The Pharmacologic Treatment of Osteoarthritis

Lee S. Simon

Vibeke Strand

Osteoarthritis (OA), a heterogeneous disorder that affects a majority of people older than 60 years, is typically observed as an inflammatory and/or painful process once a patient finally presents to a treating clinician. The precipitating event may not be temporally related to inflammation but instead may be associated with a mechanical process; that initial event may have been remote in time. The patient usually presents with complaints of pain with or without obvious inflammation and occasionally limited range of motion.

Once the patient has pursued nonpharmacologic interventions, it is likely that therapy with a drug will be required. The choice of which specific drug or combination treatment to use remains to be individualized (Table 15-1). Most therapies are targeted to symptomatic response, although therapeutic interventions designed to stimulate new cartilage growth or to change the natural history of cartilage damage appear to be on the horizon. An understanding of the currently available therapies, their effectiveness and limitations, and their safety profile is of obvious import.

Simple Analgesics

The initial use of acetaminophen was recommended by Bradley and colleagues,¹^,²^,³ who demonstrated that 1000 mg four times a day was equal in its effects to ibuprofen at either 1200 or 2400 mg/day in the treatment of patients with OA of the knee or hip. The one difference in efficacy observed was that anti-inflammatory doses of ibuprofen (2400 mg/24 hr), rather than lower doses (1200 mg, an “analgesic” dose), or acetaminophen alone improved pain at rest.² Acetaminophen was better tolerated than either dose of ibuprofen. It is certainly worthwhile to initiate a trial of acetaminophen, known to be beneficial in OA patients with mild to moderate pain, on the basis of the risk/benefit ratio and cost. However, studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with better efficacy. Pincus and coworkers⁴^,⁵ demonstrated that Arthrotec (a combination of diclofenac and misoprostol) at 75 mg twice daily provided greater benefit than acetaminophen, 4000 mg/day, in treating patients with OA of the hip or knee⁴ and celecoxib 200 mgs q day was also better in terms of same outcomes.⁵ Outcomes were measured by the patient’s self-assessed functional scores, including the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC, a functional assessment that is a disease-specific tool for OA)⁶ and the multidimensional Health Assessment Questionnaire (a quality-of-life measure for patients with arthritis).⁷ In the celcoxib comparator study the patients also preferred the COX-2 selective inhibitor. Nonetheless, acetaminophen offered better gastrointestinal tolerability.

Although an absolute understanding of the mechanism of action of acetaminophen remains elusive, it has been demonstrated to be an excellent analgesic and antipyretic while not possessing effective anti-inflammatory activity.⁸^,⁹^,¹⁰^,¹¹ It has been shown at high doses to have effects in vitro on the inhibition of prostaglandin synthesis.¹² It is believed that acetaminophen affects the brain and spinal cord, perhaps through the inhibition of PG (E₂) synthesis, while having no effect on prostaglandin synthesis in peripheral tissues.¹³

TABLE 15-1 AGENTS TO TREAT PAIN AND/OR INFLAMMATION

Simple analgesics

Acetaminophen

Tramadol

Topical agents

Capsaicin

Nonsteroidal anti-inflammatory drugs

COX-2 selective inhibitors

Intra-articular glucocorticoid injections

Intra-articular hyaluronic acid injections

Opioid analgesics

Nutraceuticals

Glucosamine

Chondroitin sulfate

Experimental therapies

Metalloproteinase inhibitors

Tetracyclines

Other data have shown that acetaminophen is metabolized uniquely in the brain into an agonist of TRPV1, thus suggesting that its main mode of action of antipyresis and analgesia may be modulated in the brain through the vanilloid receptor and may not have much to do with direct effects on cyclooxygenase activity.¹⁴

