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NSAIDs: Overview of adverse effects
Lee S Simon, MD UpToDate performs a continuous review of over 290 journals and other resources. Updates are added as important new information is published. The literature review for version 11.2 is current through April 2003; this topic was last changed on September 5, 2002. The next version of UpToDate (11.3) will be released in October 2003. INTRODUCTION — More than 17,000,000 Americans use various different nonsteroidal
antiinflammatory drugs (NSAIDs) on a daily basis, making this class of drugs one of the most
commonly used in the world (show table 1). The Centers for Disease Control 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, leading to a parallel increase in the
use of NSAIDs.
The widespread use of these drugs has led to the recognition of numerous associated adverse effects. The most important complications are: z Gastrointestinal toxicity, including dyspepsia, peptic ulcer disease, and bleeding. (See "NSAIDs: Pathogenesis of gastroduodenal toxicity" and see "NSAIDs: Adverse effects on the distal small bowel and colon") z The development of acute renal failure due to renal vasoconstriction; other forms of renal toxicity also can occur. (See "NSAIDs: Acute renal failure and nephrotic syndrome"). z Modest worsening of underlying hypertension or congestive heart failure. (See "NSAIDs: Effects in hypertension and heart failure"). z Precipitation or exacerbation of airway obstruction in aspirin sensitive individuals. (See This topic review will discuss the major side effects, other than those listed above, that can occur following use of NSAIDs. OVERVIEW OF THE TOXICITY OF NSAID — Many of the toxic effects of the NSAIDs are related
to their main mode of action, the inhibition of prostaglandin synthesis. Although this issue has
become more complex with the identification of at least two forms of cyclooxygenase, all of the
currently available NSAIDs generally inhibit both isoforms of cyclooxygenase. (See "NSAIDs:
Mechanism of action")
It is therefore difficult to name the "safest" NSAID. The nonacetylated salicylates are probably safer than the other NSAIDs, since they are weak inhibitors of cyclooxygenase activity. Many clinicians believe that ibuprofen is also quite safe, which is true when the drug is used at the lowest UpToDate®: 'NSAIDs: Overview of adverse effects' possible dose. However, increasing the dose of any NSAID is associated with an increased risk of a toxic event. Minimizing toxicity with the use of NSAIDs also depends upon a thorough patient evaluation for those characteristics which enhance their risk of developing NSAID-induced toxicity. As an example, risk factors have been identified for the development of acute renal failure and gastroduodenal toxicity. (See appropriate topic reviews). Other approaches to reducing the potential for gastroduodenal damage that accompanies use of NSAIDs are at the investigational stage and include use of NSAIDs that are also nitric oxide donors and balanced cyclooxygenase and 5-lipoxygenase inhibitors [1]. HEPATIC INJURY — Elevations of serum aminotransferases (transaminases) are commonly
associated with NSAID use; however, liver failure is quite rare [2-4]. The net hepatic risk was
illustrated in a retrospective study of 625,000 patients who received more than 2 million
prescriptions for NSAIDs and who were evaluated for newly diagnosed acute liver injury [5]. The
following results were noted:
z There were 23 cases of acute liver injury over the four year study period. z 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. z 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. z Users of NSAIDs who had rheumatoid arthritis had a tenfold increased risk of acute liver injury compared with NSAID-treated patients with osteoarthritis. Concomitant exposure to other hepatotoxic medications probably increased the risk of hepatic injury in patients with rheumatoid arthritis. z Transient minor increases in liver enzymes were not a useful predictor of diagnosed NSAID- The hepatotoxicity associated with sulindac was further studied in an analysis of reports submitted to the Food and Drug Administration [6]. 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 with features including ANA positivity and histologic evidence of chronic active hepatitis that often caused misdiagnosis and inappropriate treatment [7]. Introduction of another class of NSAID in many of these patients appeared to be safe. Possible disease-specific risk — It has been suggested that liver function abnormalities due to
NSAIDs may be disease-specific. There is, for example, evidence supporting an increased risk of
hepatotoxic reactions in patients with systemic lupus erythematosus (SLE).
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 glutamic oxaloacetic transaminase (SGOT) in patients with rheumatoid arthritis (RA) and osteoarthritis (OA) taking placebo, aspirin, or UpToDate®: 'NSAIDs: Overview of adverse effects' diclofenac[8]. The principal determinants of SGOT concentrations were found to be the baseline SGOT 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 dosage. The SGOT 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 rheumatoid arthritis [2-5]. Some of these events had serious consequences. Recommendation — It is recommended that liver enzymes and function tests be measured within
eight weeks after the initiation of chronic NSAID therapy; monitoring symptoms is not sufficient,
since symptomatic hepatitis is rare. NSAIDs 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 (suggestive of
a synthetic defect induced by the drug), or if the prothrombin time is prolonged.
