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NSAIDs: Therapeutic use and variability of response in adults

NSAIDs: Therapeutic use and variability of response in adults
Literature review current through: Jan 2024.
This topic last updated: Nov 15, 2023.

INTRODUCTION — More than 20 different nonsteroidal antiinflammatory drugs (NSAIDs) are available commercially, and these agents are used worldwide for their analgesic antipyretic and antiinflammatory effects for multiple medical conditions.

The choice of NSAID in a given patient depends upon a number of factors. The responses to NSAIDs differ between patients, and individual patients differ in their response to different NSAIDs. The bases for these variable responses are only partially understood. In addition, the selection and safety of NSAIDs depends in substantial part upon the presence of absence of various comorbidities and other medications the patient is receiving.

This topic will review the issues surrounding the differences in response to the various NSAIDs. Clinical considerations in the use of these agents, including comorbidities and cotherapies, will also be presented here. The pharmacology, mechanisms of action, and adverse effects of NSAIDs are reviewed in detail separately. (See "NSAIDs (including aspirin): Pharmacology and mechanism of action" and "Nonselective NSAIDs: Overview of adverse effects" and "Overview of COX-2 selective NSAIDs", section on 'Toxicities and possible toxicities'.)

VARIABILITY OF RESPONSES — At equipotent doses, the efficacy of the various nonsteroidal antiinflammatory drugs (NSAIDs) in patient populations is similar, although there is clear individual variation in therapeutic and adverse responses to these agents; some patients seem to respond better to one drug than to others, and responses differ between patients. The differences in the effects of the various NSAIDs have been ascribed primarily to variations in one or more of the following:

Mechanism of action, including absolute and relative differences in cyclooxygenase (COX) enzyme inhibition, different dosing intervals, and different capacities for altering non-prostaglandin-mediated biologic events (see "NSAIDs (including aspirin): Pharmacology and mechanism of action" and 'Prostaglandin-mediated' below and 'Nonprostaglandin-mediated' below)

Pharmacodynamics, pharmacokinetics, and drug metabolism, including pharmacogenetic factors (see "NSAIDs (including aspirin): Pharmacology and mechanism of action", section on 'Pharmacology' and 'Pharmacologic properties and clinical effects' below)

Some of the observed individual differences with specific NSAIDs are particularly evident more with respect to toxicity than efficacy [1]. As an example, it is not unusual for indomethacin to induce headaches after a single dose in some patients. The reason for this is unknown but may be affected by drug concentration. More commonly, individual patients have more symptoms or signs of gastrointestinal toxicity with one NSAID than another, which may be influenced both by differences in relative inhibition of COX-1 and COX-2 at therapeutic levels and by differences in absorption, distribution, and metabolism [2,3]. Other differences in the mode of action may be important as well.

While relatively little is known about how genetic variations affect responses to a given NSAID, it is likely that genetic differences, including differences in drug metabolism between different patients, also have a role in the variable responses across individuals [4].

Effects of mechanisms of action

Prostaglandin-mediated — The six major chemical classes of NSAIDs all have the common property of inhibiting COX, the enzyme which catalyzes the synthesis of cyclic endoperoxides from arachidonic acid to form prostaglandins. Different NSAIDs have varying inhibitory potentials of the two known isoforms of COX, COX-1 and COX-2 [5-10]. However, for most NSAIDs, beyond some information regarding the COX-2 selective agents, there is a paucity of data correlating the degree and type of COX inhibition with antiinflammatory efficacy in individual patients [11-13]. (See "NSAIDs (including aspirin): Pharmacology and mechanism of action" and "Overview of COX-2 selective NSAIDs".)

Through variable inhibition of COX-1 and COX-2, different NSAIDs appear to differentially impact atherothrombosis risk. The mechanisms underpinning these differences involve differential dosing, differential COX inhibition, and pharmacogenetics. However, these mechanisms are still incompletely understood [14].

Variabilities in response to NSAIDs may also result from alterations in some prostaglandin effects that have been recognized subsequent to the initial observations regarding COX inhibition. As an example, prostaglandins have been shown to be important inhibitors of apoptosis in vitro [15]. NSAID administration may reestablish the return to a more normal cell cycle via inhibition of prostaglandins, a pathway that may be significant in the downregulation of diseases driven by immunologically based functions. Additionally, many human genes are involved in COX-1 and COX-2 metabolism. In healthy volunteers, metabolism of selective COX-2 inhibitors varies significantly between individuals, suggesting further potential explanations for variability in response [16].

