December 28, 2009 — A review article published in the December 15 issue of the American Family Physician offers recommendations for prescribing nonsteroidal anti-inflammatory drugs (NSAIDs) in the primary care setting.
"...NSAIDs are commonly used to treat inflammation, pain, and fever by decreasing prostaglandin synthesis through blockage of the cyclooxygenase (COX) enzyme," write Amanda Risser, MD, MPH, from Oregon Health and Science University in Portland, and colleagues. "The two major isoforms of COX (COX-1 and COX-2) are inhibited by nonselective NSAIDs. COX-2 is also inhibited by selective NSAIDs. All nonselective NSAIDs inhibit platelet aggregation through inhibition of COX-1 and the thromboxane A2 (TXA2) pathway."
Although NSAIDs are in widespread use, there are accompanying risks, including significant upper gastrointestinal (GI) tract bleeding (particularly in older persons), risks in those receiving anticoagulant therapy, and risks in patients with a history of upper GI tract bleeding associated with NSAID use. Dyspepsia, abdominal pain, GI discomfort, and GI bleeding may be reduced by combining the NSAID with a proton pump inhibitor (PPI) or histamine H2 blocker.
Despite the cardioprotective qualities of aspirin, other NSAIDs may have adverse cardiac effects, including worsening of congestive heart failure, increase in blood pressure, myocardial infarction, and ischemia. The risk for myocardial infarction is increased with COX-2 inhibitors, although celecoxib, which is the only COX-2 inhibitor still available in the United States, is somewhat safer regarding cardiovascular effects.
NSAIDs should not be used in patients with cirrhotic liver diseases because such patients are at greater risk of bleeding and for kidney failure. However, NSAIDs rarely cause hepatic damage, and any hepatic effects are usually reversible. NSAIDs with more potential for hepatic problems include sulindac and diclofenac.
Caution is advised when NSAIDs are prescribed in the setting of anticoagulant therapy, platelet dysfunction, or immediately before surgery.
Central nervous system adverse effects of NSAIDs may include aseptic meningitis, psychosis, and tinnitus. NSAIDs may also trigger or exacerbate asthma. In patients with asthma, especially those with nasal polyps or recurrent sinusitis, NSAIDs and aspirin should be avoided.
During the last 6 to 8 weeks of pregnancy, NSAIDs should be avoided to prevent prolonged gestation from inhibition of prostaglandin synthesis, premature closure of the ductus arteriosus, and antiplatelet activity causing maternal and fetal complications. However, most NSAIDs are likely safe in pregnancy. In breast-feeding women, ibuprofen, indomethacin, and naproxen can be safely used. Parents should be educated regarding correct NSAID dosing and storage in childproof containers to prevent accidental NSAID overdose in children.
Specific key clinical recommendations for practice, and their accompanying level of evidence rating, are as follows:
Physicians should consider prescribing PPIs, double-dose histamine H2 blockers, or misoprostol with NSAIDs for persons who must take NSAIDs, although they have had an NSAID-associated ulcer. Celecoxib may also be used alone in these patients, but this drug should be avoided in patients at increased risk for myocardial infarction. Women who might become pregnant should not take misoprostol (level of evidence, C). Two systematic reviews describe the use of NSAIDs in this setting for the prevention of endoscopic ulcers.
For prevention of acute renal failure, NSAIDs should be avoided whenever possible in patients with preexisting kidney disease, congestive heart failure, or cirrhosis (level of evidence, C, based on a literature review and a summary of consensus guidelines).
For patients at risk for renal failure, and in those taking angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, physicians should consider monitoring serum creatinine levels after prescribing treatment with NSAIDs (level of evidence, C, based on a summary of consensus guidelines).
In patients taking anticoagulants, NSAIDs and aspirin should be avoided if possible. An increase in international normalized ratio (INR) should be expected if concurrent use of NSAIDs and anticoagulants is required. These patients should have appropriate INR monitoring, dosage adjustments of warfarin, and GI prophylaxis (level of evidence, C, based on a systematic review).
In breast-feeding women, ibuprofen, indomethacin, and naproxen can be safely used (level of evidence, C, based on a consensus guideline).
Editorial: Increased Cardiovascular Concerns
In an accompanying editorial, Gunnar H. Gislason, MD, PhD, from Copenhagen University Hospital Gentofte in Copenhagen, Denmark, describes increased concerns regarding the cardiovascular safety profile of NSAIDs, which have come to light during the last decade. Although these concerns were first recognized for COX-2 inhibitors, increased cardiovascular risk associated with nonselective NSAIDs has recently been identified.
Because there will always be groups of patients with pain conditions who must take NSAIDs, there is a need to focus on the balance between risk and benefit before NSAID therapy is started.
"This is especially important in persons with established cardiovascular disease in whom alternative pain treatment with lower cardiac risk (e.g., acetaminophen, weak opiates) should always be the first choice," Dr. Gislason writes. "In persons needing NSAID treatment, NSAIDs with the highest COX-1 selectivity (e.g., naproxen, ibuprofen, aspirin) should be preferred and used in the lowest dosages and for the shortest durations possible. For stronger analgesic effect, a combination with other types of analgesics should be considered."
As supplements to analgesic therapy, Dr. Gislason also recommends considering nonpharmacologic treatment, such as physiotherapy and physical exercise.
"Epidemiologic studies have demonstrated extensive use of prescription NSAIDs in the general population, as well as in persons with established cardiac disease," Dr. Gislason concludes. "Also, in many countries, NSAIDs are sold without a prescription, expert advice, limits on their use, or information on potential adverse effects. This indicates the need for reevaluation of current treatment strategies regarding NSAID use and the misconception that NSAIDs are harmless for everyone."