Nonsteroidal anti-inflammatory drugs (NSAIDs) are anti-inflammatory, analgesic, and antipyretic agents. They are used to reduce pain, decrease stiffness, and improve function in patients with osteoarthritis (OA), rheumatoid arthritis (RA), and other forms of arthritis. They are also used for the treatment of pain including headache, dysmenorrhea, and postoperative pain.^1–3 It is not known whether NSAID effectiveness results from the anti-inflammatory or analgesic effects or from other possible mechanisms.⁴ There are at least 20 different NSAIDs currently available in the United States (Table 74-1). Cyclooxygenase-2 selective inhibitors (COX-2 inhibitors [celecoxib]), have similar efficacy but with significantly decreased gastrointestinal (GI) and platelet effects.^5–7 Several topical NSAIDs including diclofenac or salicylates for chronic pain have been approved in the United States; however, similar drugs have been available in Europe for a number of years. One study of a diclofenac liquid included an oral diclofenac comparator demonstrating no difference in efficacy from the topical agent in chronic dosing in treatment of the pain of osteoarthritis of the knee.⁸

NSAIDs are the most commonly used classes of drugs. It has been reported that more than 17 million Americans use these agents on a daily basis for the relief of pain and, at times, swelling related to inflammation.⁹ With the aging of the US population, the Centers for Disease Control and Prevention (CDC) predict a significant increase in the prevalence of painful degenerative and inflammatory rheumatic conditions and thus an increased use of NSAIDs.^9,10 Approximately 60 million NSAID prescriptions are written each year in the United States; the number for elderly patients exceeds those for younger patients by approximately 3.6-fold.¹⁰ Aspirin, ibuprofen, naproxen, and ketoprofen are also available over the counter (OTC). At equipotent doses, the clinical efficacy and tolerability of the various NSAIDs are similar; however, individual responses are highly variable.^1,11,12 It is believed that if a patient fails to respond to an NSAID from one class it is reasonable to put the patient on another NSAID from a different class; however, no one has studied this in a prospective controlled manner.^11,12 There are topical NSAIDs available including diclofenac and salicylate patches that have been demonstrated to work on single joints in osteoarthritis and soft tissue sprains and strains.

Sodium salicylic acid was discovered in 1763 but more impure forms of salicylates had been used as analgesics and antipyretics throughout the previous century. Once purified and synthesized, the acetyl derivative of salicylate, acetylsalicylic acid (ASA) was found to provide more anti-inflammatory activity than salicylate alone; however, it increased the incidence of toxicity, particularly related to the upper GI tract. Phenylbutazone, an indoleacetic acid derivative, was introduced in the early 1950s. This drug was a weak prostaglandin synthase inhibitor, which induced uricosuria, and was found useful in patients with ankylosing spondylitis and gout. However, because of concerns related to bone marrow toxicity, particularly in women older than 60 years of age, this compound now is rarely prescribed. Indomethacin, an indoleacetic acid derivative, was subsequently developed in the 1960s to substitute for phenylbutazone. It had the potential for significant toxicity as well, and the search for safer (particularly GI safer) and at least equally effective NSAIDs ensued. Other clinical issues have driven the development of newer agents, such as once or twice daily dosing to improve compliance.

Some of the variability in clinical response of these drugs may be explained by the spectrum of inhibition of prostaglandin synthesis. Several NSAIDs appear to be potent inhibitors of prostaglandin synthesis, while others more prominently affect other nonprostaglandin-mediated biologic events.^1,2,13–16 Different responses have also been attributed to variations in the enantiomeric state of the drug or its pharmacokinetics and/or pharmacodynamics.^1,2,11,12 Although variability can be explained in part by absorption, distribution, and metabolism, potential differences in mechanism of action must be considered as possibly important to explain observed variable effects.^11,12