The nonacetylated salicylates (eg, salsalate) are weak inhibitors of COX, but some studies suggest that their antiinflammatory effects are similar to the non-salicylate NSAIDs, suggesting that non-prostaglandin-mediated mechanisms of action may be important for these agents [17,18]. (See 'Nonprostaglandin-mediated' below.)

Nonprostaglandin-mediated — Several non-prostaglandin-mediated NSAID-induced mechanisms may also be important in determining a patient's responsiveness to these agents. These mechanisms are generally related to the ability of NSAIDs to insert into biological membranes and disrupt a wide range of cell function and cell-to-cell interactions.

Several but not all NSAIDs may impact the levels of important transcription factors, such as nuclear factor-kappa B (NF-kB) and activator protein (AP)-1 [19]. Differences in such COX-independent mechanisms may either enhance the efficacy or diminish the toxicity of the respective compounds, in part through effects upon nitric oxide synthetase [20,21]. In addition, anti-nociceptive actions of some NSAIDs, but not all, appear to involve the L-arginine-NO-cyclic GMP-potassium channel pathways [22].

As another example, NSAIDs interfere with neutrophil-endothelial cell adherence by decreasing the availability of L-selectins, thereby removing a critical step in the migration of granulocytes to sites of inflammation [23].

Further study is required to confirm and better define the role and importance of the non-prostaglandin-mediated processes in clinical inflammation and whether these potential mechanisms of action explain the variation in individual patient response to NSAIDs or the occurrence of adverse events.

Pharmacologic properties and clinical effects — Pharmacodynamics of the individual NSAIDs, including their biochemical and physiological effects and their mechanisms of action, may be very important in predicting the ultimate clinical response and drug efficacy. By comparison, pharmacokinetic differences across NSAIDs, including differences in absorption, distribution, and differential metabolism, are probably not significant in this context. The risk of adverse events also seems to vary between individual drugs and patients; these differences in adverse event risk have been ascribed to differences in pharmacokinetics, including absorption, distribution, and metabolism.

All NSAIDs appear to be absorbed completely, have negligible first pass hepatic metabolism, are tightly bound to albumin, and have small volumes of distribution. Patients with hypoalbuminemia may, therefore, have higher free serum concentrations of drug. However, it is unclear whether the blood level of a NSAID is important in assessing its mode of action or its effectiveness, since protein-binding is saturable in the normal dose range for several NSAIDs. As a result, increases in dose may not lead to increases in steady state concentration of the drug. At equipotent doses, the clinical efficacy of the various NSAIDs in patient populations is similar [1]; by contrast, individual responses are highly variable [11].

Differences in measurable biologic responses may result in part from differences in drug pharmacodynamics. As an example, one older study performed with drugs not widely prescribed used a 2x2 factorial design to sequentially expose patients with either osteoarthritis (OA) or rheumatoid arthritis (RA) to two NSAIDs from two different classes: piroxicam (an oxicam) and ketoprofen (a phenylpropionic acid derivative) [24]. Patients were initially treated with one of the drugs for two weeks, then switched to the other for another two-week period. A number of clinical and biochemical responses were measured, and the following conclusions were drawn:

Pharmacodynamics of the individual NSAIDs, including their biochemical and physiological effects and their mechanisms of action, may be very important in predicting the ultimate response. By comparison, pharmacokinetic differences between NSAIDs in absorption, distribution, and differential metabolism appear less significant.

No clear pattern of effect could be associated with the serum concentrations of either NSAID.

Neither changes in serum concentrations of cytokines nor the absolute serum concentrations of cytokines may be as significant as changes in tissue levels or absolute tissue concentrations.

The enantiomeric state of the drugs was unimportant in determining differences in response.

Differences in effects were not due to fluctuations in disease.

ISSUES IN THE THERAPEUTIC USE OF NSAIDS — The safe and effective use of nonsteroidal antiinflammatory drugs (NSAIDs) depends in large part upon an understanding of several general principles as well as considerations of class and drug-specific drug-drug interactions and effects of comorbid conditions. (See 'General principles' below and 'Drug interactions and comorbidities' below.)

