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Optimizing NSAID management.

Acute pain is the most common reason for patients to seek treatment with their primary care provider. (1) Acute pain often results from such medical conditions as surgery, trauma and arthritis, as well as sports and recreational injury. (2,3) Low back and neck pain are the most common forms of acute musculoskeletal pain and account for 117 million cases annually. (4) Available pharmacologic options include acetaminophen, opioids and nonsteroidal anti-inflammatory drugs (NSAIDs). This article will discuss the dose-related and other risks associated with NSAIDs, the biologic mechanism of NSAIDs that may contribute to these risks, and how these risks may be mitigated by using lower dosing.

Risks of NSAIDs

NSAIDs are commonly prescribed by health care professionals as a first-line choice for the treatment of mild to moderate pain. Unfortunately, NSAIDs can be associated with serious gastrointestinal (GI), cardiovascular (CV) and renal adverse events (AEs). In the GI system, prostaglandins play a cytoprotective role through various mechanisms, reducing the secretion of gastric acid, increasing the thickness of the mucus layer in the upper GI tract, as well as stimulating bicarbonate secretion and increasing mucosal blood flow. (5) In the CV system, prostacyclin is synthesized by COX-2. Prostacyclin plays a major role in the maintenance of cardiovascular homeostasis; prostacyclin also contributes to the inhibition of thrombosis when functioning as a platelet-aggregation inhibitor and potent vasodilator. (5) An imbalance between prostacyclin and thromboxane A2, which has prothrombotic properties, can lead to an increase in thrombotic CV events or increased and prolonged bleeding. (5) In the kidneys, prostaglandins regulate cellular activity and renal blood flow. (5,6) Renal effects of NSAID-induced blockade prostaglandin production can include mild to moderate fluid and electrolyte abnormalities, acute renal failure, nephrotic syndrome, papillary necrosis and cardio-renal interactions (e.g., hypertension, chronic heart failure). (5-6) Serious adverse effects from the inhibition of prostaglandins by NSAIDs have been documented in epidemiologic studies (Figure l). (7,9) These effects have dose-dependent associations and may occur within the first week of therapy.

Biologic Mechanism of NSAID-Related Risk

The selectivity, dose, formulation and pharmacokinetics of NSAIDs are factors that contribute to the risk of serious adverse events.

Role of Selectivity With NSAIDs

Cyclooxygenase (COX) enzymes play an intermediary role in the conversion of arachadonic acid to prostanoids. The COX-1 enzymes have been shown to play a protective role, whereas COX-2 enzymes have been associated with inflammation and pain. NSAID selectivity of COX-1 and COX-2 are determined based on a comparison of the plasma concentrations required to inhibit 80% of the COX enzymes (IC80), as depicted in Figure 2. (10) Diclofenac, celecoxib and meloxicam preferentially inhibit COX-2, while naproxen and ibuprofen preferential inhibit COX-1. (10) Studies suggest agents with a greater selectivity for COX-1 inhibition confer an increased incidence of GI ADRs, while agents with a greater selectivity for COX-2 confer an increased incidence of CV ADRs.

Role of Dose in NSAIDs

The levels of both COX-1 and COX-2 that are inhibited are dose-related (Figure 3). 11,12 It has been shown that diclofenac at a dose of 50 mg TID inhibits 94% of COX-2, whereas other commonly used NSAIDs at therapeutic doses inhibit around 70% to 80% of COX-2. (11) At the doses shown in figure 3, naproxen and ibuprofen have highest levels of COX-1 inhibition, diclofenac and meloxicam have moderate levels, and rofecoxib has the lowest levels of COX-1 inhibition. Inhibition of 80% of COX-2 (IC80) has been described in literature as a reasonable marker correlated directly with the peak analgesic and anti-inflammatory activities of various NSAIDs. (13) Lower levels of COX-1 inhibition have been shown to minimize the risk of GI and renal events, whereas achieving a threshold of 95% inhibition of COX-1 has been shown to inhibit platelet aggregation and minimize risk of cardiovascular events. Lower levels of COX-1 inhibition, as seen with diclofenac and meloxicam, are shown to have minimal impact on bleeding and bleeding time. Dosing NSAIDs to coincide with IC80 concentrations of COX-2 while minimizing the COX-1 inhibition can offer the balance of the required NSAID effects while minimizing the risks of undesirable effects. (14)

Role of Formulation and Pharmacokinetics

NSAIDs with long plasma half-lives (greater than 12 hours) and slow release formulations are associated with an increased risk of serious adverse events compared to NSAIDs with shorter half-lives and immediate-release products. (15) Prostacyclin, a prostanoid, synthesized by COX-2 in the vascular endothelium, inhibits platelet aggregation and is responsible for the maintenance of homeostasis. It is hypothesized that prolonged high levels of COX-2 inhibition in the plasma can lead to an increased risk of vascular events. (16) While once-a-day dosing is often desired by patients, the potential for increased risk of adverse events associated with a long half-life or slow release formulations may negate the convenience factor. (15)

Mitigation of NSAID Risk Through Lower Dosing

In 2005 the FDA issued a Public Health Advisory informing prescribes to "use the lowest effective dose for the shortest duration consistent with individual patient treatment goals." (17) Whereas attempts have been made to mitigate the risk of NSAIDs through enteric coating, pro-drug formulations, agents with less selectivity for COX-1 and combination products to reduce upper GI complications, none of these approaches has provided an overall dose reduction in the formulation of NSAIDs.

