolism, with production of inactive metabolites that are excreted in the bile and urine. Most NSAIDs are metabolized through the microsomal cytochrome P450containing mixed-function oxidase system. NSAIDs are most often metabolized by CYP3A or CYP2C9, or both. However, some are metabolized by other cytosolic hepatic enzymes. Diff erent patients can respond to the same NSAID in a variety of ways and the basis for this individual variability remains unclear. Several pharmacologic factors related to NSAIDs may infl uence this variability, such as dose response, plasma half-life, enantiomeric conversion, urinary excretion, and pharma codynamic variation [7]. Such drug factors include protein binding, the metabolic profi le of the drug, and the percentage of the drug that is available as the active (S) enantiomer. Th ere is also genetic variability in the cytochrome P450 metabolic enzymes such that some individuals or ethnic groups metabolize drugs more slowly. For example, Asians are frequently slow metabo lizers through the CYP2C9 pathway. Finally, the pharma cokinetics of some NSAIDs are aff ected by hepatic disease, renal disease or old age.

NSAID mechanism of action
NSAIDs exert their actions by inhibiting enzymatic activity of the COX enzymes. Th ese enzymes are the fi rst committed step in the synthesis of PG from arachidonic acid ( Figure 1). Arachidonic acid is an omega-6 polyunsaturated fatty acid commonly found at the sn-2 position of cell membrane glycerophospholipids and cleaved from cell membranes by one of several diff erent phospholipase A 2 enzymes [8]. COX-1 and COX-2 are bifunctional enzymes that mediate a COX reaction whereby arachidonate plus two molecules of oxygen are converted to the cyclic endoperoxide PGG 2 , followed by a hydroperoxidase reaction in which PGG 2 undergoes a two-electron reduction to PGH 2 [8]. Th e unstable intermediate PGH 2 spontaneously rearranges or is enzymatically converted by specifi c synthases to biologically active PG, of which there are many isoforms [9]. Th e overall regulation of the type and amount of PG produced in a given cell or tissue is determined by the expression levels of COX-1, COX-2, and terminal synthase enzymes.
All of the NSAIDs are synthetic inhibitors of the COX active site, but subtle mechanistic diff erences in the manner in which individual NSAIDs interact and bind with the active site are responsible for some of the diff erences in their pharmacologic characteristics [10]. Acetylsalicylic acid is the only covalent, irreversible modifier of COX-1 and COX-2, whereas all of the other NSAIDs are competitive inhibitors, competing with arachidonic acid for binding in the active site.

Cyclooxygenase-2 selectivity
COX isozyme selectivity is defined most commonly using the concentration of drug required to inhibit PG production by 50% in a particular assay system (inhibitory concentration). Ratios using values obtained for COX-1 50% inhibitory concentrations compared with COX-2 50% inhibitory concentrations can be calculated and used as a standard measure for comparing the degrees of selectivity of a particular NSAID for one or the other COX isoform [6]. PG assay systems can vary widely, however, making it diffi cult to compare directly results from studies using diff erent assay systems. To circumvent such problems, most clinicians have accepted the use of the in vitro whole-blood assay to compare NSAID selectivities. In this system, COX-1 inhibition is assessed as a function of the reduction of thromboxane made by platelets after clot formation. Inhibition of COX-2 is based on the inhibition of PGE 2 production in a heparinized blood sample after lipopolysaccharide stimu la tion. A COX-2-selective NSAID lacks an inhibitory eff ect on platelet COX-1 at concentrations at or above those that maximally inhibit COX-2 [11,12]. Traditional NSAIDs, such as meloxicam, nimesulide, etodolac, and diclofenac show some selectivity for inhibit ing COX-2 over COX-1. After the discovery of COX-2, eff orts to further enhance COX-2 selectivity led to the development of celecoxib, valdecoxib, rofecoxib, etoricoxib and lumiracoxib. Most COX-2-selective NSAIDs are diaryl compounds containing a sulfonamide (cele coxib, valdecoxib) or a methylsulfone (rofecoxib, etoricoxib) rather than a carboxyl group, while lumiracoxib is an analog of diclofenac and the only acidic COX-2-selective NSAID. Lumiracoxib is available in only a few countries worldwide. Valdecoxib and rofecoxib are no longer available in any country because of concerns for excess cardiovascular adverse eff ects. Etoricoxib is approved in the European Union but not in the United States, while celecoxib is available worldwide. Celecoxib and etoricoxib are weak time-independent inhibitors of COX-1, but strong time-dependent inhibitors of COX-2 that require entry into and stabilized binding in the catalytic pocket. Because these drugs lack a carboxyl group, arginine 120 is not involved, but multiple sites of hydrogen and hydrophobic binding stabilize drugs at the catalytic site. Th e sulfur-containing phenyl ring of COX-2-selective NSAIDs plays a pivotal role in binding stability by occupying the hydrophobic side pocket characteristic of the COX-2 catalytic site. If this side pocket is removed by mutagenesis, all isozyme selectivity is lost [13].

NSAID formulation
NSAIDs are produced in a variety of dosage forms, including intravenous, slow-release and sustained-release oral preparations, and topical preparations in various forms including gels and patches, and suppositories. Given the desire to reduce NSAID toxicity while preser ving drug delivery to a specifi c site, eff orts continue to alter drug formulation and delivery systems. Nano particles, liposomes, and micro spheres are under investigation  to allow dose reduction and specifi c targeting. Intraarticular delivery is under consideration, but because joints have very effi cient lymphatic clearance systems the utility of this form of targeting remains to be proved.
Topical NSAID formulations were developed to reduce systemic exposure while preserving effi cacy. Several factors -including the drug, formulation, and site of application -are important for effi cacy [14]. Diclofenac, for example, is available as a solution, gel, or patch. Th e systemic eff ects are directly proportional to the surface area, and this method of delivery results in a relatively stable systemic diclofenac level compared with oral administration [15]. A recent Chochrane review con cludes that topical NSAIDs can provide good levels of pain relief and that gastrointestinal adverse events are reduced compared with oral NSAIDs [16].
NSAIDs have also been combined with agents having gastroprotective eff ects into polypills that are currently available on the market. Th is strategy may increase compliance with eff ective protective agents, thereby reducing adverse eff ects in clinical practice. Combining diclofenac with the synthetic PGE 1 analog misoprostol (arthrotec) is shown to reduce risk of NSAID-related peptic ulcerations and mucosal injury, but utility of the combination is often limited by misoprostol-induced cramping and diarrhea [17]. In population-based studies, arthrotec was more eff ective than diclofenac and misoprotsol co-prescription in preventing hospitalization for peptic ulcer disease or gastrointestinal hemorrhage [18]. Several poly-pills containing NSAIDs and proton-pump inhibitors are approved for use in rheumatic diseases including ketoprofen with omeprazole (axorid) [19]. Th e combination of enteric-coated naproxen and the proton pump inhibitor esomeprazole (vimovo) was shown to reduce endoscopically detected gastric ulcers [20]. Th e combi nation of ibuprofen and the H 2 -blocker famotidine (duexis) was also shown to reduce endoscopically detected gastric and duodenal ulcers [21].
A diff erent strategy is nitric oxide-releasing NSAIDs, which are synthesized by the ester linkage of a nitric oxide-releasing moiety to conventional NSAIDs including aspirin, fl urbiprofen, diclofenac, sulindac, and others [22]. Th e nitric oxide moiety is slowly released by enzymatic activity in vivo, probably by esterases, resulting in slow accumulation of the parent NSAID. Th e lower rate of gastrointestinal ulceration associated with these drugs is probably related to nitric oxide-associated vasodilation and the relatively lower concentration of parent NSAID.

