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An Overview of Pain Management: The Clinical Efficacy and Value of Treatment
Srinivas Nalamachu, MD
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Quantifying the Impact of NSAID-Associated Adverse Events
Michael Fine, MD

Quantifying the Impact of NSAID-Associated Adverse Events

Michael Fine, MD
Although the FDA warns against long-term use of NSAIDs, several studies have found that the increased risk for GI-, CV-, and renal-related complications is present even when NSAID use is relatively short in duration.7,24,25 As shown in Table 1,7,24,25 the risk increases within the first few weeks of treatment and persists during the course of NSAID therapy. These data suggest that safety and tolerability risks of short-term NSAID therapy should not be overlooked by clinicians.

In addition, as outlined above, studies illustrate that GI, CV, and renal adverse events associated with NSAID use are dose-dependent. It also important to note that dosing used in many of these trials reflect NSAID use that is common to clinical practice; in other words, everyday use of NSAIDs carries notable risk.

Strategies for Reducing the NSAID-Related Burden

Various strategies have been employed to help mitigate the risk for adverse events (Table 2).1,7,26-28 COX-2 inhibitors were initially developed as a safer alternative to traditional NSAIDs. However, data soon emerged that linked their use to an elevated risk for CV-related adverse events. Another strategy involves the addition of an enteric coating, which is often used on aspirin and ibuprofen to help alleviate stomach irritation.

Another option used by some clinicians is to add a gastroprotective agent to the NSAID regimen. This approach has shown some reduction in GI events. However, a pharmacoeconomic study comparing the cost of GI adverse events in patients taking NSAIDs (n = 10,540) with those taking NSAIDs plus the gastroprotective agent misoprostol (n = 1533) found that the groups had statistically similar rates of GI-related hospitalizations, GI-related healthcare resource utilization, and costs associated with these resources over the 2-year period.29 Additionally, none of these strategies address the risk for CV or renal complications.

Over the past decade, data have shown that the risk for adverse events is strongly associated with baseline risk, NSAID dosage, and duration of use. It is up to the clinician to carefully weigh the risk and benefits for each patient based on his or her pain symptoms and baseline risk for GI, CV, or renal complications. While individual risk factors are an important consideration, another key strategy to reduce risk for all patients is for clinicians to prescribe the lowest effective dose for the shortest possible duration, as recommended by the FDA and numerous other regulatory bodies and medical organizations.30


NSAIDs remain a viable choice among clinicians and patients for the treatment of a variety of painful conditions. Efforts to mitigate the common GI-related adverse events have had mixed results, and have failed to address the added risk for serious CV and renal complications. Moreover, several studies comparing the safety of traditional NSAIDs with the newer COX-2 inhibitors on the market have shown that the RR varies, and that neither drug class has a clear safety advantage. The available data suggest that NSAID-related adverse events place a substantial clinical and economic burden on the healthcare system. Finding the lowest effective dose and shortest duration of treatment that still provides sufficient clinical efficacy should be the goal for physicians who are managing their patients’ pain with NSAIDs.

