Thursday, January 7, 2010

NSAID Pain Reliever Risks & Precautions Reviewed

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely available without prescription and used by millions of persons to treat fever, inflammation, and acute or chronic pain. Clearly, however, there can be serious risks associated with their use according to a review published in American Family Physician, which also offers precautions and recommendations for safe prescribing.

Amanda Risser, MD, MPH, and coauthors from Oregon Health and Science University in Portland write that the risks of NSAIDS include 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 [Risser et al. 2009]. They further note that there is little evidence to support differences in pain relief afforded by the many available NSAIDs, which can range broadly in monthly cost from less than $5 USD (generic aspirin 325 mg/day or naproxen 440 mg/day) to $165 USD (generic indomethacin extended release 150 mg/day) to $248 USD (Celebrex® 400 mg/day).

The authors offer 5 key clinical recommendations for practice…
  1. In persons who have had NSAID-associated ulcers, practitioners should consider prescribing protein pump inhibitors (PPIs), double-dose histamine H2 blockers, or misoprostol along with NSAIDs. Celecoxib may be used alone in these patients [but it should be avoided in patients at increased risk for myocardial infarction]. Women who might become pregnant should not take misoprostol.

  2. Whenever possible, NSAIDs should be avoided in patients with preexisting kidney disease, congestive heart failure, or cirrhosis to prevent acute renal failure.

  3. For patients at risk for renal failure, and in those taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, practitioners should consider monitoring serum creatinine levels after starting NSAID therapy.

  4. NSAIDs and aspirin should be avoided if possible in patients taking anticoagulants. If it is necessary to combine NSAID and anticoagulant use, an increase in international normalized ratio (INR) should be expected and patients should have appropriate INR monitoring, warfarin dose adjustments, and GI prophylaxis.

  5. In breast-feeding women, ibuprofen, indomethacin, and naproxen are considered safe to use.
It should be noted that all of the recommendations are based on evidence rated at level “C”; that is, coming from consensus statements, expert opinion, case series, or commonly accepted practice. The highest level of evidence (“A”) would have come from consistent, good-quality, patient-oriented evidence such as randomized, controlled clinical trials — but this was unavailable.

A summary of this article from Medscape [Lie 2009] highlights several additional points of interest:
  • Dyspepsia and GI discomfort occur in 10% to 20% of persons taking NSAIDs, but such symptoms are not predictive of clinically significant ulcers. In some cases, 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.

  • 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, respectively. Concomitant anticoagulant use increases the risk by 5 to 6 times.

  • Use of PPIs or double-dose antihistamines with NSAIDs decreases the rate of endoscopically diagnosed ulcers.

  • NSAIDs, other than low-dose aspirin, are associated with an increased risk for worsening congestive heart failure, adverse cardiovascular events, and increased blood pressure (by 5 mm Hg).

  • Idiosyncratic liver toxicity may occur in those with hepatitis C or underlying liver impairment.

  • 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). However, in high-risk persons with recent myocardial infarction or stent placement, aspirin should be continued before and after surgery.

  • Bronchoconstriction has been associated with NSAID use, especially in those with underlying respiratory disease such as asthma.

  • NSAIDs are not teratogenic in humans, but their use close to term in pregnant women is associated with prolonged labor or gestation, blood loss and anemia, and increased risk of neonatal bleeding.
Commentary: It is surprising that higher quality research evidence is unavailable for pharmacotherapies like NSAIDs that have been available for so long, are in such widespread use, and in many cases are easily available over-the-counter. Adverse effects from NSAIDs can occur at any time while taking them, but there is some evidence that adverse effects increase with longer duration and greater dosing. Research has not shown whether intermittent dosing or drug holidays are effective as risk reduction strategies. Furthermore, it is doubtful that the general public is fully aware of the many specific risks associated with the use of NSAIDs, so healthcare providers must remember to question patients with pain about their use of these products. In many patients, the prescription of weak opioids, whether or not combined with low-dose acetaminophen or an NSAID, may be a better choice of analgesic therapy to avoid NSAID risks; albeit, opioids carry certain risks of their own that require management.

Risser et al. [2009] clearly point out that risks of GI bleeding with NSAIDs increase with duration of use, comorbidities, anticoagulant use, a history of bleeding ulcers, and patient age. Along with that, central nervous system effects of NSAIDs — including tinnitus, cognitive changes, confusion, and depression — are rare but occur mainly in elderly persons. Recently, the American Geriatrics Society [AGS 2009] recommended in updated guidelines that NSAIDs and COX-2 inhibitors should be rarely considered in older populations. Rather, they propose that all elderly patients with moderate to severe pain, pain-related functional impairment, or diminished quality of life due to pain be considered for opioid therapy.

> AGS (American Geriatrics Society). Pharmacological management of persistent pain in older persons. J Am Geriatr Soc. 2009;57(8):1331-1346 [
summary here].
> Lie D, Recommendations for prescribing NSAIDs in the primary care setting. Medscape CME. 2009(Dec 28) [
available here].
> Risser A, Donovan D, Heintzman J, Page T. NSAID prescribing precautions. Am Fam Physician. 2009;80(12):1371-1378 [
available here].

ADDENDUM: Naproxen (eg, Aleve®, Naprosyn®, others) has been associated with less cardiotoxicity, so it is often recommended for patients with cardiovascular problems. However, a recently reported study encompassing 11,000 patients in California hospitalized due to gastric or duodenal ulcers found that naproxen use conferred a 2.5- to more than 3-fold risk of hospitalization due to such upper GI complications. Even the lowest doses of naproxen, available over-the-counter, carried substantial risk of upper GI problems. The study was presented at a conference and, during their presentation, the authors recommended concomitant gastroprotective therapy regardless of naproxen dose. Their research was supported in part by AstraZeneca Pharmaceuticals, manufacturer of the proton pump inhibitors esomeprazole and omeprazole.

Reference: Singh G, et al. Naproxen use increases the risk for complicated gastroduodenal ulcers in a dose-dependent fashion. Poster presented at: Annual Meeting of the American College of Gastroenterology; October 23-28, 2009; San Diego, CA. Abstract P55 [
available here].