Therapeutic eff ects of NSAIDS in rheumatic diseases
NSAIDs are frequently used as fi rst-line agents for the symptomatic relief of many diff erent infl ammatory conditions. In double-blind, randomized clinical trials of infl ammatory arthritis, NSAIDs have been compared with placebo, aspirin, and each other. Clinical trials of NSAID effi cacy in RA and OA most often employ a design whereby the current NSAID is discontinued and the patient must have an increase in symptoms or fl are to enter the study. Although there is some variation in primary outcome measures, most include parameters that make up the American College of Rheumatology-20. Effi cacy superior to that of placebo is easily demonstrated for NSAIDs within 1 to 2 weeks in patients with active RA who are not receiving corticosteroids or other antiinfl ammatory medications [23]. Comparisons of adequate doses of traditional NSAIDs or COX-2-selective NSAIDs with one another almost always show comparable effi cacy. Despite improvement in pain and stiff ness with NSAIDs, these agents do not usually reduce acute-phase reactants, nor do they modify radiographic progression. Th e anti-infl ammatory eff ects of NSAIDs have also been demonstrated in OA, rheumatic fever, juvenile rheumatoid arthritis, ankylosing spondylitis, gout, and systemic lupus erythematosus. Although not as rigorously proven, their effi cacy is also accepted in treatment of reactive arthritis, psoriatic arthritis, acute and chronic bursitis, and tendonitis.
Virtually all NSAIDs relieve pain when used in doses substantially lower than those required to suppress infl ammation. Th e analgesic action of NSAIDs is due to inhibition of PG production in peripheral tissues and in the central nervous system. In the periphery, PGs do not induce pain per se, but sensitize peripheral nociceptors to the eff ects of mediators such as bradykinin or histamine [24]. PGs released during inflammation or other trauma lower the activation threshold of tetrodotoxin-resistant sodium channels on sensory neurons. In the central nervous system, where NSAIDs and acetaminophen exert analgesic eff ects, PGs also play an important role in neuronal sensitization. COX-2 is constitutively expressed in the dorsal horn of the spinal cord, and its expression is increased during inflammation [25]. Centrally generated PGE 2 activates spinal neurons and also microglia that contribute to neuropathic pain [26]. Both COX-1 and COX-2 play a role in nociception, as demonstrated by reductions of experimental pain in mice defi cient in either COX-1 or COX-2 [27].

Adverse eff ects
NSAIDs share a common spectrum of clinical toxicities, although the frequency of particular side eff ects varies with the compound (Table 2). Th e hazards of individual NSAIDs are related to their pharmacologic characteristics, such as bioavailability and half-life, as well as their potency for inhibition of COX-1 and COX-2 [5,6,28]. Th e focus of this review is on renal, hepatic, and cardio vascular adverse eff ects that are particularly important in patients with rheumatic diseases due to the age of the patients and medication use. Gastrointestinal adverse eff ects are common and important causes of morbidity and mortality, but are reviewed in detail in other manuscripts in this supplement.

Renal eff ects
Prostaglandins play a vital role in solute and renovascular homeostasis [29][30][31]. Sodium retention has been reported to occur in up to 25% of NSAID-treated patients and may be particularly apparent in patients who have an existing avidity for sodium, such as those with mild heart failure or liver disease [32]. Decreased sodium excretion in NSAID-treated patients can lead to weight gain and peripheral edema. Th is eff ect may be suffi ciently important to cause clinically important exacerbations of congestive heart failure.
NSAIDs may cause altered blood pressure, with average increases in mean arterial pressure of between 5 and 10 mmHg. Using NSAIDs has also been reported to possibly increase the risk of initiating antihypertensive therapy in older patients, with the magnitude of increased risk being proportional to the NSAID dose [33]. Furthermore, in a large (n = 51,630) prospective cohort of women aged 44 to 69 without hypertension in 1990, incident hypertension over the following 8 years was signifi cantly more likely in frequent users of aspirin, aceta mino phen, and NSAIDs [34]. NSAIDs can attenuate the eff ects of antihypertensive agents including diuretics, angiotensin-converting enzyme inhibitors, and βblockers, interfering with blood pressure control.
NSAID-treated patients may develop hyporeninemic hypoaldosteronism that manifests as type IV renal tubular acidosis and hyperkalemia [32]. Th e degree of hyperkalemia is generally mild; however, patients with renal insuffi ciency or those that may otherwise be prone to hyperkalemia (for example, patients with diabetes mellitus and those on angiotensin-converting enzyme inhibitors or potassium-sparing diuretics) may be at greater risk.
Acute renal failure is an uncommon consequence of NSAID treatment. Th is failure is due to the vasocon strictive eff ects of NSAIDs and is reversible. In most cases, renal failure occurs in patients who have a depleted actual or eff ective intravascular volume (for example, congestive heart failure, cirrhosis, or renal insuffi ciency) [32]. Marked reduction in medullary blood fl ow may result in papillary necrosis that may arise from apoptosis of medullary interstitial cells. Inhibition of COX-2 may be a predisposing factor for renal failure [31,35].
Another adverse renal eff ect resulting from NSAIDs involves an idiosyncratic reaction accompanied by massive proteinuria and acute interstitial nephritis. Hyper sensitivity phenomena, such as fever, rash, and eosinophilia, may occur. Th is syndrome has been observed with most NSAIDs.
Use of analgesics, particularly acetaminophen and aspirin, has been associated with nephropathy leading to chronic renal failure. In one large case-control study, the regular use of aspirin or acetaminophen was associated with a risk of chronic renal failure 2.5 times as high as that for nonuse, and the risk increased signifi cantly with an increasing cumulative lifetime dose [36]. In subjects regularly using both acetaminophen and aspirin, the risk was also signifi cantly increased compared with users of either agent alone. No association between the use of non-aspirin NSAIDs and chronic renal failure could be detected after adjusting for acetaminophen and aspirin use. Pre-existing renal or systemic disease was a necessary precursor to analgesic-associated renal failure, and those without pre-existing renal disease had only a small risk of end-stage renal disease [36,37].

