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Further Evidence That CELEBREX Is a Do Not Use Drug; New Designation of Diclofenac (VOLTAREN) as a Do Not Use Drug; and Other Do Not Use NSAIDS

Worst Pills, Best Pills Newsletter article June, 2014

Public Citizen’s Health Research Group already lists certain nonsteroidal anti-inflammatory drugs (NSAIDs) as Do Not Use, and certain others as Limited Use. Recently published research adds to the already mounting evidence that NSAIDs may endanger heart health. This new data confirms our Do Not Use designation for celecoxib (CELEBREX) and has prompted us to reclassify diclofenac (VOLTAREN) from Limited Use to Do Not Use. Furthermore, while researchers state that low-dose ibuprofen (ADVIL,...

Public Citizen’s Health Research Group already lists certain nonsteroidal anti-inflammatory drugs (NSAIDs) as Do Not Use, and certain others as Limited Use. Recently published research adds to the already mounting evidence that NSAIDs may endanger heart health. This new data confirms our Do Not Use designation for celecoxib (CELEBREX) and has prompted us to reclassify diclofenac (VOLTAREN) from Limited Use to Do Not Use. Furthermore, while researchers state that low-dose ibuprofen (ADVIL, MOTRIN, MOTRIN IB) seems to be fairly safe for both cardiovascular and gastrointestinal complications, higher doses reportedly greatly increase the risk of both outcomes.

Recent NSAID research

Valuable information, for patients and doctors, about the increased cardiovascular risks of drugs such as celecoxib and diclofenac needs to be derived from experimental randomized studies and community studies of more typical, and often lower-dose, use. Both have been conducted over the past few years.

A collective statistical review, commonly referred to as a meta-analysis, published in 2013 measured the comparative cardiovascular and gastrointestinal adverse effects of NSAIDs. The review involved data from 639 studies in which more than 300,000 patients were randomized to receive an NSAID or a placebo (or, in some studies, another NSAID). The researchers found that high doses of all drugs in an NSAID subcategory called coxibs — rofecoxib (VIOXX) or celecoxib — as well as diclofenac and ibuprofen increase the risk of major vascular events (nonfatal heart attack, nonfatal stroke or vascular death). The study also showed that high-dose naproxen (ALEVE, ANAPROX, NAPROSYN) is not associated with these increased risks.[1]

A 2011 paper examined 51 nonrandomized, community-based, controlled observational studies. This data enabled the authors to look at comparative risks for a wider range of doses, including lower doses, than would have been possible in an analysis solely of randomized trials such as the 2013 review. The researchers concluded that naproxen and low-dose ibuprofen are least likely to increase cardiovascular risk. But they also found that cardiovascular risk was also significantly elevated with low doses of both celecoxib (26 percent elevation of risk) and diclofenac (22 percent elevation), and the risk rose in each case with higher doses.[2]

A 2013 review in The Lancet added that all NSAIDs (both coxibs and traditional NSAIDs such as naproxen) increase the risks of congestive heart failure and of peptic ulcer complications and other gastrointestinal bleeding. The reviewer found that in both kinds of studies, risk occurred shortly after drug initiation. Observational studies have also shown that risk does not wane over years of continued use but falls quickly after use ceases.

Public Citizen Actions on NSAIDS

Celecoxib (CELEBREX)

In March 2001, we warned consumers not to use celecoxib for five years because it was a new drug about which the Food and Drug Administration (FDA) had concerns regarding serious heart risk even before its approval.

But before those five years were over, there were enough additional data about heart risks for Public Citizen to petition the FDA to ban the drug in early 2005. A large randomized study comparing celecoxib to a placebo to prevent polyps had found a statistically significant elevation in the risk for a major fatal or nonfatal cardiovascular event (cardiovascular death, heart attack or stroke) in those patients taking celecoxib compared to those getting placebo. Because of this danger, the trial was prematurely stopped. At the time, the FDA released an explanatory statement, saying, “While we have not seen all available data on Celebrex, these findings are similar to recent results from a study of Vioxx (rofecoxib), another drug in the same class as Celebrex. Vioxx was recently voluntarily withdrawn by Merck.” We had warned Worst Pills readers not to use VIOXX in 2001, three years before it was banned in 2004.[3] CELEBREX is still classified as Do Not Use by Public Citizen.

Diclofenac (VOLTAREN)

We have previously listed diclofenac as a Limited Use drug, but in light of the studies reviewed in this article showing its increased cardiovascular risk compared to most other NSAIDs, we are reclassifying it as Do Not Use.

Other Do Not Use NSAIDs

Piroxicam (FELDENE): Twenty years ago, in 1994, we petitioned the FDA to remove piroxicam from the market because of its somewhat unique gastrointestinal toxicity, demonstrated in multiple studies. The FDA rejected our petition, and we have classified piroxicam as a Do Not Use drug since the publication of the Worst Pills, Best Pills book in 1988.

Ketoralac (TORADOL): This drug also has been listed as Do Not Use since 1999 because it is no more effective than other NSAIDS and causes a higher rate of ulcers.

Indomethacin (INDOCIN): Categorized as Do Not Use since 1988, this drug can cause depression, mood changes and confusion, in addition to many other adverse effects.

Meloxicam (MOBIC): We have listed meloxicam as a Do Not Use drug since the 2005 edition of the Worst Pills, Best Pills book because there is no evidence that it is safer or more effective than some of the older NSAIDs, such as ibuprofen, and because of its excessive cost compared to the older, generic NSAIDs.


What You Can Do

Low-dose ibuprofen and naproxen are least likely to increase cardiovascular risk.

In addition to considering celecoxib and diclofenac Do Not Use drugs because of increased cardiovascular toxicity, Public Citizen lists four other NSAIDs — piroxicam, ketorolac, indomethacin and meloxicam — as Do Not Use for other reasons. You should never stop taking these or any drug without the advice of your physician. Some drugs can cause severe adverse effects when they are stopped suddenly.

The Lancet review, cited above, makes the following additional points, which we strongly endorse:

  • No available NSAID improves arthritis or prevents progression of painful conditions.
     
  • NSAIDs should generally be avoided for patients at high risk of heart failure or with chronic kidney disease.
     
  • Though they carry serious risks, and evidence of their efficacy in treatment of chronic pain is not strong, opioids can be used for some patients.
     
  • Patients should use evidence-based nonpharmacological treatments such as application of heat or cold, exercise, or weight loss.


References

[1] Coxib and traditional NSAID Trialists’ (CNT) Collaboration. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013;382(9894):769-779. http://dx.doi.org/10.1016/S0140-6736(13)60900-9. Published online May 30, 2013.

[2] McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med. 2011;8:e1001098.

[3] FDA statement on the halting of a clinical trial of the Cox-2 inhibitor Celebrex. Dec 17, 2004. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2004/ucm108384.htm.

Disclaimer

The information on this website is not intended to substitute for professional medical advice, diagnosis, or treatment. Consult your doctor before changing or discontinuing any medication.