The discussion here is a general guide to the administration of NSAIDs. The indications for and efficacy of NSAIDs vary by patient and disease. Discussions of the use of these drugs in specific disorders are presented in the appropriate topic reviews.

General principles

Dosing and duration — Dosing issues that affect the therapeutic response include:

Dosing frequency Drug adherence is enhanced when medications are dosed less frequently [25]. Studies supporting this view have frequently been performed in asymptomatic hypertensive patients. Such patients may be more likely to comply with a once- or twice-daily regimen than with a more frequent and demanding regimen. In comparison, patients in chronic discomfort may be more adherent to a regimen that alleviates their discomfort, independent of dose schedule (but within limits). If the drug is adequately analgesic, it is more likely that patients will take drugs more frequently than once daily. Unfortunately, patient preference for specific NSAID dosing regimens has not been well studied.

Drug dosing For patients being treated for inflammatory disorders, the NSAID dose should start at the lowest effective dose but may be titrated up to the maximal antiinflammatory range (table 1). In patients with a history of an inadequate response to one NSAID, it is important to ascertain whether an adequate antiinflammatory dose was used.

Different doses of aspirin are required to achieve certain therapeutic effects due to the level of cyclooxygenase (COX) inhibition:

Low doses (eg, 75 to 81 mg/day) result in antiplatelet effects due to irreversible acetylation of COX-1, which prevents platelets from making thromboxane A2. The antiplatelet effects of aspirin are discussed in detail elsewhere. (See "Platelet biology and mechanism of anti-platelet drugs", section on 'COX inhibitors (aspirin and other NSAIDs)'.)

Intermediate doses (eg, 650 mg to 4 g/day) result in the analgesic and antipyretic effects due to broader COX inhibition and subsequent decrease in prostaglandin production.

Duration of drug trial and role of drug class switching In patients who experience an inadequate response to an NSAID of one class, the substitution of an NSAID of a different class is a reasonable therapeutic option. However, this strategy has never been evaluated in a prospective well-controlled study. Each attempt to achieve a response should last for about two weeks; this duration is based upon limited data and clinical experience. As an example, in one study, the response after two weeks was predictive of the more long-term response seen at 12 weeks [26].

Route of administration — NSAIDs are available in various forms, including oral, intravenous (IV), intramuscular (IM), and topical formulations. Oral, IV, and IM NSAIDs have systemic absorption. Oral NSAIDs are most commonly used for systemic therapy, but IV and IM formulations may be substituted when patients are unable to tolerate medications by mouth. Due to systemic absorption, these types of NSAIDs have the potential to cause drug interactions and other adverse effects. (See 'Drug interactions and comorbidities' below and "Nonselective NSAIDs: Overview of adverse effects" and "Overview of COX-2 selective NSAIDs", section on 'Toxicities and possible toxicities'.)

Topically applied NSAIDs penetrate local tissues in the area of application but have limited systemic absorption [27] and therefore fewer drug interactions and associated side effects [28]. Accumulating data demonstrate relative safety and good benefit of topical NSAIDs for localized pain compared with other analgesics, including oral NSAIDs. A systematic review and meta-analysis of topical NSAIDs used for patients with osteoarthritis (OA) demonstrated very slight increases in risk compared with placebo for most NSAID-associated toxicities [29]. In addition, in a network meta-analysis evaluating NSAIDs for patients with OA, diclofenac gel and solution appeared at least as effective as (and possibly more effective than) several commonly used oral NSAIDs [30]. The use of topical NSAIDs for patients with various conditions is discussed in separate topic reviews.

Laboratory monitoring — In patients being treated chronically with daily NSAIDs, particularly with use of antiinflammatory continuous dosing, we obtain a complete blood count, blood urea nitrogen and creatinine, and aspartate aminotransferase at least once yearly. In patients at increased risk of adverse effects, such as anemia, kidney disease, and drug-related liver injury, more frequent testing is usually required.

Drug interactions and comorbidities — There is greater risk of adverse effects when NSAIDs are used in patients who are at increased risk for gastrointestinal, kidney, or cardiovascular adverse reactions, although, in general, NSAIDs are relatively safe drugs. However, NSAIDs can also interact with numerous drugs. Thus, to help avoid adverse effects, it is important to take a careful history to identify comorbidities and other therapies that may interact with NSAID therapy. A good clinician evaluation will often highlight these risks, and appropriate action should then be taken to minimize the likelihood of a poor outcome. (See "Nonselective NSAIDs: Overview of adverse effects".)

