William Simonson, PharmD, BCGP, FASCP
Oregon State University, Corvallis, OR, USA
Non-steroidal anti-inﬂammatory medications (NSAIDs) are among the most commonly used pain relievers. They are frequently used to treat pain and fever from many different long- and short-term medical conditions such as arthritis, menstrual cramps, headaches, colds and inﬂuenza.1
In 1984 ibuprofen was the ﬁrst NSAID to receive FDA approval in the United States. Now, 18 different NSAIDs have received FDA approval as over-the-counter (OTC) and/or prescription products and are available as tablets or as creams or gels to be applied top-ically. Early on it has been known that NSAIDs may cause gastric irritation and bleeding as well as reversible kidney damage. Since 2005 the FDA has required that all NSAIDs carry a “Boxed Warning” (commonly though incorrectly referred to as a “black-box warn-ing”) that this class of medications may increase the risk of heart attack or stroke.
After further review, in 2015 the FDA strengthened the warning and required additional information reﬂecting the following2:
Risk of heart attack and stroke can occur as early as the ﬁrst weeks of NSAID therapy. The risk appears greater at higher doses. Risk is increased in patients with and without heart disease but it is higher in patients with heart disease or risk factors. Patients who had already experienced a heart attack are more
likely to die if they are treated with NSAIDs after the heart attack. NSAID use increases the risk of heart failure.
NSAIDs relieve pain by inhibiting enzymes involved with inflammation which leads to pain. The enzymes involved are known as cyclooxygenase (COX) and there are two, logically named COX-1 and COX-2. Most of the available NSAIDs, including diclofenac (Voltaren), ibuprofen (Advil, Motrin, Nuprin), meloxicam (Mobic), naproxen (Aleve, Naprosyn) and oxaprozin (Daypro) inhibit both of these enzymes so they are referred to as “non-selective” NSAIDs. I will note here that aspirin is also a non-selective NSAID but the warnings for increased heart attack and stroke do not apply to aspirin so I will omit it from further discussion.
Several additional NSAIDs, including rofecoxib (Vioxx), and celecoxib (Celebrex) selectively block the COX-2 enzyme but not the COX-1 enzyme so they are referred to as “selective” NSAIDs and this property provides a distinct advantage. Since COX-1 plays a role in protecting the stomach lining it is best not to inhibit this protective effect. The COX-2 speciﬁc products are less likely to cause GI bleeding while they still have anti-inﬂammatory effect by blocking the COX-2 enzyme.3 However, shortly after Vioxx was approved by the FDA in 1999, there were signs that its use increased the risk of heart attack and stroke. The same concerns existed for another selective COX-2 inhibitor, valdecoxib (Bextra). After four years of controversy, Vioxx was removed from the market in 2004 with Bextra being withdrawn the following year, also due to safety concerns.2 Similar concerns existed about celecoxib but the cause-and-effect relation-ship was less clear and it did not appear to cause heart attack and stroke, at least not to the degree that rofecoxib did, so it was allowed to remain on the market, but only as a prescription product.
The degree to which celecoxib increased the risk of heart attack and stroke remained an important question to be answered. Because of its ability to protect the stomach lining from NSAID-induced ulcers while effectively relieving pain it could prove to be the best NSAID to use when considering risk vs. beneﬁt.
Recently, results of a clinical trial designed to look at the car-diovascular risk of the selective NSAID celecoxib, compared to the non-selective NSAIDs ibuprofen and naproxen were published in the prestigious New England Journal of Medicine.4
This worldwide trial enrolled more than 24,000 patients with osteoarthritis or rheumatoid arthritis also with established cardio-vascular disease (CVD) or at increased risk of CVD who required NSAIDs for at least 6 months. Patients were randomly assigned to celecoxib 100 mg twice daily, ibuprofen 600 mg three times daily, or naproxen 375 mg twice daily, with the option to increase therapy for unrelieved symptoms. All patients also received esomeprazole (Nexium)20e40 mg for prevention of gastric irritation or bleeding.