Issues regarding acetaminophen-induced toxicity have reached prominence. This includes hepatotoxicity as well as potential renal damage.¹⁵^,¹⁶^,¹⁷^,¹⁸^,¹⁹^,²⁰ Acute overdose is associated with liver damage, which at times can be irreversible. If patients are taking more than 2 ounces of alcohol on a daily basis, the dose of acetaminophen should be decreased to a maximum of 2 to 2.5 g/24 hr.²¹^,²²^,^22a Perneger and colleagues¹⁷ demonstrated in a case-controlled study that chronic use of acetaminophen may be associated with interstitial kidney damage leading to chronic renal failure. Investigators recruited patients from the End-Stage Renal Disease Program in the United States and an age-matched control population without kidney disease. Telephone interviews queried patients about regular acetaminophen or ASA use during the preceding 10 years. Patients with renal failure had taken significantly more acetaminophen and ASA than the control population did. Unfortunately, there are significant confounders to these observations. Patients in the End-Stage Renal Disease Program in the United States are typically allowed to use acetaminophen only for pain relief; thus, there is intrinsic bias in this study. Nonetheless, it is possible that chronic use of acetaminophen may lead to interstitial nephritis similar to that reported for the parent product, phenacetin. However, given its broad use as a pain reliever worldwide, this is likely to be a rare event.

Data have suggested that acetaminophen, long considered to be safe when it is used with clinically important anticoagulation therapy such as warfarin, has a potential effect on the prothrombin time. In patients requiring a higher international normalized ratio (INR) for control of their clotting tendency, the concomitant use of acetaminophen at high dose is a risk; therefore, more frequent monitoring of the INR should be planned.²³^,²⁴

There is also accumulating evidence of concern regarding the potential cardiovascular (CV) risk of acetaminophen. Chan et al. published a prospective cohort study nested within the nurses health study (NHS) that demonstrated that acetaminophen, when taken more than 15 days of the month chronically, is associated with an increased incidence of CV events which is similar to that seen with both the nonselective NSAIDs and the cyclooxygenase-2 (COX-2) selective inhibitors.²⁵

The risk/benefit ratio for use of acetaminophen in patients with little inflammation but mild to moderate pain and who derive benefit argues for its continued broad use. Its ubiquity and low cost means that most patients will already have tried acetaminophen, often at less than maximum doses; although a number of patients will have only a limited therapeutic response, it is important to ascertain whether the patient has given the drug a fair trial before determining this treatment to be a failure. Intermittent use or inadequate daily doses should be followed with a several-week trial of acetaminophen of up to 4 g/24 hr with care toward monitoring for untoward events, particularly the development of worsening hypertension.²⁶

Topical Analgesics

Topical agents with significant local effects have been used for years as tried and true home remedies, including menthol rubs, alcohol rubs, and substances such as camphor. Few clinical trials demonstrate adequate evidence to support recommendations for their use. The process of application may be the important therapeutic event, and massage is also a source of benefit. If there is benefit, there is also little risk.

In contrast, capsaicin 0.025 or 0.075%, derived from pepper, is a counterirritant. When it is used regularly, substance P and calcitonin gene-related peptide (CGRP), important neurotransmitters for pain, are depleted in the local tissues within a week.²⁷^,²⁸ Clinical trials have shown benefit when the cream or ointment is applied four times daily. Toxicity is minimal, predominantly associated with application of the cream or ointment where it is not indicated. Care needs to be taken, and hands should be washed quickly to prevent accidental application of the drug to mucous membranes or the eyes. The counterirritant effect of the pepper derivative, which may be important for clinical effect, can occasionally be intolerable and may also induce rashes.²²^,²⁷^,²⁸

There is increasing evidence to support the use of topical NSAIDs. Although as of this writing there are still none approved in the United States, these drugs have been available around the world for years. These authors await further publications as these products have been studied more extensively in recent years.

