NSAIDs: Therapeutic use and variability of response in adults
- Daniel H Solomon, MD, MPH
Daniel H Solomon, MD, MPH
- Matthew H. Liang Distinguished Chair in Arthritis and Population Health
- Professor of Medicine
- Harvard Medical School
- Section Editor
- Daniel E Furst, MD
Daniel E Furst, MD
- Section Editor — Treatment Issues in Rheumatology
- Professor of Rheumatology, University of Washington, Seattle
- Professor of Rheumatology, Washington University of Florence, Florence, Italy
- Professor of Rheumatology, University of California in Los Angeles (Emeritus)
- Director of Research, Pacific
A variety of nonsteroidal antiinflammatory drugs (NSAIDs) are readily available (at least 20 in the United States and more elsewhere) and are widely used throughout the world (table 1). In the United States, aspirin, ibuprofen, naproxen, and ketoprofen can also be obtained without prescription. Each year, approximately 60 million NSAID prescriptions are written, with the number of prescriptions for older patients approximately 3.6-fold higher than that for younger patients [1,2].
Questions concerning the variability of response to the effects of the different NSAIDs have led to efforts to understand the potential and real differences between these drugs. All NSAIDs appear to be absorbed completely, have negligible first pass hepatic metabolism, are tightly bound to albumin, and have small volumes of distribution. Patients with hypoalbuminemia may, therefore, have higher free serum concentrations of drug.
However, it is unclear whether the blood level of a NSAID is important in assessing its mode of action or its effectiveness, since protein-binding is saturable in the normal dose range for several NSAIDs. As a result, increases in dose may not lead to increases in steady state concentration of the drug. At equipotent doses, the clinical efficacy of the various NSAIDs in patient populations is similar ; in contrast, individual responses are highly variable .
Some of the observed individual differences with specific NSAIDs are particularly evident with respect to toxicity . As an example, it is not unusual for indomethacin to induce headaches after a single dose in some patients. More commonly, individual patients have more symptoms or signs of gastrointestinal toxicity with one NSAID than with another . Some differences in toxicity may be explained by variations in absorption, distribution, and metabolism. Differences in the mode of action may be important as well.
This topic will review the issues surrounding the differences in response to the various NSAIDs [4,6]. Clinical considerations in the use of these agents will also be discussed, while the different types of toxicity that may be seen with both nonselective and COX-2 selective NSAIDs are presented separately. (See "Nonselective NSAIDs: Overview of adverse effects" and "Overview of selective COX-2 inhibitors".)
- Baum C, Kennedy DL, Forbes MB. Utilization of nonsteroidal antiinflammatory drugs. Arthritis Rheum 1985; 28:686.
- Hamerman D. Clinical implications of osteoarthritis and ageing. Ann Rheum Dis 1995; 54:82.
- Agency for Healthcare Research and Quality. Comparative Effectiveness Review Number 38. Analgesics for osteoarthritis: An update of the 2006 comparative effectiveness review. Executive summary. www.effectivehealthcare.ahrq.gov/ehc/products/180/805/Analgesics-Update_executive-summary_20111007.pdf (Accessed on March 16, 2012).
- Furst DE. Are there differences among nonsteroidal antiinflammatory drugs? Comparing acetylated salicylates, nonacetylated salicylates, and nonacetylated nonsteroidal antiinflammatory drugs. Arthritis Rheum 1994; 37:1.
- Heymann MA. Non-narcotic analgesics. Use in pregnancy and fetal and perinatal effects. Drugs 1986; 32 Suppl 4:164.
- Brooks PM, Day RO. Nonsteroidal antiinflammatory drugs--differences and similarities. N Engl J Med 1991; 324:1716.
- Bradley JD, Brandt KD, Katz BP, et al. Treatment of knee osteoarthritis: relationship of clinical features of joint inflammation to the response to a nonsteroidal antiinflammatory drug or pure analgesic. J Rheumatol 1992; 19:1950.
- Meade EA, Smith WL, DeWitt DL. Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs. J Biol Chem 1993; 268:6610.
- Cush JJ, Jasin HE, Johnson R, Lipsky PE. Relationship between clinical efficacy and laboratory correlates of inflammatory and immunologic activity in rheumatoid arthritis patients treated with nonsteroidal antiinflammatory drugs. Arthritis Rheum 1990; 33:623.
- Hla T, Neilson K. Human cyclooxygenase-2 cDNA. Proc Natl Acad Sci U S A 1992; 89:7384.
- Mitchell JA, Akarasereenont P, Thiemermann C, et al. Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Natl Acad Sci U S A 1993; 90:11693.
- Patrignani P, Panara MR, Greco A, et al. Biochemical and pharmacological characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthases. J Pharmacol Exp Ther 1994; 271:1705.
- Bombardier C, Peloso PM, Goldsmith CH. Salsalate, a nonacetylated salicylate, is as efficacious as diclofenac in patients with rheumatoid arthritis. Salsalate-Diclofenac Study Group. J Rheumatol 1995; 22:617.
- Does the acetyl group of aspirin contribute to the antiinflammatory efficacy of salicylic acid in the treatment of rheumatoid arthritis? The Multicenter Salsalate/Aspirin Comparison Study Group. J Rheumatol 1989; 16:321.
- Lu X, Xie W, Reed D, et al. Nonsteroidal antiinflammatory drugs cause apoptosis and induce cyclooxygenases in chicken embryo fibroblasts. Proc Natl Acad Sci U S A 1995; 92:7961.
- Fries S, Grosser T, Price TS, et al. Marked interindividual variability in the response to selective inhibitors of cyclooxygenase-2. Gastroenterology 2006; 130:55.
- Díaz-González F, González-Alvaro I, Campanero MR, et al. Prevention of in vitro neutrophil-endothelial attachment through shedding of L-selectin by nonsteroidal antiinflammatory drugs. J Clin Invest 1995; 95:1756.
- Amin AR, Vyas P, Attur M, et al. The mode of action of aspirin-like drugs: effect on inducible nitric oxide synthase. Proc Natl Acad Sci U S A 1995; 92:7926.
- Hawkey CJ. Future treatments for arthritis: new NSAIDs, NO NSAIDs, or no NSAIDs? Gastroenterology 1995; 109:614.
- Ortiz MI, Granados-Soto V, Castañeda-Hernández G. The NO-cGMP-K+ channel pathway participates in the antinociceptive effect of diclofenac, but not of indomethacin. Pharmacol Biochem Behav 2003; 76:187.
- Walker JS, Sheather-Reid RB, Carmody JJ, et al. Nonsteroidal antiinflammatory drugs in rheumatoid arthritis and osteoarthritis: support for the concept of "responders" and "nonresponders". Arthritis Rheum 1997; 40:1944.
- Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 2001; 345:1809.
- Derry S, Moore RA, Rabbie R. Topical NSAIDs for chronic musculoskeletal pain in adults. Cochrane Database Syst Rev 2012; :CD007400.
- HYPOTHESES CONCERNING VARIABILITY OF RESPONSE
- Mechanism of action
- - Prostaglandin-mediated
- - Nonprostaglandin-mediated
- Clinical studies
- ISSUES IN THE THERAPEUTIC USE OF NSAIDS
- Dosing regimen
- Nonanalgesic effects
- Drug interactions
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS