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Nonselective NSAIDs: Overview of adverse effects
Author:
Daniel H Solomon, MD, MPH
Section Editor:
Daniel E Furst, MD
Deputy Editor:
Paul L Romain, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2018. | This topic last updated: Mar 21, 2018.

INTRODUCTION — Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used for multiple conditions for their analgesic, antipyretic, and antiinflammatory properties. More than 17 million Americans use various NSAIDs (table 1) on a daily basis, making this class of drugs one of the most commonly used in the world.

The side effects that can occur following the use of nonselective NSAIDs (nsNSAIDs) that block both cyclooxygenase (COX)-1 and COX-2 will be reviewed here. The side effects associated with the selective COX-2 inhibitors are discussed separately. (See "Overview of selective COX-2 inhibitors" and "COX-2 selective inhibitors: Adverse cardiovascular effects".)

Detailed discussions of selected adverse effects of nsNSAIDs are presented separately for each of the following types of adverse effects:

NSAID poisoning – (See "Nonsteroidal antiinflammatory drug (NSAID) poisoning".)

Anaphylaxis and allergy – (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions".)

NSAID-exacerbated respiratory disease – (See "Aspirin-exacerbated respiratory disease".)

Renal and electrolyte – (See "NSAIDs: Acute kidney injury (acute renal failure)" and "NSAIDs and acetaminophen: Effects on blood pressure and hypertension", section on 'Effect of NSAIDs on blood pressure' and "NSAIDs: Electrolyte complications".)

Gastrointestinal – (See "NSAIDs (including aspirin): Pathogenesis of gastroduodenal toxicity" and "NSAIDs: Adverse effects on the distal small bowel and colon".)

Cardiovascular – (See "Nonselective NSAIDs: Adverse cardiovascular effects".)

Use during pregnancy and lactation – (See "Safety of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation", section on 'NSAIDs'.)

OVERVIEW — Many of the toxic effects of nonsteroidal antiinflammatory drugs (NSAIDs) are related to their main mode of action, the inhibition of prostaglandin synthesis. All of the available nonselective (ns)NSAIDs generally inhibit both isoforms of cyclooxygenase (COX), COX-1 and COX-2, with the exception of the nonacetylated salicylates. (See "NSAIDs: Pharmacology and mechanism of action" and "Aspirin: Mechanism of action, major toxicities, and use in rheumatic diseases", section on 'Other proposed mechanisms of action'.)

A number of factors can increase the risk of adverse effects due to NSAIDs. These include drug dose, drug-drug interactions, and comorbidities. The latter two factors are more common in older adults, and approximately 14 million Americans 45 and over use various non-aspirin NSAIDs regularly [1]. The Centers for Disease Control and Prevention in the United States predicts that, with the aging of the population, there will be a significant increase in the prevalence of painful degenerative and inflammatory rheumatic conditions. This will probably lead to a parallel increase in the use of NSAIDs. An increased use of NSAIDs in an aging population will increase the number of adverse events related to NSAID use. It has been estimated that 5 to 7 percent of hospital admissions are related to adverse effects of drugs, and, of these hospitalizations, those that result from gastrointestinal, nervous system, renal, or allergic effects of non-aspirin NSAIDs are responsible for approximately 11 to 12 percent [2,3].

Given their common mechanisms of action and the effects of the other factors that increase risk of adverse effects, it is difficult to name a "safest" nsNSAID. As an example, many clinicians believe that ibuprofen is quite safe, which is true when the drug is used at the lowest possible dose. However, increasing the dose of any NSAID is associated with an increased risk of most related toxicities.

Drug interactions may also be the source of adverse effects. For example, a potentially clinically relevant interaction between ibuprofen and aspirin referred to as "aspirin resistance" has been observed in ex vivo platelet assays when ibuprofen is administered to healthy controls before aspirin. Similar effects, which also depend upon timing of drug administration, have been demonstrated with naproxen and may occur with other NSAIDs. (See "Nonselective NSAIDs: Adverse cardiovascular effects", section on 'Patients taking aspirin for prevention'.)

Minimizing toxicity of NSAIDs also depends upon a thorough patient evaluation for those characteristics or comorbidities that enhance their risk of developing NSAID-induced toxicity. As an example, risk factors have been identified for the development of gastroduodenal toxicity, acute renal failure, and adverse cardiovascular effects, such as a history of a gastrointestinal event, reduced renal function, or a history of cardiovascular disease, respectively. (See 'Gastrointestinal effects' below and 'Renal effects' below and 'Cardiovascular effects' below.)