The NSAIDs are primarily anti-inflammatory and analgesic by decreasing production of prostaglandins of the E series.¹⁷ Many of these prostanoic acids are proinflammatory, and increase vascular permeability and sensitivity to the release of bradykinins. Decreasing the synthesis of these mediators leads to decreased pain, swelling, and edema in the peripheral tissues. In addition, there is accumulating evidence that central effects of pain modulation may be as important as the effects on the peripheral tissues. The hypothesis is that prostaglandin synthesis is upregulated in the brain with peripheral stimulation of pain particularly associated with inflammation, and those NSAIDs that are more lipophilic penetrate better into the central nervous system (CNS) and inhibit both synthesis of peripheral and central prostaglandins.¹⁸

NSAIDs have also been shown to inhibit the formation of prostacyclin and thromboxane, resulting in complex effects on vascular permeability and platelet aggregation in peripheral tissues, which undoubtedly contributes to the overall clinical effects of these compounds.

These prostaglandins are derived from polyunsaturated fatty acids that are constituents of all cell membranes. They exist in ester linkage in the glycerols of phospholipids and are converted through multiple enzymatic steps to prostaglandins or leukotrienes first through the action of phospholipase A₂ or phospholipase C.¹⁷ Free arachidonic acid, which is released by the phospholipase from the fatty acids, acts as a substrate for the PGH synthase complex that includes cyclooxygenase (COX) and peroxidase. These enzymes catalyze the conversion of arachidonic acid to the unstable cyclic-endoperoxide intermediates, PGG₂ and PGH₂, which are then converted to the more stable PGE₂ and PGF₂ compounds by specific tissue prostaglandin synthases. NSAIDs specifically inhibit COX and thereby reduce the conversion of arachidonic acid to PGG₂.

At least two isoforms of the COX enzymes have now been identified. They are products of two different genes yet share 60% homology in the amino acid sequences considered important for catalysis of arachidonic acid. The differences are primarily in their regulation and expression.^19,20 COX-1, or prostaglandin synthase H₁ (PGHS-1), regulates normal cellular (physiologic) processes and is stimulated by hormones or growth factors. It is constitutively expressed in most tissues, and is inhibited by all NSAIDs to varying degrees depending on the applied experimental model system used to measure drug effects.^21–24 It has an important role in maintaining the integrity of the gastric and duodenal mucosa, and many of the toxic effects of the NSAIDs on the GI tract are attributed to its inhibition.^25–30 It has been described as a “housekeeping enzyme.”

The other isoform, COX-2, or prostaglandin synthase H₂ (PGHS-2) is an inducible enzyme and is usually undetectable in most tissues. Its expression is increased during states of inflammation or experimentally in response to mitogenic stimuli. In monocyte/macrophage systems, endotoxin stimulates COX-2 expression; in fibroblast studies various growth factors, phorbol esters, and interleukin-1 do so.^19,31 This isoform is also constitutively expressed in the brain, specifically the cortex and hippocampus, in the female reproductive tract, the male vas deferens, in bone, and in some models, in human kidney.^19,20 In the brain it appears that COX-2 is upregulated with increased inflammation-induced pain impulses; thus, the inhibition of COX-2 in the brain is thought to be an important modulator of pain in states of inflammation.¹⁸ The expression of COX-2 is inhibited by glucocorticoids.^19,20,31 COX-2 is also inhibited by all of the currently available NSAIDs to a greater or lesser degree, and its inhibition leads to a decrease in those prostanoid products associated with increased pain and swelling.^20–23 Therefore, we have observed the effects of prolonged inhibition of COX-2 for the last 25 years as we have used traditional nonselective NSAIDs.

The in vitro systems used to define the actions of the available NSAIDs are based on using cell-free systems, pure enzyme, or whole cells systems.²¹ Each drug studied to date has demonstrated different measurable effects within each system. As an example, it appears that nonacetylated salicylates inhibit the activity of COX-1 and COX-2 in whole cell systems but are not active against either COX-1 or COX-2 in recombinant enzyme or cell membrane systems. This suggests that salicylates act early in the arachidonic acid cascade similar to glucocorticoids, perhaps by inhibiting enzyme expression rather than direct inhibition of cyclooxygenase.