Nonsteroidal Anti-Inflammatory Drugs

NSAIDs are anti-inflammatory, analgesic, and antipyretic agents. They are widely used to reduce pain, to decrease the gelling phenomenon, and to improve function in patients with OA and rheumatoid arthritis, and for treatment of pain, including headache, dysmenorrhea, and postoperative
pain.²⁹^,³⁰^,³¹ Whether their clinical effects are solely due to their anti-inflammatory or analgesic effects or other possible properties is not known.²⁹ There are at least 20 different NSAIDs currently available in the United States (Table 15-2). In addition, COX-2-selective inhibitors (e.g., celecoxib) with similar efficacy but significantly decreased gastrointestinal and platelet effects are available.³²^,³³^,³⁴^,³⁵

TABLE 15-2 THE NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

NSAID	Trade Name	Usual Dose	Approved Use*
*CARBOXYLIC ACIDS*
ASA (acetylsalicylic acid)	Multiple	2.4–6 g/24 hr in 4-5 divided doses	RA, OA, AS, JCA, ST
Buffered ASA	Multiple	Same	Same
Enteric-coated salicylates	Multiple	Same	Same
Salsalate	Disalcid	1.5–3.0 g/24 hr bid	Same
Diflunisal	Dolobid	0.5–1.5 g/24 hr bid	Same
Choline magnesium trisalicylate	Trilisate	1.5–3 g/24 hr bid-tid	RA, OA, pain, JCA
*PROPRIONIC ACIDS*
Ibuprofen	Motrin, Rufen, OTC	OTC: 200-400 mg qid	RA, OA, JCA
Ibuprofen	Motrin, Rufen, OTC	Rx: 400, 600, 800 mg max 3200 mg/24 hr
Naproxen	Naprelan, Anaprox, Naprosyn EC	250, 375, 500 mg bid	RA, OA, JCA, ST
Fenoprofen	Nalfon	300-600 mg qid	RA, OA
Ketoprofen	Orudis	75 mg tid	RA, OA
Flurbiprofen	Ansaid	100 mg bid-tid	RA, OA
*ACETIC ACID DERIVATIVES*
Indomethacin	Indocin, Indocin SR	25, 50 mg tid or qid SR: 75 mg bid; rarely >150 mg/24 hr	RA, OA, G, AS
Tolmetin	Tolectin	400, 600, 800 mg; 800-2400 mg/24 hr	RA, OA, JCA
Sulindac	Clinoril	150, 200 mg bid (some ↑ to tid)	RA, OA, AS, ST, G
Diclofenac	Voltaren, Arthrotec	50 mg tid, 75 mg bid	RA, OA, AS
Etodolac	Lodine	200, 300 mg bid to qid max: 1200 mg/24 hr	OA, pain
*FENAMATES*
Meclofenamate	Meclomen	50-100 mg tid-qid	RA, OA
Mefenamic acid	Ponstel	250 mg qid	RA, OA
*ENOLIC ACIDS*
Piroxicam	Feldene	10, 20 mg qd	RA, OA
*NAPHTHYLKANONES*
Nabumetone	Relafen	500 mg bid up to 1500 mg/24 hr	RA, OA
*COXIBS*
Celecoxib	Celebrex	100 mg bid 200 mg qd-bid	OA, RA acute pain
*FDA approved. RA, rheumatoid arthritis; OA, osteoarthritis; AS, ankylosing spondylitis; G, gout; JCA, juvenile chronic polyarthritis; ST, soft tissue injury.

Prior to events surrounding the identification of increased cardiovascular risk with chronic use of nonselective and selective NSAIDs, these drugs represented one of the most commonly used classes of drugs in the world. It has been estimated that more than 17,000,000 Americans used these agents on a daily basis. With the aging of the U.S. population, the Centers for Disease Control and Prevention predicts a significant increase in the prevalence of painful rheumatic conditions and thus an increased burden on the need for drugs like NSAIDs.³⁶^,³⁷ Approximately 60 million NSAID prescriptions were written each year in the United States, the number for elderly patients exceeding that for younger patients by approximately 3.6-fold.³⁶ ASA ibuprofen, naproxen, and ketoprofen are also available over the counter. At equipotent doses, the clinical efficacy and tolerability of the various
NSAIDs are similar; however, individual responses are highly variable.²⁹^,³⁰^,³⁶^,³⁷ Although it is believed that it is reasonable to try another NSAID from a different class if a patient fails to respond to one NSAID of one class, no one has studied this in a prospective controlled manner.²⁹^,³⁰ As will be discussed, the use of simple analgesics and opioids has increased with the debate continuing regarding the overall risk and benefit of the NSAIDs.

