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Clinical Context

NSAIDs are commonly used to treat inflammation, pain, and fever by blockage of the COX enzyme, and there is limited evidence to support differences in effectiveness for pain treatment when comparing NSAIDs. The likelihood of adverse effects increases with duration of use and dose. However, the adverse effect profile of the different NSAIDs may differ. For example, aspirin is used for primary prevention of coronary and cardiovascular conditions such as stroke because of its antiplatelet effects, whereas COX-2 inhibitors have little antiplatelet effect.

This is a review of the adverse effects of NSAIDs and precautions needed to minimize risk when NSAIDs are prescribed. Adverse effects occur mainly in the GI, cardiovascular, hepatic, renal, hematologic, nervous, and respiratory systems.

Study Highlights

Taking drug holidays or using intermittent dosing may be strategies to reduce the risks associated with NSAID use.
Dyspepsia and GI discomfort occur in 10% to 20% of persons taking NSAIDs, but dyspeptic symptoms do not correlate well with clinically significant ulcers.
GI adverse effects are increased with age and comorbidity.
The 1-year risk of serious GI bleeding from long-term NSAID use ranges from 1 in 2100 adults younger than 45 years to 1 in 110 older than 75 years.
Risk for death for the 2 groups ranges from 1 in 12,353 to 1 in 647 adults, respectively.
Concomitant anticoagulant use increases the risk by 5 to 6 times.
In those with a history of bleeding ulcers, the risk is 5% in 6 months, even with the use of COX-2 inhibitors or nonselective NSAIDs with a PPI.
Eradication of Helicobacter pylori only minimally decreases the rate of peptic ulcer in persons taking NSAIDs.
Taking misoprostol with an NSAID reduces ulcer-related complications but is contraindicated in pregnancy (category X) and has undesirable GI effects.
Use of PPIs or double-dose antihistamines with NSAIDs decreases the rate of endoscopically diagnosed ulcers.
Although low-dose aspirin has been shown to reduce the risk for coronary artery and cerebrovascular disease, other NSAIDs are associated with an increased risk for worsening congestive heart failure, increased blood pressure, and adverse cardiovascular events.
Blood pressure increases by 5 mm Hg, whereas use of nonselective NSAIDs and some COX-2 inhibitors also increases blood pressure.
COX-2 inhibitors have been implicated in the risk for myocardial infarction, although celecoxib may be safer than the others.
COX-2 inhibitors should be avoided in persons at risk for cardiovascular events, who should consider a nonselective NSAID with misoprostol or a PPI for GI protection instead.
Sulindac and diclofenac are associated with a higher rate of hepatic dysfunction than other NSAIDs, but clinically significant events are rare.
Idiosyncratic liver toxicity may occur in those with hepatitis C or underlying liver impairment.
NSAIDs should be avoided in persons with preexisting renal disease, congestive heart failure, or cirrhosis to prevent renal failure.
It is unclear whether monitoring renal function in those with renal risk who are taking NSAIDs reduces morbidity or mortality rates.
In high-risk persons with recent myocardial infarction or stent placement, aspirin should be continued before and after surgery.
In those with bleeding risk, aspirin and other NSAIDs may be withheld before surgery for 5 elimination half-lives (eg, 7 - 10 days before surgery for aspirin and 2 days for ibuprofen).
Aspirin should be avoided in those for whom benefits do not outweigh risks.
In persons taking anticoagulants, INR monitoring is required when using NSAIDs, and GI prophylaxis should be prescribed.
Central nervous system effects are rare and occur mainly in elderly persons, including tinnitus, cognitive changes, confusion, and depression.
Indomethacin has been associated with psychosis, whereas aseptic meningitis has been seen with lupus in those taking ibuprofen or naproxen.
Bronchoconstriction has been associated with NSAID use, especially in those with underlying respiratory disease such as asthma.
NSAIDs are not teratogenic in humans, and the American Academy of Pediatrics considers ibuprofen, indomethacin, and naproxen safe in breast-feeding women.
NSAID use close to term in pregnant women is associated with prolonged labor or gestation, blood loss and anemia, and increased risk of neonatal bleeding.
Low-dose aspirin is considered safe during pregnancy and lactation.

Clinical Implications

The risk of GI bleeding with NSAID use is increased with age, duration of use, comorbidities, anticoagulant use, and a history of bleeding ulcers.
Other systemic adverse effects associated with NSAID use include those affecting the cardiovascular, hepatic, renal, hematologic, nervous, hematologic, and respiratory systems.