PULMONARY EFFECTS — The 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 quite severe) and pulmonary infiltrates with eosinophilia.
Bronchospasm — Bronchospasm or "aspirin-induced asthma" is discussed separately (See
"Aspirin-induced asthma").
Pulmonary infiltrates with eosinophilia — The syndrome of pulmonary infiltrates with
eosinophilia may occur in patients receiving NSAIDs. It is not known whether this syndrome is
associated with specific NSAIDs, or is due to the general class. In one review, the typical
presentation consisted of fever, cough, dyspnea, infiltrates on chest x-ray, and an absolute
peripheral eosinophilia [9]. Pathologic examination revealed poorly defined granulomas with
infiltrating eosinophils. Glucocorticoids were required, along with discontinuance of the drug, in
order to reverse the process.
HEMATOLOGIC EFFECTS — 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). Although phenylbutazone is now rarely used, neutropenia and antiplatelet effects
can be induced by any of the NSAIDs.
Neutropenia — Neutropenia is an infrequent complication of NSAID therapy, probably occurring in
less than 1 percent of users. A case-control study found that the adjusted odds ratio for the
occurrence of neutropenia in patients treated with NSAIDs was 4.2 compared to controls [10]. The
odds ratio 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.
Antiplatelet effects — The antiplatelet effects of NSAIDs are due to inhibition of COX-1, an
isoform of cyclooxygenase, leading to decreased production of thromboxane A2 (TxA2) [11]. 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 in
patients with coronary heart disease. (See "Antiplatelet agents in acute ST elevation (Q wave)
myocardial infarction" and see "Antiplatelet agents in unstable angina and acute non-ST elevation
(non-Q wave) myocardial infarction"). However, this same activity has potentially negative
consequences in other groups of patients:
z NSAIDs should be avoided in patients with preexisting platelet defects (eg, due to uremia or von Willebrand disease) and in those with thrombocytopenia (platelet count < 50,000/µL). UpToDate®: 'NSAIDs: Overview of adverse effects' Nonacetylated salicylates or selective COX-2 inhibiting agens are safer therapeutic alternatives in these patients. Doses of nonacetylated salicylates should remain within recommended dosage ranges (eg, 1.5 to 3.0 g/day for salsalate and choline magnesium trisalicylate) to avoid inhibition of platelet cyclooxygenase which can occur at high doses. z NSAIDs should be withheld preoperatively for at least four to five times the drug half-life. Aspirin irreversibly inhibits platelet cyclooxygenase and platelets lack the machinery to produce new cyclooxygenase; thus, patients should stop aspirin for at least one week prior toa planned surgical procedure to allow the body to repopulate the platelet pool with platelets that have not been exposed to the drug [11]. z Concomitant use of anticoagulants and NSAIDs is not strictly prohibited; however, anticoagulants may predispose to an increased risk of hemorrhage once a mucosal break has been precipitated by an NSAID. z Chronic aspirin therapy slightly increases the risk of hemorrhagic stroke. In a meta-analysis of 16 trials involving over 55,000 participants, in which aspirin was given in a average dose of 273 mg/day for a median duration of approximately three years, the absolute increase in hemorrhagic stroke was 12 events per 10,000 persons [12]. However, the benefits were much greater, as the reductions in myocardial infarction and ischemic stroke were 137 and 39 events per 10,000 persons, respectively. Thus, the benefits of aspirin appear to outweigh the risks in most populations at risk. However, when given to low-risk asymptomatic persons for primary prevention, the risk may be greater than any potential benefit. (See "Benefits of aspirin in cardiovascular disease"). New highly selective inhibitors of the COX-2 isoform of cyclooxygenase may have no effect on the platelet, since COX-2 activity has not been found in platelets. (See "NSAIDs: Mechanism of action", and see "Overview of selective COX-2 inhibitors"). Another issue that may arise is concurrent therapy with aspirin and a nonsalicylate NSAID. The dose of aspirin used to protect against cardiovascular disease is often quite low (eg, 81 to 325 mg/day of aspirin). Such patients may have an indication for NSAID use. None of the nonsalicylate NSAIDs has been evaluated for cardioprotective effects in large studies; they are therefore not a substitute for aspirin therapy. Thus, low dose aspirin should be continued in such patients, possibly increasing the risk of an untoward gastrointestinal event. Interference with aspirin's antiplatelet effect — The desirable antiplatelet effects of aspirin
may be attenuated by prior or ongoing administration of a nonselective NSAID, such as ibuprofen
[13]. This interference with the antiplatelet effects of aspirin has been demonstrated to affect in-
vitro platelet aggregation, but it is unclear whether there are any clinical consequences.