Sodium salicylic acid was discovered in 1763. Impure forms of salicylates had been used as analgesics and antipyretics throughout the previous century. Once it was purified and synthesized, the acetyl derivative of salicylate, acetylsalicylic acid (ASA), was found to provide more anti-inflammatory activity than salicylate alone. Because of the toxicity of ASA, phenylbutazone, an enolic acid derivative, was introduced in the early 1950s. This was the first nonsalicylate NSAID developed for use in patients with painful and inflammatory conditions. This drug, a weak prostaglandin synthase inhibitor, induced uricosuria and was rapidly found to be useful in patients with ankylosing spondylitis and gout. However, owing to concerns related to bone marrow toxicity, particularly in women older than 60 years, this compound is now rarely prescribed. Indomethacin, an indoleacetic acid derivative, was subsequently developed in 1958 to substitute for phenylbutazone. It had significant toxicity as well, and the search for safer (particularly gastrointestinally safer)—and at least equally effective—NSAIDs ensued. Other issues have driven the development of newer agents, such as once- or twice-daily dosing to improve compliance.

The choice of NSAID is typically based on the physician’s prescribing behavior. Historically, ASA congeners including enteric-coated ASA were the first choice for treating inflammatory and degenerative arthritic conditions. Although cost is low, gastrointestinal intolerance and the requirement of multiple regular doses throughout the day to maintain adequate anti-inflammatory blood levels pose a problem. Depending on body mass, concomitant drug use, serum albumin levels, and other physiologic factors, 10 to 20 plain ASA tablets daily, taken no more than 8 hours apart, are usually required to achieve anti-inflammatory salicylate blood levels. Doses may need to be increased if enteric-coated ASA is chosen because of variable absorption within the bowel.

Although low dose ASA has been extensively studied and used to inhibit platelet aggregation as a prophylaxis against second myocardial infarction as well as suggestive evidence of decrease in primary events, there are little data that describe higher dose ASA as beneficial except as an anti-inflammatory agent. Recently a small study of prevention of recurrent colon polyps demonstrated an increased risk of stroke which was statistically significant and dose dependent.³⁸ Furthermore there is experimental evidence that concomitant use of ibuprofen may alter the cardiovascular benefit of prophylactic low doses of ASA.³⁹

Mechanism of Action

Some NSAIDs appear to be potent inhibitors of prostaglandin synthesis, whereas others more prominently affect nonprostaglandin-mediated biologic events.²⁹^,³⁰^,⁴⁰^,⁴¹^,⁴²^,⁴³^,⁴⁴^,⁴⁵ Differential clinical effects have also been attributed to variations in the enantiomeric state of the agent as well as its pharmacokinetics, pharmacodynamics, and metabolism.²⁹^,³⁰^,⁴⁰^,⁴¹^,⁴²^,⁴³^,⁴⁴^,⁴⁵^,⁴⁶^,⁴⁷ The theoretical and real differences between NSAIDs have been reviewed by Brooks and Day²⁹ and Furst.³⁰ Although variability can be explained in part by absorption, distribution, and metabolism, potential differences in mechanism of action must be considered an important explanation for their variable effects.²⁹^,³⁰^,⁴⁷

NSAIDs are primarily anti-inflammatory and analgesic by decreasing production of prostaglandins of the E series.⁴⁸ Prostanoic acids are proinflammatory and increase vascular permeability and sensitivity to the release of bradykinins. NSAIDs have also been shown to inhibit the formation of prostacyclin and thromboxane, resulting in complex effects on vascular permeability and platelet aggregation, undoubtedly contributing to the overall clinical effects of these compounds.