ACUTE NSAID OVERDOSE — Accidental or intentional ingestion of a single larger-than-recommended dose of a nonsteroidal antiinflammatory drug (NSAID) is typically well tolerated and usually does not cause serious adverse effects. However, such ingestions may be accompanied by the taking of other analgesics, which may have more serious consequences. Among these drugs, salicylates and acetaminophen are important ones to consider. (See "Salicylate (aspirin) poisoning in adults" and "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis" and "Acetaminophen (paracetamol) poisoning in adults: Treatment".)

Symptoms of acute overdose of NSAIDs are nonspecific, and patients are most often asymptomatic; when symptoms do occur, the most common include nausea, vomiting, drowsiness, blurred vision, and dizziness.

The clinical and laboratory features, evaluation, and management of an acute NSAID overdose are presented in detail separately. (See "Nonsteroidal antiinflammatory drug (NSAID) poisoning".)

GASTROINTESTINAL EFFECTS — Nonselective nonsteroidal antiinflammatory drugs (nsNSAIDs) have potentially important gastrointestinal adverse effects, which include dyspepsia, peptic ulcer disease, and bleeding. These effects are discussed in detail separately. (See "NSAIDs (including aspirin): Pathogenesis of gastroduodenal toxicity" and "NSAIDs: Adverse effects on the distal small bowel and colon".)

The risk of gastrointestinal toxicity is increased by the presence of one or more of the following: a prior history of a gastrointestinal event (ulcer, hemorrhage), age >60, a high dose of an NSAID, the concurrent use of glucocorticoids, and the concurrent use of antiplatelet agents (eg, aspirin, clopidogrel) and anticoagulants (eg, vitamin K antagonists, heparin, direct thrombin inhibitors, and direct factor Xa inhibitors). Chronic, as opposed to short-term, use; untreated Helicobacter pylori infection; and use of selective serotonin reuptake inhibitors (SSRI) may also increase the risk of bleeding or perforation. (See "NSAIDs (including aspirin): Pathogenesis of gastroduodenal toxicity", section on 'Risk of gastrointestinal complications' and 'Antiplatelet effects' below and 'Interaction with antiplatelet agents and anticoagulants' below.)

RENAL EFFECTS — Nonselective nonsteroidal antiinflammatory drugs (nsNSAIDs) have potentially important renal adverse effects that are discussed in detail separately. They include:

The development of acute renal failure due to renal vasoconstriction. Other forms of renal toxicity also can occur. (See "NSAIDs: Acute kidney injury (acute renal failure)".)

Modest worsening of underlying hypertension. (See "NSAIDs and acetaminophen: Effects on blood pressure and hypertension", section on 'Effect of NSAIDs on blood pressure'.)

Electrolyte and fluid abnormalities including hyperkalemia, hyponatremia, and edema. (See "NSAIDs: Electrolyte complications".)

Increased risk of renal cell cancer. (See 'Malignancy' below.)

The risk of acute renal failure is increased in patients with existing glomerular disease, renal insufficiency, hypercalcemia, in states of effective volume depletion (such as heart failure and cirrhosis), and in the presence of true volume depletion due to gastrointestinal or renal salt and water losses. (See "NSAIDs: Acute kidney injury (acute renal failure)".)

CARDIOVASCULAR EFFECTS — Nonselective nonsteroidal antiinflammatory drugs (nsNSAIDs) have a variety of effects on the cardiovascular system. Chronic as well as short-term use have been shown to have a deleterious effect upon cardiovascular risk, and these agents can modestly exacerbate heart failure. Some nsNSAIDs may interfere with the beneficial antiplatelet activity of aspirin. These issues and the factors that increase the risk of adverse cardiovascular effects are discussed in detail separately. (See "Nonselective NSAIDs: Adverse cardiovascular effects".)

HEPATIC INJURY — Elevations of serum aminotransferases (transaminases) are commonly associated with nonsteroidal antiinflammatory drug (NSAID) use; however, liver failure is quite rare [4-11]. The overall risk of clinically evident liver injury has been estimated at only 1 to 8 per 100,000 patient-years of drug use and is due to hepatocellular injury [11]. Hepatotoxicity has been reported with most NSAIDs, usually occurring in the first 6 to 12 weeks of treatment and resolving within 4 to 8 weeks of discontinuation.

Clinical spectrum and frequency — Acute liver injury is uncommon and not predicted by mild increased aminotransferase levels [10,11]. The net hepatic risk was illustrated in a retrospective study of 625,000 patients who received more than two million prescriptions for NSAIDs and who were evaluated for newly diagnosed acute liver injury [10]. The following results were noted:

There were 23 cases of acute liver injury over the four-year study period.

The incidence of acute liver injury was 3.7 per 100,000 NSAID users or 1.1 per 100,000 NSAID prescriptions; none of the cases had a fatal outcome.

Sulindac was the only NSAID with a substantially greater risk than that of the overall NSAID group; the incidence of hepatic injury with this drug was 27 per 100,000 prescriptions. However, the liver injury associated with sulindac and the other NSAIDs was generally mild and reversible.

Users of NSAIDs who had rheumatoid arthritis (RA) had a 10-fold increased risk of acute liver injury compared with NSAID-treated patients with osteoarthritis (OA). Concomitant exposure to other hepatotoxic medications probably increased the risk of hepatic injury in patients with RA.

Transient minor increases in liver enzymes were not a useful predictor of diagnosed NSAID-associated acute liver injury.

The hepatotoxicity associated with sulindac was further studied in an analysis of reports submitted to the US Food and Drug Administration (FDA) [12]. This report found that sulindac injury involved women more than men and was more prevalent in patients over the age of 50. The majority of events were idiosyncratic hypersensitivity reactions.

Diclofenac has been reported to cause clinical hepatitis, including antinuclear antibody (ANA) positivity and histologic evidence of chronic active hepatitis [13]. Introduction of another class of NSAID in many of these patients appeared to be safe. Severe liver injury has been reported but remains very rare [14].

Possible disease-specific risk — It has been suggested that liver function abnormalities due to NSAIDs may be disease-specific. The possible role of the underlying disease was illustrated in a meta-analysis of over 1600 patients. This analysis studied elevations in the serum concentration of aspartate aminotransferase (AST, formerly termed serum glutamic oxaloacetic transaminase [SGOT]) in patients with RA and OA taking placebo, aspirin, or diclofenac [15]. The principal determinants of AST concentrations were found to be the baseline AST value, the use of aspirin in patients with RA, and the use of diclofenac in patients with OA. Other significant factors included duration of therapy and, possibly, daily dose. The AST elevations were minimal and were not related to the occurrence of clinical hepatitis.

In other studies, aspirin caused elevated serum aminotransferase concentrations in 40 percent of patients with active juvenile inflammatory arthritis [4-6,10]. Some of these events had serious consequences.

Laboratory testing — Hepatotoxicity is rare, and the cost-effectiveness of monitoring serum transaminase levels is uncertain. However, if the aminotransferases are noted to rise to greater than three times the upper limit of normal, if there is a fall in serum albumin (suggestive of a synthetic defect induced by the drug), or if the international normalized ratio (INR) is prolonged, NSAID toxicity should be suspected, and the potentially offending agent should be discontinued.

ANAPHYLAXIS AND ALLERGY — Anaphylaxis to nonselective nonsteroidal antiinflammatory drugs (nsNSAIDs) has been reported and is assumed to be an immunoglobulin (Ig) E-mediated immunologic reaction. The symptoms of anaphylaxis include (but are not limited to) urticaria, angioedema, generalized pruritus, tachycardia or bradycardia, hypotension, cardiac arrhythmias, nausea and vomiting, headache, and lightheadedness. Anaphylaxis and other allergic and pseudoallergic reactions in response to NSAIDs are discussed in detail elsewhere. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions".)

PULMONARY EFFECTS — Nonsteroidal antiinflammatory drugs (NSAIDs) rarely induce pulmonary problems, although the actual incidence of adverse events is unknown. The principal pulmonary reactions that can occur include bronchospasm (which can be severe) and pulmonary infiltrates with eosinophilia.

Bronchospasm — Treatment with cyclooxygenase (COX)-1-inhibiting (nonselective [ns]) NSAIDs may precipitate acute exacerbations of airway inflammation in patients with the condition "aspirin-exacerbated respiratory disease" (AERD). This may present as bronchospasm in those with underlying asthma or as acute attacks of flushing, conjunctival injection, nasal congestion, and bronchospasm in those with inflammation affecting the entire respiratory tract. The latter can be difficult to distinguish from anaphylaxis. Patients with AERD may have concomitant chronic rhinosinusitis and nasal polyposis. (See "Aspirin-exacerbated respiratory disease".)

In contrast to nsNSAIDs, selective COX-2 inhibitors are much less likely to trigger AERD in patients with this syndrome. Thus, the adverse effects of nsNSAIDs in AERD appear related to COX-1 inhibition. The adverse respiratory effects of NSAIDs are discussed in detail separately. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions".)

Pulmonary infiltrates with eosinophilia — The syndrome of pulmonary infiltrates with eosinophilia may occur in patients receiving NSAIDs, but this is very rare [16]. It is not known whether this syndrome is associated with particular NSAIDs or is due to the general class. In one review, the typical presentation consisted of fever, cough, dyspnea, infiltrates on chest radiograph, and an absolute peripheral eosinophilia [16]. Pathologic examination revealed poorly defined granulomas with infiltrating eosinophils. Glucocorticoids were required, along with discontinuance of the drug, in order to reverse the process. (See "Causes of pulmonary eosinophilia".)

HEMATOLOGIC EFFECTS — Several types of hematologic adverse effects may occur with nonsteroidal antiinflammatory drugs (NSAIDs). These include idiosyncratic and rare, but potentially serious, reactions such as neutropenia and, even less often, aplastic anemia. In addition, NSAIDs can increase bleeding risk by several mechanisms: All nonspecific NSAIDs exert direct effects upon platelets to inhibit platelet function by reducing platelet adhesion and aggregation, which can be especially problematic in patients on other antiplatelet agents or anticoagulants, and certain drug interactions by NSAIDs with other agents can also increase bleeding risk. (See 'Neutropenia and aplastic anemia' below and 'Antiplatelet effects' below and 'Interaction with antiplatelet agents and anticoagulants' below.)

Neutropenia and aplastic anemia — Neutropenia is an infrequent complication of NSAID therapy, probably occurring in less than 1 percent of users. Neutropenia can be induced by any of the NSAIDs. A case-control study found that the adjusted odds ratio (OR) for the occurrence of neutropenia in patients treated with NSAIDs was 4.2 compared with controls [17]. The OR fell slightly to 3.5 when patients treated with phenylbutazone or indomethacin were excluded. There were no specific risk factors for an event and no risks associated with particular NSAIDs; however, the number of patients treated with a single NSAID was probably too small to demonstrate a difference between drugs. (See "Drug-induced neutropenia and agranulocytosis".)

Some of the early NSAIDs (eg, phenylbutazone and, to a lesser degree, indomethacin) have been associated with an increased risk for bone marrow failure (ie, aplastic anemia). Phenylbutazone is rarely used and is no longer available for use in the United States.

Antiplatelet effects — NSAIDs exert antiplatelet effects through inhibition of the cyclooxygenase (COX)-1 isoform, leading to decreased production of thromboxane A2 (TxA2) [18]. TxA2 is released by platelets in response to a number of agonists, amplifying the platelet response and leading to aggregation. These effects have therapeutic applications, such as the use of aspirin as a prophylactic agent in patients with coronary heart disease (see "Antiplatelet agents in acute ST elevation myocardial infarction" and "Antiplatelet agents in acute non-ST elevation acute coronary syndromes"). However, this same activity has potentially negative consequences in other groups of patients:

Patients with preexisting platelet defects – NSAIDs should be avoided in patients with preexisting qualitative or quantitative platelet defects (eg, due to uremia or von Willebrand disease) and in those with thrombocytopenia (platelet count <50,000/microL). Nonacetylated salicylates or selective COX-2-inhibiting agents are safer therapeutic alternatives in these patients. Doses of nonacetylated salicylates should remain within recommended dose ranges (eg, 1.5 to 3 g/day for salsalate and choline magnesium trisalicylate) to avoid inhibition of platelet COX, which can occur at high doses.

During the immediate preoperative period – NSAIDs should generally be withheld preoperatively for four to five times the drug half-life. However, the elimination half-life correlates poorly with COX inhibition and effects upon platelet aggregation [19,20]. Additionally, the relationship between time of discontinuation of NSAIDs and intra- and postoperative clinical bleeding is not well defined. For most NSAIDs, platelet function normalizes within three days of discontinuation, suggesting that NSAIDs should generally be discontinued at least three days before surgery. In healthy individuals receiving ibuprofen for one week, platelet function appears to return to normal within 24 hours after the last dose [21]; thus, ibuprofen can be stopped 24 hours prior to surgery. (See "Perioperative medication management", section on 'Nonsteroidal antiinflammatory drugs'.)