Recent accumulated evidence has demonstrated that several NSAIDs are selective and inhibit the COX-2 enzyme more so than the COX-1 enzyme. For example, in vitro effects of etodolac and meloxicam demonstrate primary inhibition of COX-2 compared with COX-1, at low doses.^32,33 However, at higher approved therapeutic doses this effect appears to be mitigated, as both COX-1 and COX-2 are inhibited to variable degrees. Very potent, selective COX-2 inhibitors that have no measurable effect on COX-1 mediated events at therapeutic doses are now available such as celcoxib.³⁴ This COX-2 selective inhibitor (or COX-1 sparing drug) has been shown as effective at inhibiting osteoarthritis pain, dental pain, and the pain and inflammation associated with rheumatoid arthritis as naproxen at 500 mg twice daily, ibuprofen 800 mg three times daily, and diclofenac 75 mg twice daily, without endoscopic evidence of gastroduodenal damage and without affecting platelet aggregation.^5–8,34,35 Unfortunately, because of the design of the randomized controlled trials, many important questions regarding the renal effects of the selective COX-2 inhibitors remain unanswered.^19,20 Three other COX-2 selective drugs have been removed from the market throughout the world: rofecoxib due to concerns regarding increased incidence of hypertension and cardiovascular risk; valdecoxib due to increased risk of Stevens Johnson syndrome; and lumiracoxib due to increased risk of serious hepatotoxic adverse reactions. Etoricoxib and an IV form of valdecoxib, parecoxib, are still available elsewhere in the world but not in the United States.

Other possible mechanisms of action that may explain the clinical effects of the NSAIDs include several physicochemical properties of these drugs. The NSAIDs are variably lipophilic and become incorporated in the lipid bilayer of cell membranes and thereby may interrupt protein-protein interactions important for signal transduction.^13,14 For example, stimulus response coupling, which is critical for recruitment of phagocytic cells to sites of inflammation, has been demonstrated in vitro to be inhibited by some NSAIDs.¹⁴ There are data suggesting that NSAIDs inhibit activation and chemotaxis of neutrophils as well as reduce toxic oxygen radical production in stimulated neutrophils.^36,37 There is also evidence that several NSAIDs scavenge superoxide radicals.³⁶

Salicylates have been demonstrated to inhibit phospholipase C activity in macrophages. Several NSAIDs have been shown to affect T-lymphocyte function experimentally by inhibiting rheumatoid factor production in vitro. Another newly described action not directly related to prostaglandin synthesis inhibition includes interference with neutrophil-endothelial cell adherence, which is critical to migration of granulocytes to sites of inflammation. These data demonstrate that expressions of L-selectin are decreased.¹⁶ NSAIDs have been demonstrated in vitro to inhibit NF-kB (nitric oxide transcription factor) dependent transcription, thereby inhibiting inducible nitric-oxide synthetase.¹⁵ Anti-inflammatory levels of ASA have been shown to inhibit expression of inducible nitric-oxide synthetase and subsequent production of nitrite in vitro. At pharmacologic doses, sodium salicylate, indomethacin, and acetaminophen when studied had no effect, but at suprapharmacologic doses, sodium salicylate inhibited nitrite production.¹⁵

It has also been described that prostaglandins inhibit apoptosis (programmed cell death) and that NSAIDs, via inhibition of prostaglandin synthesis, may reestablish more normal cell cycle responses.^19,20 There is evidence suggesting that some NSAIDs may reduce PGH synthase gene expression, thereby supporting the clinical evidence of differences in activity in NSAIDs in sites of active inflammation.

