Over the last 10+ years, the evidence supporting the dose-related risks of certain serious adverse events associated with nonsteroidal anti-inflammatory drugs (NSAIDs) has piled up—the higher the dose, the higher the risk.1-6 Using NSAIDs in today’s complex therapeutic landscape requires more attention and thought than ever before.

The Climate of Pain Management Is Shifting

Recent concerns about opioid use have led to a decline in opioid prescriptions for the first time since 1996, and may be the reason why NSAID prescriptions are on the rise.7,8


NSAIDs may now be more on the radar than ever, especially since recent CDC guidelines specifically recommend the use of nonopioid therapies as preferred treatment options for chronic pain.

—Vijay Sikand, MD
Fellow, American Academy of Family Physicians
Adjunct Assistant Professor of Medicine, Tufts University School of Medicine

Risks: The Root of the Dilemma

Pain is very real and can often be managed effectively with NSAIDs—but we must first consider the dose-related risks.

Download peer perspective white papers on the dose-related risk of certain serious adverse events associated with NSAID use.
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    Read about the most recent clinical strategies, data, and guidelines on how to minimize NSAID-associated risks:

    1. NSAIDs and Cardiovascular Risk: An Evolving Clinical Perspective by William Hopkins, MD
    2. NSAID-Associated Risks and the Changing Landscape of Pain Management by Vijay Sikand, MD
    3. NSAID-Induced Gastropathy: Clinical Challenges and Perspectives by Byron Cryer, MD

NSAID Doses in Excess

In an effort to ease their patients’ pain, doctors have a tendency to prescribe NSAIDs at high doses.


Research has shown that after a certain dose threshold, the analgesic response of NSAIDs reaches a ceiling effect, so patients won’t necessarily experience any greater pain relief, but they may have greater potential risk for dose-related adverse events.

—James Scheiman, MD
Professor, Division of Gastroenterology
Department of Internal Medicine, University of Michigan Medical School

Perception vs Reality

Your peers have taken notice of the NSAIDilemma and are starting to change how they speak with their patients and how they prescribe NSAIDs.

The FDA Role

Responsible NSAID dosing has been in the spotlight since FDA first released a Public Health Advisory in 2005.

Public Health Advisory, 2005
Required manufacturers of all marketed prescription NSAIDs to revise product labeling to include a Boxed Warning and Medication Guide as well as recommendations to use the lowest effective dose.17
Drug Safety Communication, 2015
FDA strengthened the Boxed Warning to include statements that nonaspirin NSAIDs increase the chance of a heart attack or stroke.18
Prescription Label Update, 2016
FDA required manufacturers of all marketed prescription NSAIDs to include revised safety language within their product labels to strengthen warning of potential serious CV adverse events.

Professional Medical Organizations Are in Agreement

Recommendations from professional medical organizations consistently advise using the lowest effective dose for the shortest duration.20-25


1. García Rodríguez LA, Hernández-Díaz S. Relative risk of upper gastrointestinal complications among users of acetaminophen and nonsteroidal anti-inflammatory drugs. Epidemiology. 2001;12(5):570-576. 2. García Rodríguez LA, Tacconelli S, Patrignani P. Role of dose potency in the prediction of risk of myocardial infraction associated with nonsteroidal anti-inflammatory drugs in the general population. J Am Coll Cardiol. 2008;52(20):1628-1636. 3. 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. 4. Castellsague J, Riera-Guardia N, Calingaert B, et al; on behalf of the investigators of the Safety of Non-Steroidal Anti-Inflammatory Drugs (SOS) Project. 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. 5. 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):1-18. 6. Coxib and traditional NSAID Trialists’ (CNT) 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;382:769-779. 7. Goodnough A, Tavernise S. Opioid prescriptions drop for first time in two decades. The New York Times. May 20, 2016. http://www.nytimes.com/2016/05/21/health/opioid-prescriptions-drop-for-first-time-in-two-decades.html. Accessed August 15, 2016. 8. IMS National Prescription Audit, Total Prescriptions, 2011-2015. 9. White House Asks for More Than $1 Billion in New Funding for Opioid Addiction Treatment. NCADD. https://www.ncadd.org/blogs/in-the-news/white-house-asks-for-more-than-1-billion-in-new-funding-for-opioid-addiction-treatment. Published February 11, 2016. Accessed August 22, 2016. 10. Singh G, Triadafilopoulos G. Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol. 1999;56:18-24. 11. Howard RL, Avery AJ, Slavenburg S, et al. What drugs cause preventable admissions to hospital? A systematic review. Br J Clin Pharmacol. 2007;63(2):136-147. 12. 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. 13. Helin-Salmivaara A, Saarelainen S, Grönroos JM, Vesalainen R, Klaukka T, Huupponen R. 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. 14. Data on file, Iroko Pharmaceuticals, LLC. 15. Wilcox CM, Cryer B, Triadafilopoulos G. Patterns of use and public perception of over-the-counter pain relievers: focus on nonsteroidal antiinflammatory drugs. J Rheumatol. 2005;32(11):2218-2224. 16. Data on File. Iroko Pharmaceuticals, LLC. 2016 HCP NSAID Survey. September 2016. 17. US Food and Drug Administration. Public health advisory – FDA announces important changes and additional warnings for COX-2 selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs). http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm150314.htm. Published April 7, 2005. Accessed August 15, 2016. 18. US Food and Drug Administration Drug Safety Communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes. http://www.fda.gov/Drugs/DrugSafety/ucm451800.htm. Published July 9, 2015. Accessed August 15, 2016. 19. US Food and Drug Administration. Joint meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee: nonsteroidal anti-inflammatory drugs and cardiovascular thrombotic risk. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM383180.pdf. Published February 10-11, 2014. Accessed August 15, 2016. 20. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 2002 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction). Circulation. 2007;116:e148-e304. 21. National Kidney Foundation. Pain medicines (analgesics). Available from: https://www.kidney.org/atoz/content/painMeds_Analgesics. Accessed August 15, 2016. 22. Wilcox CM, Allison J, Benzuly K, et al. Consensus development conference on the use of nonsteroidal anti-inflammatory agents, including cyclooxygenase-2 enzyme inhibitors and aspirin. Clin Gastroenterol Hepatol. 2006;4(9):1082-1089. 23. American College of Rheumatology Ad Hoc Group on Use of Selective and Nonselective Nonsteroidal Anti-inflammatory Drugs. Recommendations for use of selective and nonselective nonsteroidal anti-inflammatory drugs: an American College of Rheumatology white paper. Arthritis Rheum. 2008;59(8):1058-1073. 24. Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage. 2008;16(2):137-162. 25. American Geriatrics Society Panel on the Pharmacological Management of Persistent Pain in Older Persons. J Am Geriatr Soc. 2009;57(8):1331-1346.