Hepatic eff ects
Small elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs, and notable elevations of ALT or AST (approximately ≥3 times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials of NSAIDs. Patients usually have no symptoms, and discontinuation or dose reduction generally results in normalization of the transaminase values -although rare, fatal outcomes have been reported with almost all NSAIDs. Th ose NSAIDs most likely to be associated with hepatic adverse events are diclofenac and sulindac.

Cardiovascular eff ects
Th e risk of adverse cardiovascular eff ects associated with NSAID use was not widely appreciated until COX-2selective NSAIDs were introduced into clinical practice. Rofecoxib, a potent highly specifi c COX-2 inhibitor with a very long half-life, was shown to have a substantially increased risk of myocardial infarction and stroke and was removed from the market because of this adverse eff ect [28,38]. Th e relationship between excess cardio vascular risk for all NSAIDs, not only COX-2-selective NSAIDs, is proposed to be related to the degree of COX-2 inhibition and an absence of complete inhibition of COX-1 [39]. Investi gators have shown an increased relative risk of myo cardial infarction for drugs that inhibit COX-2 <90% at therapeutic concentrations in the whole blood (relative risk = 1.18, 95% confi dence interval = 1.02 to 1.38), whereas drugs that inhibit COX-2 to a greater degree present a relative risk of 1.60 (95% confi dence interval = 1.41 to 1.81) [39]. Relative inhibition of the COX isoforms is not the only mechanism that contributes cardiovascular hazard. Other actions of NSAIDs -including eff ects on blood pressure, endothelial function, and nitric oxide production, and other renal eff ects -may play a role in cardiovascular risk [28,40,41]. Multiple analyses have demonstrated that the risk for cardiovascular hazard is significantly higher in those patients with pre-existing coronary artery disease. Some NSAIDs, notably ibuprofen, may interfere with the irrever sible inhibition of platelet COX-1 by aspirin, thereby increasing cardiovascular hazard in aspirin users [39]. It is prudent to recommend that aspirin be taken 2 hours prior to ibuprofen dosing [42,43].
A number of large-scale randomized controlled trials comparing NSAIDs with placebo or with each other have been performed and analyzed to determine the risk of myocardial infarction, stroke, cardiovascular death, death from any cause, and Antiplatelet Trialists' Collaboration composite outcomes [28]. Because event rates in most of these studies were low, uncertainty regarding absolute and relative risk remains. For example, there were only 554 myocardial infarctions in aggregate across all trials included in the most comprehensive analysis to date. Nevertheless, it appears from analyses of these aggregated clinical trials that all traditional and COX-2selective NSAIDs except naproxen carry an excess risk >30% compared with placebo [28]. Pairwise comparisons of the most commonly used traditional and COX-2selective NSAIDs studied in clinical trials also suggest that naproxen may have lower cardiovascular risk [28]. One meta-analysis explored the eff ects of dose and dosing regimen in a pooled analysis of six randomized placebo controlled trials of celecoxib [44]. Lower doses and once-daily regimens were associated with lower relative risks for the Antiplatelet Trialists' Collaboration outcomes. Th is fi nding confi rms fi ndings from other studies that suggest avoiding continuous interference with PG biosynthesis is associated with lower cardiovascular risk [39].
Because clinical trials have been underpowered to specifi cally address relative cardiovascular risk of NSAIDs, investigators have turned to observational datasets. Using a very large observational database with 8,852 cases of nonfatal myocardial infarction, a recent casecontrol study also identifi ed a 35% increase in the risk for MI in current use of NSAIDs [39]. Th is type of study also identifi es naproxen as potentially having a lower risk. In this analysis, a long half-life was an independent predictor of MI hazard. Th e eff ect of dose and a slowrelease formulation demonstrated that risk was a direct consequence of prolonged drug exposure. Th e risk associated with these pharmacologic factors may be even more important than COX-2 specifi city for most NSAIDs [28,39].
A number of strategies have been suggested to mitigate cardiovascular risks associated with NSAID use (Table 3) [43]. Th ese recommendations take into account a patient's underlying risk, aspirin use, and the interaction between NSAIDs. In addition, the specifi c choice of NSAID should consider the pharmacologic properties [28,39].
NSAIDs are associated with reduced sodium excretion, volume expansion, increased preload, and hypertension. As a result of these properties, patients with pre-existing heart failure are at risk of decompensation with a relative risk of 3.8 (95% confi dence = 1.1 to 12.7). After adjusting for age, sex, and concomitant medication, the relative risk was 9.9 (95% confi dence = 1.7 to 57.0) [45]. Studies disagree about whether NSAIDs are a risk for new heart failure, but older patients may be at particular risk for heart failure exacerbation [45,46].