Ideally, NSAIDs should be prescribed in doses that result in plasma concentrations that are high enough to provide the desired anti-inflammatory and analgesic effects, but without plasma levels so high as to reduce the protective effects of the COX-1 enzyme and the associated prostaglandin formation.14 Selection of the correct dose, selectivity, formulation and pharmacokinetics of NSAIDs are important in achieving the optimal balance of analgesia while minimizing the risk of undesirable effects. Ultimately, the decision model for selection of a NSAID should consider dosing as a major part of the overall strategy to reduce potential ADRs.


(1.) McCarberg B, Gibofsky A. Need to develop new nonsteroidal anti-inflammatory drug formulations. Clinical Therapeutics. Sep 2012;34(9): 1954-1963.

(2.) Institute of Medicine, Committee on Advancing Pain Research, Care, and Education. Relieving pain in America: a blueprint for transforming prevention, care, education, and research. Washington, D.C: Academies Press; 2011.

(3.) Loeser J, Butler S, Chapman R, Turk D. Bonica's Management of Pain, 3rd ed.: Lippincott Williams & Wilkins; 2001.

(4.) Buurma A, Sosa M, Witt A. Acute Pain: Pain Management Study. 2012.

(5.) Simmons DL, Botting RM, Hla T. Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacological Reviews. Sep 2004;56(3):387-437.

(6.) Suleyman H, Demircan B, Karagoz Y. Anti-inflammatory and side effects of cyclooxygenase inhibitors. Pharmacological Reports : PR. May Jun 2007;59(3):247-258.

(7.) Garcia Rodriguez LA, Hemandez-Diaz S. Relative risk of upper gastrointestinal complications among users of acetaminophen and nonsteroidal anti-inflammatory drugs. Epidemiology (Cambridge, Mass.). Sep 2001; 12(5):570-576.

(8.) Garcia Rodriguez LA, Tacconelli S, Patrignani P. Role of dose potency in the prediction of risk of myocardial infarction associated with nonsteroidal anti-inflammatory drugs in the general population. Journal of the American College of Cardiology. Nov 11 2008;52(20): 1628-1636.

(9.) Huerta C, Castellsague J, Varas-Lorenzo C, Garcia Rodriguez LA. Nonsteroidal anti-inflammatory drugs and risk of ARF in the general population. American Journal of Kidney Diseases : The Official Journal of the National Kidney Foundation. Mar 2005;45(3):531-539.

(10.) Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane JR. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclooxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci USA. 1999 Jun 22;96(13):7563-7568.

(11.) Van Hecken Al, Schwartz JI, Depre M, De Lepeleire I, Dallob A, Tanaka W, Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers. J Clin Pharmacol. 2000 Oct;40(10):1109-1120.

(12.) Hinz B, Dormann H, Brune K. More pronounced inhibition of cyclooxygenase 2, increase in blood pressure, and reduction of heart rate by treatment with diclofenac compared with celecoxib and rofecoxib. Arthritis Rheum. 2006 Jan;54(l):282-291.

(13.) Huntjens DR, Danhof M, Della Pasqua OE. Pharmacokinetic-pharmacodynamic correlations and biomarkers in the development of COX-2 inhibitors. Rheumatology (Oxford, England). Jul 2005;44(7):846-859.

(14.) Cryer B, Feldman M. Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs. The American Journal of Medicine. May 1998;104(5):413-421.

(15.) Masso Gonzalez EL, Patrignani P, Tacconelli S, Garcia Rodriguez LA. Variability among nonsteroidal anti-inflammatory drags in risk of upper gastrointestinal bleeding. Arthritis Rheum. Jun 2010;62(6): 1592-1601.

(16.) Brune K, Renner B, Hinz B. Using pharmacokinetic principles to optimize pain therapy. Nat Rev Rheumatol. 2010 Oct;6(10):589-598.

(17.) Administration FaD. Public Health Advisory--FDA Announces Important Changes and Additional Warnings for COX-2 Selective and Non-Selective Non-Steroidal Anti-Inflammatory Drags (NSAIDs). 2005; ucml50314.htm. Accessed March 19,2014.

Gregory Holmquist, Pharm.D., has been practicing clinical pain management for over 20 years. In the past decade he has been invited to present hundreds of educational programs across the country on pain management, side effect management, patient care and appropriate pharmacological principles.

Dose-Related Risk of Serious Adverse Events With NSAIDs

                             Low-medium Dose   High Dose

GI Complications (7)             2.4              4.9
Myocardial Infarction (8)        1.2              1.6
Acute Renal Failure (9)          2.5              3.4

Adapted from Garcia Rodriguez 2001, Garcia Rodriguez
2008. Huerta 2006.

Note: Table made from bar graph.

Dose-Related Inhibition of COX-1 and COX-2

rofecoxib *        69%
25 mg QD (11)

meloxicam          78%
15 mg QD (11)

diclofenac         94%
50 mg TID (11)

ibuprofen          71%
800 mg TID (11)

naproxen           72%
500 mg BID (11)

diclofenac         99%
75 mg BID (12)

celecoxib           81%
2 200 mg BID (12)

rofecoxib           72%
25 mg BID (12)

Adapted from Van Hecken 2000, Hinz 2006.

Note: Table made from bar graph.
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Title Annotation:RX/News
Author:Holmquist, Gregory
Publication:Chain Drug Review
Date:Apr 28, 2014
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