Aspirin irreversibly inhibits platelet COX, and platelets lack the machinery to produce new COX. Thus, if aspirin is discontinued preoperatively, patients should stop aspirin for at least one week prior to a planned surgical procedure to allow the body to generate new platelets that have not been exposed to aspirin [18]. (See "Perioperative medication management", section on 'Aspirin'.)

The antiplatelet effects of aspirin are discussed in detail elsewhere. (See "Aspirin: Mechanism of action, major toxicities, and use in rheumatic diseases", section on 'Anticoagulant effects' and "Platelet biology", section on 'Aspirin' and "Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'Mechanisms of action'.)

Highly selective inhibitors of the COX-2 isoform of cyclooxygenase have little or no effect on the platelet since COX-2 activity has not been found in platelets. (See "NSAIDs: Pharmacology and mechanism of action" and "Overview of selective COX-2 inhibitors".)

Concurrent therapy with low-dose aspirin for cardiovascular prophylaxis and a nonsalicylate NSAID for another indication could potentially increase the risk of an untoward gastrointestinal event but is usually well tolerated, and NSAIDs and low-dose aspirin can generally be used concurrently. However, none of the nonsalicylate NSAIDs has been evaluated for cardioprotective effects in large studies, and they are not a substitute for aspirin therapy.

As mentioned, concomitant use of low-dose aspirin and nonsalicylate NSAIDs may interfere with the beneficial cardiovascular effects of aspirin. (See "Nonselective NSAIDs: Adverse cardiovascular effects", section on 'Patients taking aspirin for prevention'.)

Interaction with antiplatelet agents and anticoagulants — The combination of NSAIDs, with their antiplatelet effects (see 'Antiplatelet effects' above), with either other antiplatelet agents (eg, aspirin or clopidogrel) or anticoagulants (eg, warfarin and other vitamin K antagonists, heparin, and factor Xa inhibitors) results in substantially increased risks of bleeding compared with either NSAIDs or the other agents alone [22-24]. NSAIDs can also increase bleeding risk by effects that increase the international normalized ratio (INR) in patients on vitamin K antagonists.

Combined effects of NSAIDs with other agents also affecting bleeding risk – As examples, in a large cohort of patients followed after a new diagnosis of atrial fibrillation who started on warfarin, aspirin, or clopidogrel, there were increases in the absolute risk of a serious bleeding event at three months after 14 days of NSAID exposure compared with no NSAID exposure [25]. The absolute increase in bleeding risk ranged from 2.1 to 2.5 bleeds per 1000 patients.

In another example, the risk of bleeding (requiring hospitalization) in relation to NSAID administration was examined in patients receiving antithrombotic therapy following a first-time myocardial infarction (and alive 30 days later) in a Danish nationwide registry of patients [26]. Bleeding events occurred in 8.5 percent of patients. They were significantly more likely in patients receiving NSAIDs in addition to aspirin, clopidogrel, oral anticoagulants, or a combination of such agents, compared with patients on aspirin or other anticoagulants not receiving prescription NSAIDs (crude incidence rates per 100 person-years of 4.2, 95% CI 3.8-4.6, versus 2.2, 95% CI 2.1-2.3). In multivariate adjusted analyses, the risk of bleeding was doubled in patients receiving NSAIDs (hazard ratio [HR] 2.02, 95% CI 1.81-2.26). Most of the study patients (over 90 percent) were receiving nonselective (ns)NSAIDs. The increase in bleeding risk was seen as early as the first three days of NSAID use. Concomitant use of NSAIDs with antithrombotic agents in these patients was also associated with an increased rate of adverse cardiovascular events. (See "Nonselective NSAIDs: Adverse cardiovascular effects", section on 'Patients with known coronary heart disease' and "COX-2 selective inhibitors: Adverse cardiovascular effects", section on 'Use in patients on aspirin, other antiplatelet agents, and anticoagulants'.)

Drug-drug interactions increasing the international normalized ratio – In addition, when NSAIDs and vitamin K antagonists (eg, warfarin) are taken concurrently, a clinically significant increase in INR may occur. This was illustrated in a study of 112 Dutch patients treated with the oral anticoagulant acenocoumarol who received an NSAID (diclofenac, naproxen, or ibuprofen) [27]. Twelve patients (11 percent) had increases in INR to more than six. Thus, more frequent monitoring of the INR is necessary if an NSAID is added to concomitant anticoagulation with a warfarin derivative or if the dose of either drug is changed. (See "Biology of warfarin and modulators of INR control", section on 'Aspirin/NSAIDs'.)