The choice of one NSAID over another should consider patient-specific risk factors for toxicity and the way in which the drug is metabolized. In older patients, for example, the possible benefit of increased adherence with longer-acting drugs is probably offset by the enhanced incidence of gastrointestinal toxicity associated with prominent enterohepatic circulation of active metabolites. NSAIDs with a short half-life and no enterohepatic circulation may be the best choices for older chronically ill patients, although use of nonselective NSAIDs would generally be avoided in such patients because of their potential toxicity in this population. In addition, all agents should be used at the lowest effective dose.

Many of the toxic effects of the NSAIDs are related to their main mode of action, the inhibition of prostaglandin synthesis. However, the relative degree of COX-1 and COX-2 enzyme inhibition affects the risk of certain adverse effects, including both gastrointestinal adverse effects, which may be reduced with the selective COX-2 inhibitors, and cardiovascular adverse effects, which were more likely with several of the COX-2 selective agents that are no longer commercially available. (See "Overview of COX-2 selective NSAIDs" and "COX-2 inhibitors and gastroduodenal toxicity: Major clinical trials" and "NSAIDs: Adverse cardiovascular effects".)

It is, therefore, difficult to identify the "safest" NSAID. Many clinicians believe that ibuprofen is quite safe, which is generally true when the drug is given at the lowest possible dose. However, increasing doses of any NSAID is associated with an increased risk of a toxic event.

Switching to a different drug class upon the occurrence of an adverse effect is not necessarily applicable to patients who develop a toxic effect with one NSAID. Although some toxicities are unique to particular classes of NSAIDs, others are related to the general mode of action of inhibition of prostaglandin synthesis. One such example is acute kidney failure due to renal vasoconstriction, which is mediated by decreased production of vasodilator prostaglandins and may be similar across agents.

Topical NSAIDs offer an additional option for the localized delivery of an antiinflammatory analgesic that has similar efficacy to oral NSAIDs for OA for at least the first several weeks of treatment [31]. (See "Management of knee osteoarthritis", section on 'Topical NSAIDs'.)

Drug interactions — NSAIDs can interact with numerous drugs. In some patients, interactions may occur due to NSAID-related reduction in kidney perfusion or additive hemorrhagic toxicity. Furthermore, some NSAIDs modestly inhibit CYP-2C9 (eg, ibuprofen, ketoprofen, flurbiprofen, indomethacin, diclofenac, meloxicam) or CYP-2C8/2D6 (eg, celecoxib) and/or glucuronidation (eg, ibuprofen, flurbiprofen), which may increase concentrations of drugs highly dependent on these pathways for clearance.

Since all NSAIDs but aspirin are highly protein bound, interactions between NSAIDs and other highly protein-bound drugs may be clinically important. For example, NSAIDs may cause displacement of protein-bound phenytoin and warfarin, resulting in an increased biologic effect when they are concurrently prescribed with a NSAID. Similarly, NSAIDs may increase the international normalized ratio (INR) in patients receiving warfarin, particularly with the initiation of simultaneous therapy, adding to the anticoagulant effect of NSAID-induced platelet dysfunction.

The effects of some interactions are listed below. (See the drug interactions program included in UpToDate for additional information, including suggestions for management, and to check for other potential interactions.)

Methotrexate – The interaction of NSAIDs with methotrexate (MTX), which can decrease renal clearance of the MTX and result in higher MTX drug levels, generally requires avoidance of NSAID use in patients receiving antineoplastic doses, while both may be used concurrently with standard MTX monitoring approaches in patients receiving low-dose MTX (eg, for the treatment of rheumatologic disorders) [32]. (See "Use of methotrexate in the treatment of rheumatoid arthritis".)

Angiotensin-converting enzyme inhibitors – NSAIDs may attenuate the efficacy of angiotensin-converting enzyme (ACE) inhibitors by blocking vasodilator and natriuretic prostaglandins and potentiating hyperkalemia. (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers", section on 'Hyperkalemia'.)

