Seven commonly used drugs for pain management are associated with higher absolute risk for cardiovascular problems compared to placebo, according to findings published online first in the British Medical Journal.

Peter Jüni, MD, of the University of Bern, and colleagues from several other sites in Switzerland, analyzed data from 31 clinical trails and 116,429 patients. The network meta-analysis involved all randomized controlled trials that compared any non-steroidal anti-inflammatory drug (NSIAD) with other NSAIDs or placebo.

The drugs involved included naproxen (Aleve, Naprosyn), ibuprofen (Advil, Motrin), diclofenac (Cataflam, Voltaren), celecoxib (Celebrex), etoricoxib (Arcoxia), rofecoxib (Vioxx) and lumiracoxib (Prexige). Overall, 554 myocardial infarctions occurred in 29 trials, 377 strokes in 26 trials and 676 deaths in 28 trials.

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Although the total number of cardiovascular events was low, the researchers found that relative to placebo, the drugs posed some important risks.

Rofecoxib (RR= 2.12, 95% CI: 1.26-3.56) and lumiracoxib (RR=2.00, 95% CI: 0.71-6.21) were associated with double the rate of myocardial infarction. Furthermore, risk for stroke nearly tripled with ibuprofen (RR=3.36, 95% CI: 1.00-11.6), followed closely by diclofenac (RR=2.86, 95% CI: 109-8.36).

Data indicated that the highest risk of cardiovascular death occurred among patients taking etoricoxib (RR=4.07, 95% CI: 1.23-15.7) and diclofenac (RR=3.98, 95% CI=1.48-12.7).

Naproxen appears to be the safest analgesic in terms of cardiovascular events, the researchers advised. However, they noted that clinicians should pay special attention to gastrointestinal toxicity with this drug and the potential concomitant need for proton pump inhibitors for many patients.

“Although uncertainty remains, little evidence exists to suggest that any of the investigated drugs are safe in cardiovascular terms,” the researchers wrote. “Cardiovascular risk needs to be taken into account when prescribing any non-steroidal anti-inflammatory drug,” the researchers wrote.

In an accompanying editorial, Wayne A. Ray, PhD, professor and director of the division of pharmacoepidemiology in the department of preventive medicine at Vanderbilt University, wrote that it is time to evaluate a broader range of pain relief alternatives.

“The controversy and confusion about the cardiovascular safety of drugs to relieve chronic musculoskeletal symptoms provides an important lesson. Drugs for symptomatic relief must be evaluated with regard to the target symptoms as well as less frequent yet serious adverse effects,” Ray wrote.

Until more large scale comparative trials examining safety and efficacy become available, Ray agreed with researchers that naproxen seems to be the best pain relief option in terms of cardiovascular safety, and that patients with a high risk of CVD should avoid COX-2 inhibitors.