Nonsteroidal antiinflammatory drugs (NSAIDs) are a heterogenous group of non-opioid analgesics and anti-inflammatory agents. Their use is ubiquitous, from treating a simple tension headache to a sprained ankle. NSAIDs are available over the counter and in prescription form.
NSAID use in the United States is rising; from 2005 to 2010, prescriptions for NSAIDs increased by 41%.1 These numbers will continue to rise with the increasing population age and subsequent demand for analgesics to treat conditions related to increasing age such as osteoarthritis.
In patients with chronic pain, unrelated to cancer, diclofenac improves functional outcomes, more than opioids, such as oxycodone and morphine (but not tramadol), which have greater reductions in pain scores.2 Long-term efficacy data on opioid analgesics are lacking; however, given the side effect profile of opioids and addictive nature of these agents, there is a trend moving away from chronic use of opioids.3
NSAIDs inhibit cyclooxygenase (COX), an enzyme involved in the production of prostaglandins. Although COX-1 is present in most tissues, it plays a crucial role in gastric cytoprotection and platelet aggregation. COX-2 is primarily involved in the inflammatory response, with additional role in vasoprotection and regulation of renal blood flow. Based on their COX-2 selectivity, NSAIDs can be grouped into 3 categories: Non-selective (ibuprofen, naproxen), COX-2 selective (celecoxib), and partially selective (meloxicam, diclofenac).
What drives the use of one NSAID over another? Side effect profile, patient co-morbidities, and pharmacokinetics of the drug can help separate the individual NSAIDs and allow for a more tailored approach.
The analgesic benefit and anti-inflammatory properties of NSAIDs are COX-2 dependent.4 When used for a short duration (less than 6 months), oral NSAIDs have no significant differences in general analgesic potency.5
In patients with osteoarthritis of the knee or hip, diclofenac 150 mg is clinically shown to improve both pain and physical function, outperforming other NSAIDs, included naproxen, ibuprofen, and celecoxib, all of which performed superior to acetaminophen.6
Gastrointestinal side effects:
The gastrointestinal (GI) side effects from NSAIDs are directly related to inhibition of COX-1, and therefore selectivity of COX-2 inhibition.4 Selective COX-2 inhibitors showed the least likelihood of GI side effects including perforation, bleeding, or obstruction.7 Diflocanec showed a 2-fold increase in GI side effects, while ibuprofen and naproxen showed a 4-fold increase.
Although less likely to cause GI symptoms, selective COX-2 inhibitors are associated with an increased cardiovascular risk. These selective COX-2 inhibitors showed an increased risk of myocardial infarction (MI), stroke, and heart failure.8 Selective COX-2 inhibition is theorized to cause a relative pro-thrombotic state leading to increased number of cardiovascular events.
In a meta-analysis, selective COX-2 inhibitors, diclofenac, and ibuprofen showed elevated rates of coronary events (non-fatal MI or death from coronary disease).7 Compared to other NSAIDs, high dose naproxen did not show the increased risk of major coronary or vascular events. Nonetheless, nearly all NSAID regimens displayed a 2-fold increase in the risk of hospitalization due to heart failure, possibly related to sodium retention.8
In a large, country-wide observational study in Denmark, researchers found a correlation between NSAID use and death rate, with COX-2 selective inhibitors having an increased hazard ratio for death. Ibuprofen used in quantities greater than 1,200 mg were associated with an increased hazard ratio for the composite end-point of myocardial infarction (MI) and death, as was diclofenac dosages greater than 100 mg, and selective COX-2 inhibitors such as celecoxib. Naproxen use was not associated with increased hazard ratio for death and MI.9
In 2007, the American Heart Association released a update recommending the avoidance of selective COX-2 inhibitors in patients with, or at high risk of, cardiovascular disease.10 In 2015, the US Food and Drug Administration strengthened its warning that non-aspirin NSAIDs can cause adverse cardiovascular outcomes, include myocardial infarction, stroke, and heart failure.11
Acute Kidney Injury:
In otherwise healthy individuals, prostaglandins do not play a significant role in the hemodynamics of the kidney; however, in the setting of prolonged vaso-constriction, prostaglandin synthesis is increased to preserve glomerular filtration rate. Prolonged NSAID use can limit prostaglandins synthesis below the required level, resulting in acute kidney injury.12 This relationship between NSAID use and acute kidney injury is well established. A systematic review comparing individual NSAIDs found no significant difference in regards to risk of acute kidney injury; however, elevated risks were noted for selective and partially selective NSAIDs (diclofenac, meloxicam, celecoxib).13
All NSAIDs are absorbed completely, and have small volumes of distribution (Table 1). NSAIDs are tightly bound to albumin; therefore, in patients low levels of albumin, serum levels of NSADS will be elevated.