Eff ects of concomitant drugs, diseases, and aging
Because of the widespread use of prescription and nonprescription NSAIDs, there are ample opportunities for interaction with other drugs and for interactions with patient-specifi c factors [47]. Specifi c drug interactions are listed on the package inserts of individual agents.

Drug-drug interactions
Since most NSAIDs are extensively bound to plasma proteins, they may displace other drugs from binding sites or may themselves be displaced by other agents. NSAIDs may increase the activity or toxicity of sulfonylurea, hypoglycemic agents, oral anticoagulants, phenytoin, sulfonamides, and methotrexate by displacing these drugs from their protein binding sites and increasing the free fraction of the drug in plasma [47]. However, a recent Cochrane review concluded that concurrent use of NSAIDs with methotrexate appeared safe provided appro priate monitoring was performed [48]. NSAIDs may blunt the antihypertensive eff ects of β-blockers, angiotensin-converting enzyme inhibitors, and thiazides, leading to de-stabilization of blood pressure control [49]. Th ere is an increased risk of gastrointestinal toxicity when NSAIDs and selective serotonin reuptake inhibitors are taken concomitantly compared with taking either agent alone, and this is greater than the additive risk [50].

Drug-disease interactions
RA and other diseases (for example, hepatic and renal disease) that decrease serum albumin concentrations are associated with increased concentrations of free NSAIDs. Hepatic and renal diseases may also impair drug metabolism or excretion, and thereby increase the toxicity of a given dose of NSAID to an individual patient. Renal insuffi ciency may be accompanied by accumulated endogenous organic acids that may displace NSAIDs from protein binding sites.

Drug reactions in older people
Aging is accompanied by changes in physiology, resulting in altered pharmacokinetics and pharmacodynamics. Decreased drug clearance may be the consequence of reductions in hepatic mass, enzymatic activity, blood fl ow, renal plasma fl ow, glomerular fi ltration rate, and tubular function associated with aging. Older people are more likely to experience adverse gastrointestinal and renal eff ects related to NSAIDs. Th e increased risk of cardiovascular disease in older patients raises concerns of accelerated myocardial infarction or stroke. Th e use of aspirin for prevention of cardiovascular disease increases the toxicity of NSAIDs and, conversely, the concomitant use of NSAIDs may increase aspirin resistance. Use of proton pump inhibitors for gastroprotection may interfere with the effi cacy of antiplatelet agents such as clopidogrel [42]. Older people have more illnesses than younger patients and therefore take more medications, increasing the possibility of drug-drug interactions. Older patients may also be more likely to self-medicate or make errors in drug dosing. For these reasons, frequent monitoring for compliance and toxicity should be a part of the use of NSAIDs in this population.