Low-dose aspirin – All of the non-salicylate, non-COX-2 selective NSAIDs and acetylsalicylic acid (aspirin) inhibit platelet aggregation via inhibition of platelet COX-1 activity. However, aspirin inhibits platelet COX-1 in an irreversible manner and thus has proven benefits in reducing the risk of secondary thrombotic cardiovascular events. These properties may be important enough to warrant its continued use in the patient who also needs a typical NSAID. (See "Aspirin in the primary prevention of cardiovascular disease and cancer".)

Additionally, the beneficial effect of aspirin may be attenuated by prior or ongoing administration of some nonselective NSAIDs, such as ibuprofen or naproxen. Thus, regular NSAID use should be avoided, if possible, in patients taking low-dose aspirin for cardiovascular protection. In patients on aspirin who require NSAIDs on an occasional short-term basis, aspirin should be taken at least two hours before the NSAID. (See "NSAIDs: Adverse cardiovascular effects", section on 'Aspirin and other antithrombotic agents'.)

The more limited gastrointestinal toxicity of COX-2 selective agents, such as celecoxib, compared with nonselective NSAIDs may be offset by concurrent use of low-dose aspirin. (See "Overview of COX-2 selective NSAIDs".)

Glucocorticoids – The risk of peptic ulcer disease increases significantly when glucocorticoids are used in combination with an NSAID, compared with the use of either alone [33,34]. Such cotherapy may warrant the use of additional measures to prevent gastrointestinal toxicity. (See "Major adverse effects of systemic glucocorticoids", section on 'Gastrointestinal effects' and "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".)

Warfarin and other anticoagulants – In patients on warfarin or other chronic anticoagulation therapies, we avoid the use of nonselective NSAIDs because of their capacity to inhibit platelet function, thus increasing bleeding risk. NSAIDs which do not affect platelet function, such as the coxibs (eg, celecoxib), can be used cautiously in this setting in patients at low cardiovascular risk, as can nonacetylated salicylates, but the relative risks and benefits of these agents should be emphasized when informing patients. (See "Nonselective NSAIDs: Overview of adverse effects", section on 'Antiplatelet effects' and "Overview of COX-2 selective NSAIDs", section on 'Lack of platelet inhibition and use during anticoagulation'.)

NSAIDs increase the risk of bleeding in vitamin K antagonist treated patients by multiple mechanisms including gastrointestinal toxicity, increase in the INR, and interference with platelet function. (See "Biology of warfarin and modulators of INR control".)

Selective serotonin reuptake inhibitors – The use of selective serotonin reuptake inhibitors (SSRIs) in combination with NSAIDs is associated with an increased risk of gastroduodenal toxicity compared with the use of drugs from either class alone [35].

Other NSAIDs and higher-dose acetaminophen We generally avoid the use of multiple NSAIDs in combination (including concurrent therapy with both oral and topical NSAIDs) because of the potentially greater risk of adverse events with higher total NSAID doses and with multiple medications and because of the lack of evidence or clinical experience that the use of two or more NSAIDs concurrently is associated with improved efficacy that justifies the increased risk of high total NSAID doses [36,37]. Similarly, we generally avoid the combination of acetaminophen (paracetamol) at doses of 2 g/day or greater together with an NSAID because of the possibility that it might have a higher risk of gastrointestinal complications and a lack of clinically meaningful greater efficacy than with an NSAID alone. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation", section on 'Clinical factors that may influence toxicity'.)

Other agents Additional agents that may interact with NSAIDs or be problematic when used in combination with NSAIDs include anticoagulants other than warfarin, antiplatelet agents in addition to aspirin, various antihypertensives, calcineurin inhibitors (cyclosporine and tacrolimus), digoxin, diuretics, lithium, and other medications. Additional information may be found using the drug interactions program included in UpToDate.

NSAID use and comorbidities — We avoid the use of either nonselective NSAIDs or coxibs, or use them with particular caution, in certain groups of patients:

Gastrointestinal disease – In patients with a history of peptic ulcer disease or at elevated risk for gastroduodenal disease, which includes older adults (greater than approximately 60 years of age), we use measures to decrease the risk of adverse effects such as gastropathy and gastric ulcer. These may include cotherapy with a gastroprotective agent (eg, by also using a proton pump inhibitor or misoprostol, or by use of a combination product such as esomeprazole-naproxen), using a coxib (eg, celecoxib) rather than a nonselective NSAID, or other approaches to therapy (eg, topical NSAIDs, non-NSAID analgesics, other measures). We avoid the use of both nonselective and COX-2 selective NSAIDs in patients with active peptic ulcer disease. The prevention of NSAID-induced gastroduodenal damage is discussed separately. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity" and "NSAIDs (including aspirin): Treatment and secondary prevention of gastroduodenal toxicity".)

