Non-steroidal anti-inflammatory drugs (NSAIDs) are some of the most widely used medications globally, frequently administered to patients experiencing acute, chronic, and inflammatory forms of pain. However, both traditional nonselective NSAIDs, which inhibit the molecular cyclooxygenase pathway, and second-generation NSAIDs, which block cyclooxygenase-2, may cause adverse events, especially at prescription-level doses 1.
First, NSAIDs can result in gastrointestinal complications. Studies since 2012 have consistently demonstrated that both traditional NSAIDs and cyclooxygenase-2 inhibitors increase the dose-dependent risk of upper gastrointestinal complications, in the form of upper gastrointestinal bleeding or perforation and peptic ulcers 2. A prior history of peptic ulcer, an older age, and concomitant aspirin use predispose individuals to such gastrointestinal complications 3.
Second, NSAIDs may yield cardiovascular complications, including in the form of myocardial infarction and stroke. A 2009 study demonstrated an increased risk of heart disease-associated hospitalization and death linked to all NSAIDs, including rofecoxib, celecoxib, ibuprofen, diclofenac, and naproxen, among others 4. This was confirmed by a landmark study in 2013 revealing that the administration of prescription NSAIDs dose-dependently increased an individual’s risk of heart failure, major vascular events, and mortality 5.
Finally, renal adverse events may result from the use of prescription-level NSAIDs. A 2006 study found that NSAID compared to non-NSAID use incurred a 3-fold greater risk of acute renal failure after adjusting for age, sex, body mass index, and several comorbidities 6. This risk was dose-dependent and increased with long-term use of NSAIDs, as confirmed since by various recent studies.
Various strategies have been put into place to help mitigate the risk of prescription-level NSAID-associated gastrointestinal, cardiovascular, and renal complications. First, cyclooxygenase-2 inhibitors, despite their slightly improved gastrointestinal safety as compared to traditional NSAIDs, have been particularly linked to an increased risk of developing cardiovascular-related events – either selective or nonselective NSAIDs should thus be selected depending on context and patient background. Second, an enteric coating may be used to protect the gastrointestinal tract of at-risk patients. This is often used with aspirin and ibuprofen to help alleviate stomach irritation. A number of different gastroprotectants have been proven effective to this end 3. Finally, some clinicians may choose to add a gastroprotective agent to a patient’s medication regimen. Gastroprotective agents have been found to result in an overall reduction in gastrointestinal complications 7. This said, additional strategies need to be developed to specifically target a reduction in cardiovascular and renal complications.
Understanding the factors predisposing individuals to adverse events from prescription-level NSAIDs is key to curbing them through heightened clinician awareness and education. For example, patients with a high gastrointestinal or cardiovascular risk should be considered for alternative therapies. In the future, additional research should seek to further specify the factors that increase a patient’s risk for adverse events in order to ensure the best patient-centric preventive medicine steps are taken. The most effective way to minimize the risk of complications is to use the minimal effective dose of NSAIDs: in 2005, the US Food and Drug Administration issued a public health advisory establishing that “NSAIDs should be administered at the lowest effective dose for the shortest duration consistent with individual patient treatment goals,” corroborated in 2007 by an additional detailed NSAID administration guide.
1. Fine, M. Quantifying the impact of NSAID-associated adverse events. American Journal of Managed Care (2013).
2. Castellsague, J. et al. Individual NSAIDs and upper gastrointestinal complications: A systematic review and meta-analysis of observational studies (the SOS Project). Drug Safety (2012). doi:10.2165/11633470-000000000-00000
3. Sostres, C., Gargallo, C. J., Arroyo, M. T. & Lanas, A. Adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs, aspirin and coxibs) on upper gastrointestinal tract. Best Pract. Res. Clin. Gastroenterol. (2010). doi:10.1016/j.bpg.2009.11.005
4. Gislason, G. H. et al. Increased mortality and cardiovascular morbidity associated with use of nonsteroidal anti-inflammatory drugs in chronic heart failure. Arch. Intern. Med. (2009). doi:10.1001/archinternmed.2008.525
5. Baigent, C. et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: Meta-analyses of individual participant data from randomised trials. Lancet (2013). doi:10.1016/S0140-6736(13)60900-9
6. Schneider, V., Lévesque, L. E., Zhang, B., Hutchinson, T. & Brophy, J. M. Association of selective and conventional nonsteroidal antiinflammatory drugs with acute renal failure: A population-based, nested case-control analysis. Am. J. Epidemiol. (2006). doi:10.1093/aje/kwj331
7. Rahme, E. et al. Gastrointestinal-related healthcare resource usage associated with a fixed combination of diclofenac and misoprostol versus other NSAIDs. Pharmacoeconomics (2001). doi:10.2165/00019053-200119050-00011