|Table 1: Pharmacokinetics of various NSAIDs|
|NSAID||Peak Plasma Time, hrs||Half-life, hrs||Equivalent dosing, mga||COX Selectivity|
|Ibuprofen||2 (tablet)||2–4||600 tid||Non-selective|
|Naproxen||1–4 (tablet)||< 12||500 bid||Non-selective|
|Diclofenac||1 (tablet)||1.2–2||50 tid||Partially COX-2 selective|
|Meloxicam||4-5||15–20||7.5 qd||Relatively COX-2 selective|
|Celecoxib||< 3||11||200 bid||COX-2 selective|
|Abbreviations: tid, three times daily; bid, twice daily; qd, once daily
aBased off of medium dose14
In summary, there are many choices when deciding which NSAID to use in our patients. Diclofenac appears to have lower GI toxicity, whereas data suggests that naproxen has the least cardiotoxic effects. Practitioners should take into account patient bleeding risk, cardiovascular risk, and frequency of dosing to help guide appropriate therapy.
Dr. Vishal Shah is an internal medicine resident at NYU Langone Health
Peer reviewed by David Kudlowitz, MD, chief resident, internal medicine, NYU Langone Health
Image courtesy of Wikimedia Commons
- Zhou Y, Boudreau DM, Freedman AN. Trends in the use of aspirin and nonsteroidal anti-inflammatory drugs in the general U.S. population. Pharmacoepidemiol Drug Saf. 2014 Jan;23(1):43-50. doi: 10.1002/pds.3463.
- Furlan A, Sandoval J, Mailis-Gagnon A, and Tunks E. Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects. CMAJ. 2006 May 23; 174(11): 1589–1594. doi: 10.1503/cmaj.051528
- Dowell, D. Haergerich T. Chou R. CDC Guidelines for Prescribing Opioids for Chronic Pain – United States, 2016. Centers for Disease Control. March 18, 2016. https://www.cdc.gov/mmwr/volumes/65/rr/rr6501e1.htm
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- Peterson K, McDonagh M, Thakurta S, eta al. Drug Class Review: Nonsteroidal antiinflammatory drugs (NSAIDs). Update 4 final report.[Internet]. Portland (OR): Oregon Health & Science University; 2010 Nov. http://www.ncbi.nlm.nih.gov/books/NBK53955.
- Da Costa BR, Reichenbach S, Keller N, et al. Effectiveness of non-steroidal anti-inflammatory drugs for the treatment of pain in knee and hip osteoarthritis: a network meta-analysis.Lancet. 2016 Mar 17. [Epub ahead of print]
- 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;382:769-79.
- Solomon SD, McMurray JJ, Pfeff er MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. New Engl J Med 2005; 352: 1071–80.
- Fosbol E, Gislason G, Jocobsen S et al. Risk of Myocardial Infarction and Death Associated with the Use of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Among Healthy Individuals: A Nationwide Cohort Study. Clin Pharmacol Ther. 2009 Feb;85(2):190-7. doi: 10.1038/clpt.2008.204. Epub 2008 Nov 5.
- Antman, E.M. et al. Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association. Circulation 115, 1634–1642 (2007).
- U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA Strengthens warning that non-aspirin nonsteroidal antinflammatory drugs can cause heart attacks or strokes. July 9, 2015. Accessed August 1 2016. http://www.fda.gov/Drugs/DrugSafety/ucm451800.htm
- Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal antiinflammatory drugs. N Engl J Med 1984; 310:563.
- Ungprasert P, Cheungpasitporn W, Crowson CS, et al. Individual non-steroidal anti-inflammatory drugs and risk of acute kidney injury: A systematic review and meta-analysis of observational studies. Eur J Intern Med. 2015 May;26(4):285-91. doi: 10.1016/j.ejim.2015.03.008.
- Chou R, McDonagh M, Nakamoto E, et al. Analgesics for Osteoarthritis: An update of the 2006 Copmarative Effectiveness Review. Comparative Effectiveness Reviews, No. 38. Oregon Evidence-based Practice Center. 2011 Oct. http://www.ncbi.nlm.nih.gov/books/NBK65646/