Surprisingly, results of the trial demonstrated noninferiority of celecoxib compared to naproxen or ibuprofen with respect to cardiovascular safety which means that cardiovascular risk is essentially the same between all three products. These ﬁndings were a bit of a surprise since the previous selective agents rofecoxib and valdecoxib were clearly shown to have increased risk.
Unfortunately, this study does not provide a ﬁnal answer to the question of celecoxib toxicity especially when used for a short period of time. It is important to note that the doses used were for a prolonged period of time (at least 6 months) and were relatively large. For example, the ibuprofen dose was 600 mg three times daily which equates to taking 9 of the 200 mg. OTC tablets every day for 6 months.
As is often the case with published studies of this type, short-comings were pointed out by other researchers who noted that many study subjects did not complete participation in the study and more than 25% of subjects were lost to follow-up. So, while the data seems to add some reassurance that celecoxib is relatively safe, a ﬁnal indisputable answer is still needed.
In my opinion, a very important question that still exists is how concerned should we be about the cardiovascular risks associated with occasional use of NSAIDs for minor aches or pains?
I think that a statement attributed to Karen M. Mahoney, MD, deputy director of FDA’s Division of Nonprescription drug products provides excellent advice. “As always, consumers must carefully read the Drug Facts label for all nonprescription drugs. Consumers should carefully consider whether the drug is right for them, and use the medicine only as directed. Take the lowest effective dose for the shortest amount of time possible.” Additional advice from Dr. Mahoney is to avoid use of more than one NSAID-containing product at a time.5
The FDA provides some additional advice to lower the risk of taking NSAIDs including that the clinician should know the patient’s complete medical history, including any history of cardiovascular disease or stomach ulcers in order to perform a risk/beneﬁt analysis. The chance for stomach irritation can be lessened through steps such as taking the NSAID with a meal. Also, steps can be taken to lower the risk of cardiovascular disease but that is typically a longer-term intervention.
Available scientiﬁc data do not suggest an increased risk of serious cardio-vascular events for short-term, low-dose use of OTC NSAIDs, but it is not known if that is because there is no risk or because there are many challenges when trying to study the use of OTC NSAIDs. Consumers should be aware that current OTC NSAID labeling states that if NSAIDs are used for longer than 10 days, a health care provider should be consulted and, the lowest effective dose should be used for the shortest time. 2,6
If it does turn out that celecoxib has the most favorable risk/beneﬁt proﬁle consumers and health plans will still have to consider the important consideration of cost/beneﬁt. If this is demonstrated it is likely that celecoxib will become the NSAID of choice, especially considering that the ﬁrst generic version of celecoxib was approved in 2014 and presently the product is marketed by many different companies. Use will be further increased if and when an OTC version becomes available.
- FDA strengthens warning that non-aspirin nonsteroidal anti-inï¬‚ammatory drugs (NSAIDs) can cause heart attacks or strokes. FDA Drug Safety Communication. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm451800.htm; July 9, 2015. Accessed 1 December 2016.
- Hertz S. The beneï¬ts and risks of pain relievers. FDA Consumer Health Information. Available at: http://www.fda.gov/downloads/ForConsumers/ConsumerUpdates/UCM107859.pdf; September 2015. Accessed 1 December 2016.
- Gorczyca P, Manniello M. NSAIDs: balancing the risks and benefits. US Pharm. 2016;41:24e26.
- Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. NEJM. Published November 13, 2016, at NEJM.org. http://dx.doi.org/10.1056/NEJMoa1611593.
- FDA strengthens warning of heart attack and stroke risk for non-steroidal anti-inflammatory drugs. FDA Consumer Health Information. Available at: http://www.fda.gov/downloads/ForConsumers/ConsumerUpdates/UCM454066.pdf;July2015. Accessed 1 December 2016.
- Medication Guide for Non-Steroidal Anti-Inï¬‚ammatory Drugs (NSAIDs) Available at: http://www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformation forpatientsandproviders/ucm106241.pdf. Accessed 1 December 2016.