Author affiliation: Health Net, Laguna Beach, California.
Funding source: This supplement was sponsored by Iroko Pharmaceuticals, LLC.
Author disclosure: Dr Fine reports no significant financial relationships with commmercial interests.
Authorship information: Concept and design; analysis and interpretation of data; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.
Address correspondence to: Michael Fine, MD, Medical Director, Health Net, 736 Kendall Dr, Laguna Beach, CA 92651. E-mail:
  1. Castellsague J, Riera-Guardia N, Calingaert B, et al. Individual NSAIDs and upper gastrointestinal complications: a systematic review and meta-analysis of observational studies (the SOS project). Drug Saf. 2012;35(12):1127-1146.
  2. McCarberg B, Gibofsky A. Need to develop new nonsteroidal anti-inflammatory drug formulations. Clin Ther. 2012;34(9):1954-1963.
  3. Laine L. Approaches to nonsteroidal anti-inflammatory drug use in the high-risk patient. Gastroenterology. 2001;120(3):594-606.
  4. The State of Aging and Health in America 2013. Atlanta, GA:Centers for Disease Control and Prevention, US Dept of Health and Human Services; 2013.
  5. Lee C, Straus WL, Balshaw R, et al. A comparison of the efficacy and safety of nonsteroidal antiinflammatory agents versus acetaminophen in the treatment of osteoarthritis: a meta-analysis. Arthritis Rheum. 2004;51(5):746-754.
  6. Coxib and traditional NSAID Trialists’ Collaboration. Bhala N, Emberson J, Merhi A, et al. 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.
  7. Huerta C, Castellsague J, Varas-Lorenzo C, García Rodríguez LA. Nonsteroidal anti-inflammatory drugs and risk of ARF in the general population. Am J Kidney Dis. 2005;45(3):531-539.
  8. Howard RL, Avery AJ, Slavenburg S, et al. Which drugs cause preventable admissions to hospital? a systematic review. Br J Clin Pharmacol. 2007;63(2):136-147.
  9. Schneider V, Lévesque LE, Zhang B, Hutchinson T, Brophy JM. Association of selective and conventional nonsteroidal antiinflammatory drugs with acute renal failure: a population-based, nested case-control analysis. Am J Epidemiol. 2006;164(9):881-889.
  10. Public health advisory: FDA announces important changes and additional warnings for COX-2 selective and non-selective nonsteroidal anti-inflammatory drugs (NSAIDs). US Food and Drug Administration website. Published April 7,2005. Accessed September 20, 2013.
  11. International Association for the Study of Pain. What is the problem? Published 2010. Accessed October 1, 2013.
  12. Institute of Medicine. Relieving pain in America: a blueprint for transforming prevention, care, education, and research. Washington, DC: The National Academies Press; 2011.
  13. Coda BA, Bonica JJ. General considerations of acute pain. In: Loeser JD, Butler SH, Chapman CR, Turk DC, eds. Bonica’s Management of Pain. 3rd ed. Hagerstown, MD: Lippincott Williams & Wilkins; 2001:222-240.
  14. Agency for Healthcare Research and Quality. Medical expenditure panel survey. Accessed October 1, 2013.
  15. Jacobson L, Mariano AJ. General considerations of chronic pain. In: Loeser JD, Butler SH, Chapman CR, Turk DC, eds. Bonica’s Management of Pain. 3rd ed. Hagerstown, MD: Lippincott Williams & Wilkins; 2001:241-254.
  16. Health, United States, 2012: with special feature on emergency care. Hyattsville, MD: National Center for Health Statistics; 2013.
  17. Decision Resources, LLC. Pain management study: acute pain. Burlington, MA. 2012.
  18. Ong KL, Wu BJ, Cheung BM, Barter PJ, Rye KA. Arthritis: its prevalence, risk factors, and association with cardiovascular diseases in the United States, 1999 to 2008. Ann Epidemiol. 2013;23(2):80-86.
  19. Roemer M. Health care expenditures for the five most common conditions of adults ages 40 to 64, 2009. Accessed September 2013.
  20. Bidaut-Russell M, Gabriel SE. Adverse gastrointestinal effects of NSAIDs: consequences and costs. Best Pract Res Clin Gastroenterol. 2001;15(5):739-753.
  21. Rahme E, Joseph L, Kong SX, Watson DJ, LeLorier J. Gastrointestinal health care resource use and costs associated with nonsteroidal antiinflammatory drugs versus acetaminophen: retrospective cohort study of an elderly population. Arthritis Rheum. 2000;43(4):917-924.
  22. Haag MD, Bos MJ, Hofman A, et al. Cyclooxygenase selectivity of nonsteroidal anti-inflammatory drugs and risk of stroke. Arch Intern Med. 2008;168(11):1219-1224
  23. Gislason GH, Rasmussen JN, Abildstrom SZ, et al. Increased mortality and cardiovascular morbidity associated with use of nonsteroidal anti-inflammatory drugs in chronic heart failure. Arch Intern Med. 2009;169(2):141-149.
  24. Helin-Salmivaara A, Virtanen A, Vesalainen R, et al. NSAID use and the risk of hospitalization for first myocardial infarction in the general population: a nationwide case-control study from Finland. Eur Heart J. 2006;27(14):1657-1663.
  25. Helin-Salmivaara A, Saarelainen S, Grönroos JM, et al. Risk of upper gastrointestinal events with the use of various NSAIDs: a case-control study in a general population. Scand J Gastroenterol. 2007;42(8):923-932.
  26. McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PloS Med. 2011;8(9):e1001098.
  27. Spiegel BM, Chiou CF, Ofman JJ. Minimizing complications from nonsteroidal antiinflammatory drugs: cost-effectiveness of competing strategies in varying risk groups. Arthritis Rheum. 2005;53(2):185-197.
  28. Rossat J, Maillard M, Nussberger J, Brunner HR, Burnier M. Renal effects of selective cyclooxygenase-2 inhibition in normotensive salt-depleted subjects. Clin Pharmacol Ther. 1999;66(1):76-84.
  29. Rahme E, Joseph L, Kong SX, Watson DJ, Pellissier JM, LeLorier J. Gastrointestinal-related healthcare resource usage associated with a fixed combination of diclofenac and misoprostol versus other NSAIDs. Pharmacoeconomics. 2001;19(5, pt 2):577-588.
  30. Medication guide for non-steroidal anti-inflammatory drugs (NSAIDs). US Food and Drug Administration website. Accessed September 20, 2013.
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