Cardiovascular disease and disease risk – In patients with or at increased risk of cardiovascular disease, including myocardial infarction, stroke, heart failure, unstable angina, or hypertension, the use of both NSAIDs, including both nonselective NSAIDs and coxibs, may be restricted. Use in these settings is described in detail elsewhere. (See "NSAIDs: Adverse cardiovascular effects" and "NSAIDs and acetaminophen: Effects on blood pressure and hypertension".)

Chronic kidney disease and disease risk – In patients at risk of chronic kidney insufficiency, such as those with intrinsic kidney disease, heart failure, or cirrhosis, and those receiving diuretic therapy, there is increased risk for developing reversible kidney failure while using either nonselective or COX-2 selective NSAIDs. In these settings, the synthesis of vasodilator renal prostaglandins helps to maintain kidney perfusion; interfering with this protective response with an NSAID can lead to kidney ischemia and an elevation in the plasma creatinine concentration. This risk is further increased in patients also receiving an ACE inhibitor and/or a diuretic. NSAIDs should be avoided in patients with stage 4 or 5 chronic kidney disease (estimated glomerular filtration rate of <30 mL/min per 1.73 m2 or treatment by dialysis). (See "NSAIDs: Acute kidney injury".)

Aspirin-exacerbated respiratory disease – In patients with aspirin sensitivity syndrome, we avoid the use of nonselective NSAIDs. Celecoxib may be less likely to provoke symptoms in aspirin sensitive reactive airways disease. This issue is discussed in more detail elsewhere. (See "Aspirin-exacerbated respiratory disease".)

Chronic liver disease and hepatic cirrhosis – NSAIDs are associated with an increased risk of variceal hemorrhage, impaired kidney function, and the development of diuretic-resistant ascites. Thus, NSAIDs (including aspirin) should generally be avoided in patients with advanced chronic liver disease or cirrhosis. (See "Management of pain in patients with advanced chronic liver disease or cirrhosis", section on 'Nonselective NSAIDs'.)

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.)

Basics topics (see "Patient education: Nonsteroidal antiinflammatory drugs (NSAIDs) (The Basics)")

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

SUMMARY

Variability of responses – The efficacy of the various nonsteroidal antiinflammatory drugs (NSAIDs) in patient populations is similar when given at equipotent doses. However, there is clear individual variation in therapeutic and adverse responses to these agents; some patients seem to respond better to one drug than to others, and responses differ between patients. The differences in the effects of the various NSAIDs have been ascribed to variations in mechanism of action, including absolute and relative differences in cyclooxygenase (COX) enzyme inhibition; different capacities for altering non-prostaglandin-mediated biologic events; and differences in pharmacodynamics, pharmacokinetics, and drug metabolism, including pharmacogenetic factors. (See 'Variability of responses' above and 'Effects of mechanisms of action' above and 'Pharmacologic properties and clinical effects' above.)

Pharmacologic properties and clinical effects – The risk of adverse events also seems to vary between individual drugs and patients. These differences in adverse event risk have been ascribed to differences in pharmacokinetics, including absorption, distribution, and metabolism. Such pharmacokinetic differences across NSAIDs, including differences in absorption, distribution, and differential metabolism, are probably not significant with respect to therapeutically beneficial effects. (See 'Pharmacologic properties and clinical effects' above.)

Dosing and duration – Dosing issues that affect the therapeutic response include the daily dose, frequency of drug administration, and the duration of use. (See 'Dosing and duration' above.)

Laboratory monitoring – In patients being treated chronically with daily NSAIDs, particularly with use of antiinflammatory continuous dosing, we obtain a complete blood count, blood urea nitrogen and creatinine, and aspartate aminotransferase at least once yearly. In patients at increased risk of adverse effects, such as anemia, kidney compromise, and drug-related liver injury, more frequent testing is usually required. (See 'Laboratory monitoring' above.)