These effects on the INR are most commonly seen when a vitamin K antagonist is combined with an nsNSAID and are typically not observed with COX-2-selective NSAIDs, although this phenomenon can be seen on occasion with the COX-2-selective agents as well.

Combined risks of NSAIDs and antidepressants – Antidepressants, particularly selective serotonin reuptake inhibitors (SSRI), also appear to increase the risk of gastrointestinal bleeding; such risk, which may be related to effects on platelet serotonin, is further increased by use in combination with NSAIDs. (See "NSAIDs (including aspirin): Pathogenesis of gastroduodenal toxicity", section on 'Risk of gastrointestinal complications'.)

In addition, although neither NSAIDs nor antidepressants alone have been associated with increased risks of intracranial bleeding, a retrospective nationwide cohort study of Koreans found that the combination of NSAIDs with antidepressants, across all classes of antidepressants, significantly, although only slightly, increased the risk of intracranial hemorrhage within 30 days of combined use, compared with use of antidepressants alone (HR 1.6, 95% CI 1.32-1.85) [28]. The absolute risks of such bleeding were relatively low (5.7 versus 1.6 per 1000 person-years).

MALIGNANCY — Nonselective nonsteroidal antiinflammatory drugs (nsNSAIDs) have been associated with an increased risk of renal cell cancer [29,30], although decreased risk for several other malignancies, including colorectal, prostate, and breast cancer, has also been described with NSAID use [31-33]. (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma", section on 'Analgesics' and "NSAIDs (including aspirin): Role in prevention of colorectal cancer" and "Factors that modify breast cancer risk in women" and "Factors that modify breast cancer risk in women", section on 'Medications'.)

Regular use (at least two doses weekly) of nonaspirin NSAIDs, but not of aspirin or acetaminophen, was associated with an increased risk of renal cell cancer in a study involving nearly 127,000 individuals for whom data were prospectively collected during 16 to 20 years of follow-up (relative risk for users versus nonusers of nonaspirin NSAIDs 1.51, 95% CI 1.12-2.04) [29]. Risk increased with greater duration of use and was independent of other known risk factors including obesity, hypertension, and smoking. However, the absolute risk was very small; absolute risk differences for users versus nonusers of nonaspirin NSAIDs were 9.2 and 10.9 per 100,000 person-years for women and men, respectively.

NEUROLOGIC

Central nervous system – The reported central nervous system (CNS) side effects of nonsteroidal antiinflammatory drugs (NSAIDs) include aseptic meningitis, psychosis, and cognitive dysfunction [34-36]. Indomethacin use is associated with CNS side effects of headache.

Psychosis and cognitive impairment are more prevalent in older patients, particularly with the use of indomethacin, which has been associated with side effects including headache and altered mental status. Thus, indomethacin should be prescribed judiciously in geriatric patients, with close attention to mental status changes. NSAID doses in general should be minimized as much as possible in this population.

Aseptic meningitis seems to be more prevalent in patients with systemic lupus erythematosus (SLE) who are treated with NSAIDs of the phenylpropionic acid class (eg, ibuprofen, naproxen); however, a relationship to the drug should be considered in any patient with aseptic meningitis who has been using an NSAID. (See "Aseptic meningitis in adults".)

Tinnitus and hearing loss – Tinnitus and hearing loss are common problems in patients who are prescribed high doses of salicylates. Although it can occur with all of the available NSAIDs, it is less commonly seen among nonsalicylate NSAIDs. Tinnitus is typically reversible upon cessation of drug therapy and is a good warning sign to identify those patients who are developing high blood levels of the drug. However, it may not be as evident in patients at the extremes of age [36]. Chronic use of ibuprofen has also been associated with an increased risk of self-reported hearing loss [37].

Ocular manifestations – Ocular manifestations of NSAIDs are typically unimportant clinically. They include the deposition of drug crystals in the cornea and, rarely, the development of corneal edema. The latter is reversible, although, when present, it may affect vision. Rare idiosyncratic and anecdotal events, including optic nerve insults whose biology remains poorly understood, have also been reported [34].