The NSAIDs have been demonstrated to have variable effects on many biologic processes; however, how important some of these effects are clinically remains unknown. Although nonacetylated salicylates have been shown in vitro to inhibit neutrophil function and to have equal efficacy in patients with rheumatoid arthritis,³⁸ no clinical evidence exists to suggest that these biologic effects are more important than prostaglandin synthase inhibition.

The NSAIDs are efficiently absorbed after oral administration, but absorption rates may vary in patients with altered GI blood flow or motility. Certain NSAIDs when taken with food have decreased absorption.^1,2 Enteric coating may reduce direct effects of NSAIDs on the gastric mucosa but may also reduce the rate of absorption.

Most NSAIDs are weak organic acids; once absorbed they are over 95% bound to serum albumin. This is a saturable process. Clinically significant decreases in serum albumin levels or institution of other highly protein-bound medications may lead to an increase in the free component of NSAID in serum. This may be important in patients who are elderly or are chronically ill, especially those with associated hypoalbuminemic states. Importantly, as a result of increased vascular permeability in localized sites of inflammation, this high degree of protein binding may result in delivery of higher levels of NSAIDs.

NSAIDs are metabolized predominantly in the liver by the cytochrome P-450 system and the CYP 2C9 isoform, and excreted in the urine. This must be taken into consideration when prescribing NSAIDs for patients with hepatic or renal dysfunction. Several NSAIDs (e.g., indomethacin, sulindac, piroxicam) have a prominent enterohepatic circulation, resulting in a prolonged half-life and should be used with caution in elderly patients. In patients with renal insufficiency, some inactive metabolites may be resynthesized in vivo to the active compound. Diclofenac, flurbiprofen, and celecoxib are metabolized in the liver. These agents should be used with care and at lowest possible doses, if used at all, in patients with clinically significant liver disease, including patients with cirrhosis with or without ascites, prolonged prothrombin times, falling serum albumin levels, and important elevations in liver transaminases in blood.

Salicylates are the least highly protein bound NSAID: approximately 68%. Zero order kinetics is dominant in salicylate metabolism. Thus, increase of the dose of a salicylate is effective over a narrow range, but once the metabolic systems are saturated, incremental dose increases may lead to very high serum salicylate levels. Thus, changes in salicylate doses need to be carefully considered at chronic steady-state levels, particularly in patients with altered renal or hepatic function.

Significant differences in plasma half-lives of the NSAIDs may be important in explaining their diverse clinical effects. Those with long half-lives typically do not attain maximum plasma concentrations quickly and important clinical responses may be delayed. In most chronic conditions that are appropriate for the use of these drugs, the acute effects are not as important as in the treatment of headache or acute pain. Plasma concentrations can vary widely because of differences in renal clearance and metabolism. Piroxicam has the longest serum half-life of currently marketed NSAIDs: 57 ± 22 hours. In comparison, diclofenac has one of the shortest: 1.1 ± 0.2 hours (see Table 74-1). Although drugs have been developed with very long half-lives to improve patient adherence with therapy, in the older patient it is sometimes preferable to use drugs of shorter half-life so that, when the drug is discontinued, any unwanted effects may more rapidly disappear.

Sulindac and nabumetone are “prodrugs” in which the active compound is produced after first-pass metabolism through the liver. In theory, prodrugs were intended to decrease the exposure of the GI mucosa to the local effects of the NSAIDs. Unfortunately, as noted, with adequate inhibition of COX-1 the patient is placed at substantial risk of an NSAID-induced upper GI event as long as COX-1 activity is inhibited. This is true for drugs such as ketorolac given as an injection or by these prodrugs when given at adequate therapeutic doses.³⁹

Other pharmacologic properties may be important clinically. NSAIDs that are highly lipid soluble in serum will penetrate the CNS more effectively and occasionally may produce striking changes in mentation, perception, and mood.^40,41 Indomethacin has been associated with these side effects, even after a single dose, particularly in elderly persons.