Drug interactions – NSAIDs can interact with numerous drugs. In particular, some interactions occur due to NSAID-related reduction in kidney perfusion or additive hemorrhagic toxicity, and others due to effects upon drug metabolism. Among the major concerns are interactions with methotrexate (MTX), particularly in patients receiving high-dose chemotherapy; angiotensin-converting enzyme (ACE) inhibitors; aspirin and other antiplatelet agents; glucocorticoids; warfarin and other anticoagulants; selective serotonin reuptake inhibitors (SSRIs); and other NSAIDs and acetaminophen. (See 'Drug interactions' above.)

NSAID use and comorbidities – NSAIDs should be used with particular caution in patients with gastrointestinal, cardiovascular, and kidney disease and in patients at risk for such conditions, as they may worsen or increase risk of such conditions. They may also have similar effects to aspirin in patients with aspirin-exacerbated respiratory disease. (See 'NSAID use and comorbidities' above.)

  1. Agency for Healthcare Research and Quality. Comparative Effectiveness Review Number 38. Analgesics for osteoarthritis: An update of the 2006 comparative effectiveness review. Executive summary. www.effectivehealthcare.ahrq.gov/ehc/products/180/805/Analgesics-Update_executive-summary_20111007.pdf (Accessed on March 16, 2012).
  2. Heymann MA. Non-narcotic analgesics. Use in pregnancy and fetal and perinatal effects. Drugs 1986; 32 Suppl 4:164.
  3. Buttgereit F, Burmester GR, Simon LS. Gastrointestinal toxic side effects of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2-specific inhibitors. Am J Med 2001; 110 Suppl 3A:13S.
  4. Rollason V, Samer CF, Daali Y, Desmeules JA. Prediction by pharmacogenetics of safety and efficacy of non-steroidal anti- inflammatory drugs: a review. Curr Drug Metab 2014; 15:326.
  5. Bradley JD, Brandt KD, Katz BP, et al. Treatment of knee osteoarthritis: relationship of clinical features of joint inflammation to the response to a nonsteroidal antiinflammatory drug or pure analgesic. J Rheumatol 1992; 19:1950.
  6. 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.
  7. Cush JJ, Jasin HE, Johnson R, Lipsky PE. Relationship between clinical efficacy and laboratory correlates of inflammatory and immunologic activity in rheumatoid arthritis patients treated with nonsteroidal antiinflammatory drugs. Arthritis Rheum 1990; 33:623.
  8. Hla T, Neilson K. Human cyclooxygenase-2 cDNA. Proc Natl Acad Sci U S A 1992; 89:7384.
  9. Mitchell JA, Akarasereenont P, Thiemermann C, et al. Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Natl Acad Sci U S A 1993; 90:11693.
  10. 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.
  11. Furst DE. Are there differences among nonsteroidal antiinflammatory drugs? Comparing acetylated salicylates, nonacetylated salicylates, and nonacetylated nonsteroidal antiinflammatory drugs. Arthritis Rheum 1994; 37:1.
  12. Brooks PM, Day RO. Nonsteroidal antiinflammatory drugs--differences and similarities. N Engl J Med 1991; 324:1716.
  13. Ong CK, Lirk P, Tan CH, Seymour RA. An evidence-based update on nonsteroidal anti-inflammatory drugs. Clin Med Res 2007; 5:19.
  14. Grosser T, Ricciotti E, FitzGerald GA. The Cardiovascular Pharmacology of Nonsteroidal Anti-Inflammatory Drugs. Trends Pharmacol Sci 2017; 38:733.
  15. Lu X, Xie W, Reed D, et al. Nonsteroidal antiinflammatory drugs cause apoptosis and induce cyclooxygenases in chicken embryo fibroblasts. Proc Natl Acad Sci U S A 1995; 92:7961.
  16. Fries S, Grosser T, Price TS, et al. Marked interindividual variability in the response to selective inhibitors of cyclooxygenase-2. Gastroenterology 2006; 130:55.
  17. Bombardier C, Peloso PM, Goldsmith CH. Salsalate, a nonacetylated salicylate, is as efficacious as diclofenac in patients with rheumatoid arthritis. Salsalate-Diclofenac Study Group. J Rheumatol 1995; 22:617.