SKIN REACTIONS — Various skin reactions may develop in association with the use of nonsteroidal antiinflammatory drugs (NSAIDs). Severe, potentially life-threatening reactions such as toxic epidermal necrolysis (TEN) and the Stevens-Johnson syndrome (SJS) are uncommon. Morbilliform rashes and urticaria are also seen with this class of drugs. (See "Drug eruptions".)

TEN and Stevens-Johnson syndrome — TEN and SJS are characterized by blistering skin lesions that may begin as erythematous macules and SJS by target-like areas anywhere on the body. Either one may cause mucosal blistering or ulceration as well. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

In one study of 373 cases of TEN or SJS and 1720 controls, the oxicam NSAIDs (piroxicam and tenoxicam) had the highest risk (relative risk of 34), while the relative risks were less with diclofenac and ibuprofen (4.1 and 5.3, respectively) and were not significantly increased for ketoprofen [38]. However, even with use of piroxicam or tenoxicam, the estimated incidence of TEN or SJS is 1 per 100,000 patients during the first eight weeks of treatment. Rates of SJS and TEN reported spontaneously for diflunisal, sulindac, oxaprozin, and etodolac were "comparable" to those for piroxicam in the United States [38].

Pseudoporphyria — Blistering can also occur in sun-exposed areas as a result of NSAID use. This phenomenon has been referred to as pseudoporphyria. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis", section on 'Differential diagnosis'.)

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 nonsteroidal antiinflammatory drugs (nsNSAIDs) or cyclooxygenase (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. In studies in rodents, both nonselective and COX-2-selective NSAIDs can interfere with normal fracture healing, an effect that appears to be mediated by the inhibition of COX-2 [39,40]. At present, we would not avoid the use of these agents in patients with fractures, given the very small absolute risk of nonunion.

A 2010 systematic review and meta-analysis of 11 case-control and cohort studies, which compared 2067 NSAID-exposed patients with 9984 nonexposed controls, found that the degree of risk (pooled odds ratio [OR]) for nonunion was significantly elevated in NSAID-exposed patients when both moderate-quality studies of long-bone fractures and higher-quality studies of spinal fusion were analyzed together (OR 3.0, 95% CI 1.6-5.6) [41]. However, when only the higher-quality studies were considered, a significant increase in risk was not observed (OR 2.2, 95% CI 0.8-6.3). There were no randomized trials that qualified for inclusion in the meta-analysis.

Given the retrospective nature of these studies, it is not clear whether NSAID use contributed to the occurrence of nonunion events or resulted from their use to treat painful nonhealing fractures. In the largest study included in the meta-analysis, including a cohort of nearly 10,000 patients with humeral shaft fractures, the timing of drug use was analyzed with respect to the risk of nonunion [42]. Exposure to either nsNSAIDs or opioids in the period 61 to 90 days after the fracture was associated with nonunion; however, exposure to either drug class during earlier time periods did not correlate significantly with this complication. Rather than medication use resulting in nonunion, this observation is most consistent with the development of painful nonhealing fractures subsequently requiring either NSAIDs or opioids for pain relief.

The basis for the differences between the animal experiments and human studies, whether from differences in the biology or dosing, is unknown. Whether differences in NSAID effects between long bones and the spine are due to study design or biologic differences in the healing processes is also unclear. Because nonunion is a rare event (approximately 1 percent for long-bone fractures) with modern treatment regimens, adequately powered studies would need to be very large to demonstrate a relationship if one were present.

Possible effect on tendon injury — Animal studies suggest a theoretical adverse impact of some NSAIDs (both nonselective and COX-2 selective) on healing from tendon and ligament injuries for which NSAIDs are often used [43,44]. However, there are no published human data demonstrating such effects. The common use of NSAIDs in such patients is based upon the positive experience of clinicians and patients, although many of these injuries also heal without specific treatment.

SPECIAL POPULATIONS

Pregnancy and lactation — The safety of nonsteroidal antiinflammatory drugs (NSAIDs) during pregnancy and lactation is discussed separately. (See "Safety of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation", section on 'NSAIDs'.)

Older adults — NSAIDs should be used cautiously in older adults and generally for a limited duration, given the increased risk of toxicity in this population, including gastrointestinal bleeding, renal impairment, and heart failure. (See "Drug prescribing for older adults" and "Drug prescribing for older adults", section on 'Care in the use of common drugs'.)