Polyunsaturated fatty acids including arachidonic acid, constituents of all cell membranes, exist in ester linkage in the glycerols of phospholipids and are ultimately converted to prostaglandins or leukotrienes first through the action of phospholipase A₂ or phospholipase C.⁴⁸ Free arachidonic acid released by the phospholipase acts as a substrate for the prostaglandin endoperoxide (PGH) synthase complex, which includes both cyclooxygenase and peroxidase. The enzymes catalyze the conversion of arachidonic acid to the unstable cyclic endoperoxide intermediates Prostaglandin G2 (PGG₂) and prostaglandin H2 (PGH₂). These arachidonic acid metabolites are then converted to the more stable PGE₂ and PGF₂ compounds by specific tissue prostaglandinsynthases. NSAIDs specifically inhibit cyclooxygenase and thereby reduce the conversion of arachidonic acid to PGG₂.

There are at least two isoforms of the cyclooxygenase enzymes. Although they share 60% homology in the amino acid sequences considered important for catalysis of arachidonic acid, they are products of two different genes. They differ most importantly in their regulation and expression.⁴⁹^,⁵⁰ COX-1 or prostaglandin synthase H₁ is a “house-keeping enzyme” that regulates normal cellular 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.⁵¹^,⁵²^,⁵³^,⁵⁴ It is important in maintaining the integrity of the gastric and duodenal mucosa, and many of the toxic effects of the NSAIDs on the gastrointestinal tract are attributed to its inhibition.⁵⁵^,⁵⁶^,⁵⁷^,⁵⁸^,⁵⁹^,⁶⁰

The other isoform, prostaglandin synthase H₂ or COX-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. For example, in monocyte-macrophage systems, endotoxin stimulates COX-2 expression; in fibroblasts, various growth factors, phorbol esters, and interleukin-1 do so.⁶¹ This isoform is also constitutively expressed in the brain (specifically cortex and hippocampus), in the female reproductive tract, in the male vas deferens, in bone, and at least in some models in human kidney.⁴⁹^,⁵⁰ The expression of COX-2 is inhibited by glucocorticoids.⁴⁹^,⁵⁰^,⁶² COX-2 is also inhibited by all of the presently available NSAIDs to a greater or lesser degree.⁵¹^,⁵²^,⁵³^,⁵⁴

The in vitro systems used to define the actions of the available NSAIDs are based on cell-free systems, pure enzyme systems, or whole cell systems.⁵¹ 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 inhibition of enzyme expression rather than by direct inhibition of cyclooxygenase.

Evidence has accumulated that several NSAIDs are selective for COX-2 enzyme effects over COX-1. For example, in vitro effects of etodolac demonstrate an approximately tenfold inhibition of COX-2 compared with COX-1 at low doses.⁶³^,⁶⁴ However, at higher anti-inflammatory doses, this specificity appears to be mitigated, because both enzymes are affected. Celecoxib is the only COX-2 selective inhibitor that is currently available in the U.S.⁶⁴ This COX-2-selective inhibitor has been shown to be as effective at inhibiting OA pain, dental pain, and the pain and inflammation associated with rheumatoid arthritis as naproxen (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.³²^,³³^,³⁴^,³⁵^,⁶⁵^,⁶⁶ Unfortunately, owing to the design of the randomized clinical trials, many of the important questions regarding the renal effects of this COX-2 inhibitor remain unanswered.⁴⁹^,⁵⁰

Arachidonic acid can also serve as a substrate for 5- or 12-lipoxygenase. These enzymes catalyze the conversion of arachidonic acid to biologically active leukotriene and hydroxyeicosatetraenoic acids. None of the presently available NSAIDs inhibits 5-lipoxygenase directly, although several compounds presently under development may have inhibitory effects on both cyclooxygenase and lipoxygenase. It remains to be seen whether these will be clinically useful.