Choosing anti-infl ammatory analgesic therapy
In choosing an NSAID for a particular patient, the clinicia n must consider effi cacy, potential toxicity related to concomitant drugs and patient factors, and cost [1]. A study to assess patient preferences for treatment-related benefi ts and risks of NSAIDs for OA suggested that reductions in ambulatory pain and diffi culty doing daily activities were the most important benefi ts. Th e risk of myocardial infarction and stroke were the most important risk outcomes. However, patients were willing to accept a small increased risk of myocardial infarction to reduce ambulatory, but not resting, pain [51]. Furthermore, patient preference for factors such as the dosing regimen may be taken into account. In addition to choices from the perspective of the individual patient and physician, it may be important to take a broader view. Choice of anti-infl ammatory analgesic therapy can also be considered from the perspective of healthcare institutions and payers. Th e symptoms and conditions for which NSAIDs are used are extraordinarily common. Consequently, the cost of NSAIDs as a proportion of total drug costs can be high when drugs are expensive. Th e increased cost of branded NSAIDs has an important pharmacoeconomic impact. On the other hand, adverse events can have important economic consequences, and improved safety may be cost-eff ective.
Choosing anti-infl ammatory analgesic therapy has become increasingly complex with the increased understanding of their associated toxicities. Prospectively considering the presence of gastrointestinal and cardiovascular risk factors is essential when considering treatment options (Table 4) [1]. Gastrointestinal risks are well known and strategies to prevent ulceration and bleeding are available. Th ere are many questions regarding the risk for cardiovascular events in patients using NSAIDs; in general, the data suggest that physicians should be cautious of using NSAIDs in patients with known cardiovascular disease. In those patients with risks for NSAID toxicity, avoiding potent drugs with a long halflife or extended-release formulations is prudent. Intermittent dosing rather than continuous daily use reduces toxicity.
An absence of anti-infl ammatory activity reduces the eff ectiveness of acetaminophen for diseases accompanied by a signifi cant component of infl ammation (for example, RA, gout). However, acetaminophen is a safe and eff ective alternative for milder pain conditions, including OA. With respect to patient preference, a survey study demonstrated that only 14% of a large group of rheumatic disease patients (n = 1,799) with RA, OA, or fi bromyalgia preferred acetaminophen over NSAIDs, while 60% preferred NSAIDs [52]. In a head-to-head clinical trial of acetaminophen versus diclofenac plus misoprostol, there was signifi cantly greater improvement in pain scores for patients in the diclofenac group. Th is fi nding was magnifi ed in those patients with more severe disease at baseline [53].
Acetaminophen should be tried as the initial therapy in patients with mild to moderate pain for reasons of safety and cost. However, if patients have moderate to severe symptoms or if evidence of infl ammation is present, moving to treatment with NSAIDs may provide more rapid and eff ective relief [54].

Key messages
• NSAIDs are eff ective treatments for relief of pain, swelling, and stiff ness of arthritis and other rheumatic diseases. • Th e chemical class and pharmacology of individual NSAIDs signifi cantlly infl uence their toxicity. • Co-morbid conditions should be considered in prescribing NSAIDs and special care should be taken in prescribing these drugs to older patients. • Th e lowest dose of a short-acting NSAID for the shortest time required is recommended for patients at risk of adverse eff ects.

Competing interests
The author declares that she has no competing interests. Editor assisted the journal in preparing the outline of the project but did not have oversight of the peer review process. The Guest Editor serves as a clinical and regulatory consultant in drug development and has served as such consultant for companies which manufacture and market NSAIDs including Pfi zer, Pozen, Horizon Pharma, Logical Therapeutics, Nuvo Research, Iroko, Imprimis, JRX Pharma, Nuvon, Medarx, Asahi. The articles have been through the journal's standard peer review process. Publication of this supplement has been supported by Horizon Pharma Inc. Duexis (ibuprofen and famotidine) is a product marketed by the sponsor.