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 AND RECOMMENDATIONS

Gastrointestinal, neurologic, renal, and allergic effects of nonaspirin nonsteroidal antiinflammatory drugs (NSAIDs) are responsible for approximately 12 percent of hospital admissions related to adverse effects of drugs. Many of the toxic effects of the NSAIDs are related to their main mode of action, the inhibition of prostaglandin synthesis. Minimizing toxicity of NSAIDs depends upon a thorough patient evaluation for characteristics that enhance the risk of developing NSAID-induced toxicity, such as specific factors that increase risk for acute renal failure or gastrointestinal toxicity. (See 'Introduction' above and 'Overview' above.)

Accidental or intentional ingestion of a larger-than-recommended dose of an NSAID is typically well tolerated and does not cause serious adverse effects. However, such ingestions may be accompanied by the taking of other analgesics that may have more serious consequences, such as salicylates or acetaminophen. (See 'Acute NSAID overdose' above.)

Nonselective (ns)NSAIDs have potentially important gastrointestinal, renal, and cardiovascular effects. Adverse gastrointestinal effects include dyspepsia, peptic ulcer disease, and bleeding. Renal adverse effects include acute renal failure due to renal vasoconstriction, worsening of underlying hypertension, and electrolyte and fluid abnormalities. Additionally, the risk of renal cell cancer may be increased. Cardiovascular effects include interference by some agents with the antiplatelet activity of aspirin, an effect on coronary risk, and worsening of heart failure. (See 'Gastrointestinal effects' above and 'Renal effects' above and 'Malignancy' above and 'Cardiovascular effects' above.)

Elevations of serum aminotransferases (transaminases) are commonly associated with NSAID use. However, these elevations are generally mild and reversible, and liver failure is quite rare. Reactions may be more common with some NSAIDs (eg, sulindac, diclofenac, and aspirin) and in patients on other hepatotoxic medications or with certain disorders, including juvenile inflammatory arthritis. The potentially offending agent should be discontinued if the aminotransferases rise to greater than three times the upper limit of normal, if there is a fall in serum albumin, or if the prothrombin time is prolonged. (See 'Hepatic injury' above.)

Pulmonary reactions are uncommon; they include bronchospasm and pulmonary infiltrates with eosinophilia. Bronchospasm can result from the condition "aspirin-exacerbated respiratory disease" (AERD), which appears related to cyclooxygenase (COX)-1 inhibition. Patients with AERD may have concomitant chronic rhinosinusitis and nasal polyposis; inflammation affecting the entire respiratory tract may be difficult to distinguish from anaphylaxis in some patients. Anaphylaxis to NSAIDs has also been reported and is assumed to be an immunoglobulin (Ig) E-mediated immunologic reaction. (See 'Pulmonary effects' above and 'Anaphylaxis and allergy' above.)

nsNSAIDs have several important hematologic effects. The antiplatelet effects of NSAIDs, which are due to inhibition of COX-1, lead to diminished production of thromboxane A2, resulting in decreased platelet aggregation. NSAIDs should thus be avoided in patients with preexisting platelet defects and should be withheld preoperatively for at least four to five times the drug half-life. Chronic aspirin therapy slightly increases the risk of hemorrhagic stroke.

Use of nonselective nonsalicylate NSAIDs together with warfarin may increase the international normalized ratio (INR) and may increase bleeding risk due to the additional antiplatelet effect. Aplastic anemia has been most strongly associated with some of the early NSAIDs (eg, phenylbutazone and indomethacin); neutropenia is seen in less than 1 percent of patients. (See 'Hematologic effects' above and 'Antiplatelet effects' above and 'Interaction with antiplatelet agents and anticoagulants' above and 'Neutropenia and aplastic anemia' above.)

Central nervous system (CNS) side effects of NSAIDs include aseptic meningitis, psychosis, and cognitive dysfunction. Tinnitus and hearing loss are common problems, particularly with high doses of salicylates, but can occur with any NSAID. Tinnitus is typically reversible upon cessation of drug therapy and is a good warning sign to identify some of those patients who are developing high blood levels of the drug. (See 'Neurologic' above.)

Various skin reactions may develop in association with the use of NSAIDs. Severe, potentially life-threatening reactions such as toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are uncommon. Morbilliform rashes and urticaria are also seen. (See 'Skin reactions' above.)

A small increased risk of nonunion in patients with bone fractures has been reported with the use of nsNSAIDs 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. (See 'Possible effect on fracture healing' above.)

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