  18. Does the acetyl group of aspirin contribute to the antiinflammatory efficacy of salicylic acid in the treatment of rheumatoid arthritis? The Multicenter Salsalate/Aspirin Comparison Study Group. J Rheumatol 1989; 16:321.
  19. Tegeder I, Pfeilschifter J, Geisslinger G. Cyclooxygenase-independent actions of cyclooxygenase inhibitors. FASEB J 2001; 15:2057.
  20. Amin AR, Vyas P, Attur M, et al. The mode of action of aspirin-like drugs: effect on inducible nitric oxide synthase. Proc Natl Acad Sci U S A 1995; 92:7926.
  21. Hawkey CJ. Future treatments for arthritis: new NSAIDs, NO NSAIDs, or no NSAIDs? Gastroenterology 1995; 109:614.
  22. Ortiz MI, Granados-Soto V, Castañeda-Hernández G. The NO-cGMP-K+ channel pathway participates in the antinociceptive effect of diclofenac, but not of indomethacin. Pharmacol Biochem Behav 2003; 76:187.
  23. Díaz-González F, González-Alvaro I, Campanero MR, et al. Prevention of in vitro neutrophil-endothelial attachment through shedding of L-selectin by nonsteroidal antiinflammatory drugs. J Clin Invest 1995; 95:1756.
  24. Walker JS, Sheather-Reid RB, Carmody JJ, et al. Nonsteroidal antiinflammatory drugs in rheumatoid arthritis and osteoarthritis: support for the concept of "responders" and "nonresponders". Arthritis Rheum 1997; 40:1944.
  25. Coleman CI, Limone B, Sobieraj DM, et al. Dosing frequency and medication adherence in chronic disease. J Manag Care Pharm 2012; 18:527.
  26. Bingham CO 3rd, Smugar SS, Wang H, Tershakovec AM. Early response to COX-2 inhibitors as a predictor of overall response in osteoarthritis: pooled results from two identical trials comparing etoricoxib, celecoxib and placebo. Rheumatology (Oxford) 2009; 48:1122.
  27. Haroutiunian S, Drennan DA, Lipman AG. Topical NSAID therapy for musculoskeletal pain. Pain Med 2010; 11:535.
  28. Makris UE, Kohler MJ, Fraenkel L. Adverse effects of topical nonsteroidal antiinflammatory drugs in older adults with osteoarthritis: a systematic literature review. J Rheumatol 2010; 37:1236.
  29. Honvo G, Leclercq V, Geerinck A, et al. Safety of Topical Non-steroidal Anti-Inflammatory Drugs in Osteoarthritis: Outcomes of a Systematic Review and Meta-Analysis. Drugs Aging 2019; 36:45.
  30. Zeng C, Wei J, Persson MSM, et al. Relative efficacy and safety of topical non-steroidal anti-inflammatory drugs for osteoarthritis: a systematic review and network meta-analysis of randomised controlled trials and observational studies. Br J Sports Med 2018; 52:642.
  31. Derry S, Moore RA, Rabbie R. Topical NSAIDs for chronic musculoskeletal pain in adults. Cochrane Database Syst Rev 2012; :CD007400.
  32. Colebatch AN, Marks JL, Edwards CJ. Safety of non-steroidal anti-inflammatory drugs, including aspirin and paracetamol (acetaminophen) in people receiving methotrexate for inflammatory arthritis (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, other spondyloarthritis). Cochrane Database Syst Rev 2011; :CD008872.
  33. Tseng CL, Chen YT, Huang CJ, et al. Short-term use of glucocorticoids and risk of peptic ulcer bleeding: a nationwide population-based case-crossover study. Aliment Pharmacol Ther 2015; 42:599.
  34. Narum S, Westergren T, Klemp M. Corticosteroids and risk of gastrointestinal bleeding: a systematic review and meta-analysis. BMJ Open 2014; 4:e004587.
  35. Anglin R, Yuan Y, Moayyedi P, et al. Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis. Am J Gastroenterol 2014; 109:811.
  36. Hochberg MC, Altman RD, Brandt KD, et al. Guidelines for the medical management of osteoarthritis. Part I. Osteoarthritis of the hip. American College of Rheumatology. Arthritis Rheum 1995; 38:1535.
  37. McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage 2014; 22:363.
Topic 7993 Version 31.0

References

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