Nevertheless, until the issue is better understood, it may be prudent to avoid the combined use of
nonselective NSAIDs and aspirin if possible. Selective COX-2 inhibitors may be preferred when an
NSAID and aspirin must be used together. However, as discussed above, this combination may
largely eliminate the gastroduodenal safety advantage of the COX-2 inhibitor, and thus require, for
the patient at high risk of gastrointestinal ulceration or bleeding, additional antiulcer therapy. (See
"Benefits of aspirin in cardiovascular disease", and see "NSAIDs: Prevention and treatment of
gastroduodenal toxicity").
BLOOD PRESSURE — Patients with treated hypertension may have elevated levels of angiotensin
II and norepinephrine. These vasoconstrictors increase the release of vasodilator prostaglandins
from the kidney, which act locally to minimize the degree of renal ischemia [14]. When this
compensatory response is inhibited by an NSAID, the increase in renal and systemic vascular
resistance can cause an elevation in blood pressure. This effect can generally be induced by any
NSAID (including over-the-counter ibuprofen), but may be less likely to occur with sulindac or low-
UpToDate®: 'NSAIDs: Overview of adverse effects' dose aspirin, or with other types of analgesics such as acetaminophen[14,15]. (See "NSAIDs: Effects in hypertension and heart failure"). NSAID-induced blood pressure changes are small; in one meta-analysis the mean rise in supine blood pressure was 5.0 mmHg [16]. NSAIDs antagonized the antihypertensive effect of beta blockers (blood pressure elevation 6.2 mmHg) more than vasodilators and diuretics in this report. Piroxicam produced the most marked elevation in blood pressure (6.2 mmHg), while sulindac and aspirin had the least hypertensive effect. The consequences of these modest increases in blood pressure in patients taking NSAIDs have not been specifically studied. However, a 5 to 6 mmHg elevation in diastolic blood pressure over several years may be associated with a 67 percent increase in total stroke occurrence and a 15 percent increase in coronary heart disease [17]. CENTRAL NERVOUS SYSTEM — The reported central nervous system (CNS) side effects of
NSAIDs include aseptic meningitis, psychosis, and cognitive dysfunction [18,19].
z Psychosis and cognitive impairment are more prevalent in elderly patients, particularly with the use of indomethacin. 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. z Aseptic meningitis seems to be more prevalent in patients with SLE who are treated with NSAIDs of the phenylproprionic acid class (eg, ibuprofen, naproxen); however, this diagnosis should be considered in any patient with aseptic meningitis who has been using NSAIDs. Tinnitus is a common problem, particularly in patients prescribed high doses of salicylates, although it can occur with all of the available NSAIDs. Tinnitus is typically reversible upon cessationof 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 [19].
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 [18]. PREGNANCY AND LACTATION — Studies in rhesus monkeys have not found aspirin to be a
teratogen [19]. However, it is best to avoid NSAIDs if possible during pregnancy. The safety of
these drugs has not been extensively evaluated in controlled studies in pregnant women; in animal
models, NSAIDs have been shown to increase the incidence of dystocia and postimplantation loss,
and to delay parturition. In addition, the inhibition of prostaglandin synthesis by NSAIDs, particular
by aspirin, may result in premature closure of the ductus arteriosus, and other harmful effects
including smaller babies and neonatal bruising [19-21].
Despite these concerns, aspirin has been used for years in patients requiring NSAID therapy during pregnancy. A prospective study of 88 pregnant women compared the outcome in 45 who were treated with NSAIDs for a mean of 15.3 weeks during pregnancy to 43 who did not receive drug therapy [22]. There was no difference in pregnancy outcome, duration of labor, complications at delivery, or neonatal health between the two groups. It was concluded that the benefits of the NSAIDs in decreasing symptoms and signs of inflammation were greater than the risk of their use during pregnancy. Thus, aspirin can be used if absolutely necessary in pregnant women with inflammatory disease. It should be stopped in the last two months of pregnancy to avoid potential bleeding complications and premature closure of the ductus arteriosus; the shorter acting NSAIDs can be substituted with very close monitoring. UpToDate®: 'NSAIDs: Overview of adverse effects' NSAIDs are excreted in breast milk in very small amounts. It is generally agreed that salicylates in normally recommended doses are not harmful to nursing infants [20]. In contrast, misoprostol causes increased uterine contractility; it is considered an abortifacient agent. Thus, contraception isessential in women of childbearing potential who take misoprostol. Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES
1. Skelly, MM, Hawkey, CJ. Potential alternatives to COX-2 inhibitors (Editorial). BMJ 2002 324:1289.
2. Carson, JL, Strom, BL, Duff,A, et al. Safety of nonsteroidal antiinflammatory drugs with respectto acute liver disease. Arch Intern Med 1993; 153:1331.
3. Garcia Rodriguez, LA, Gutthann, SP, Walker, AM, Lueck, L. The role of non-steroidal antiinflammatory drugs in acute liver injury. BMJ 1992; 305:865.
4. Rabinovitz, M, Van Thiel, DH. Hepatotoxicity of nonsteroidal anti-inflammatory drugs. Am J Gastroenterol 1992; 87:1696.
5. Garcia Rodriguez, LA, Williams, R, Derby, LE, et al. Acute liver injury associated with nonsteroidal anti-inflammatory drugs and the role of risk factors. Arch Intern Med 1994; 154:311.
6. Tarazi, EM, Harter, JG, Zimmerman, HJ, et al. Sulindac associated hepatic injury: Analysis of 91 cases reported to the Food And Drug Administration. Gastroenterology 1993; 104:569.
7. Scully, LJ, Clarke, D, Barr, RJ. Diclofenac induced hepatitis: 3 cases with features of autoimmune chronic active hepatitis. Dig Dis Sci 1993; 38:744.
8. Furst, DE, Anderson, W. Differential effects of diclofenac and aspirin on serum glutamic oxaloacetic transaminase elevations in patients with rheumatoid arthritis and osteoarthritis. Arthritis Rheum 1993; 36:804.
9. Goodwin, SD, Glenny, RW. Nonsteroidal anti-inflammatory drug-associated pulmonary infiltrates with eosinophilia. Arch Intern Med 1992; 152:1521.
10. Strom, BL, Carson, JL, Schinnar, R, et al. Nonsteroidal anti-inflammatory drugs and neutropenia. Arch Intern Med 1993; 153:2119.
11. Patrono, C. Aspirin as an antiplatelet drug. N Engl J Med 1994; 330:1287.
12. He, J, Whelton, PK, Vu, B, Klag, MJ. Aspirin and risk of hemorrhagic stroke. A meta-analysis of controlled trials. JAMA 1998; 280:1930.
13. Catella-Lawson, F, Reilly, MP, Kapoor, SC, et al. Cyclooxygenase inhibitors and the antiplatelet effect of aspirin. N Engl J Med 2001; 345:1809.
14. Patrono, C, Dunn, MJ. The clinical significance of inhibition of renal prostaglandin synthesis. Kidney Int 1987; 32:1.
15. Pope, JE, Anderson, JJ, Felson, DT. A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure. Arch Intern Med 1993; 153:477.
16. Johnson, AG, Nguyen, TV, Day, RO. Do nonsteroidal anti-inflammatory drugs affect blood pressure? Ann Intern Med 1994; 121:289.
17. Collins, R, Peto, R, MacMahon, S, et al. Blood pressure, stroke, and coronary artery disease. Part 2: Short-term reductions in blood pressure: Overview of randomized drug trials in their epidemiological context. Lancet 1990; 335:827.
18. Hoppmann, RA, Peden, JG, Ober, SK. Central nervous system side effects of nonsteroidal anti-inflammatory drugs. Aseptic meningitis, psychosis, and cognitive dysfunction. Arch Intern Med 1991; 151:1309.
19. Simon, LS, Mills, JA. Nonsteroidal antiinflammatory drugs. N Engl J Med 1980; 302:1179.
20. Drug Facts and Comparisons, 50th ed. In: Facts and Comparison, Walter Kluwer Company, St Louis, 1996.
UpToDate®: 'NSAIDs: Overview of adverse effects' 21. Heymann, MA. Non-narcotic analgesics: Use in pregnancy and fetal and perinatal effects. Drugs 1986; 32(Suppl):164.
22. Østensen, M, Østensen, H. Safety of nonsteroidal antiinflammatory drugs in pregnant patientswith rheumatic disease. J Rheumatol 1996; 23:1045.
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