NSAIDs are lipophilic and become incorporated in the lipid bilayer of cell membranes and thereby may interrupt protein-protein interactions important for signal transduction.⁴⁰^,⁴¹^,⁵⁶ 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.³¹^,⁴⁰^,⁴¹ There are data suggesting that NSAIDs inhibit activation and chemotaxis of neutrophils as well as reduce toxic oxygen radical production in stimulated neutrophils.¹²^,³¹^,⁶⁷ There is also evidence that several NSAIDs scavenge superoxide radicals.⁶⁸

Salicylates have been demonstrated to inhibit phospholipase C activity in macrophages. Some 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 is interference with neutrophil-endothelial cell adherence, which is crucial to migration of granulocytes to sites of inflammation; expression of L-selectins is decreased.⁴³ NSAIDs have been demonstrated in vitro to inhibit NF-κB (nuclear transcription factor)-dependent transcription, thereby inhibiting inducible nitric oxide synthase.⁴²^,⁴⁵ Anti-inflammatory levels of ASA have been shown to inhibit expression of inducible nitric oxide synthase and subsequent production of nitrite in vitro. At pharmacologic doses, sodium salicylate, indomethacin, and acetaminophen were studied and had no effect; but at suprapharmacologic dosages, sodium salicylate inhibited nitrite production.⁴²

It has been described that prostaglandins inhibit apoptosis (programmed cell death) and that NSAIDs, by inhibition of prostaglandin synthesis, may reestablish more normal cell cycle responses.⁴⁹^,⁵⁰^,⁶⁹ There is also 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 importance of these prostaglandin- and nonprostaglandin-mediated processes in reducing clinical inflammation is not entirely clear. Although nonacetylated salicylates have been shown in vitro to inhibit neutrophil function and to have equal efficacy in patients with rheumatoid arthritis,⁷⁰ there is no clinical evidence to suggest that biologic effects other than prostaglandin synthase inhibition are more important.

Pharmacology

Bioavailability

All NSAIDs are completely absorbed after oral administration. Absorption rates may vary in patients with altered gastrointestinal blood flow or motility and when certain NSAIDs are taken with food.²⁹^,³⁰ For example, taking naproxen with food may decrease absorption by 16%, although this is not likely to be clinically important. 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 more than 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 with associated hypoalbuminemic states. Importantly, because of increased vascular permeability in localized sites of inflammation, this high degree of protein binding may result in delivery of higher levels of NSAIDs.

Metabolism

NSAIDs are metabolized predominantly in the liver by the cytochrome P450 system and the CYP2C9 isoform and excreted in the urine. This must be taken into consideration in prescribing NSAIDs for patients with hepatic or renal dysfunction. Some NSAIDs, such as oxaprozin, have two metabolic pathways whereby some portion is directly secreted into the bile and another part is further metabolized and excreted in the urine. Others (e.g., indomethacin, sulindac, and piroxicam) have prominent enterohepatic circulation resulting in a prolonged half-life and should be used with caution in the elderly. In patients with renal insufficiency, some inactive metabolites may be resynthesized in vivo to
the active compound. Two of the traditional NSAIDs, diclofenac and flurbiprofen, and celecoxib are metabolized in the liver and should be used with care and at the lowest possible doses in patients with clinically significant liver disease and patients with significant liver dysfunction, this means patients with significant liver dysfunction, such as patients with cirrhosis with or without ascites, prolonged prothrombin times, falling serum albumin levels, or important elevations in liver transaminases in blood.

Salicylates are the least highly protein bound NSAID, at approximately 68%. Zero-order kinetics are dominant in salicylate metabolism. Thus, increasing the dose of salicylates is effective over a narrow range, but once the metabolic systems are saturated, incremental increases in dose may lead to 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.

Plasma Half-Life

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 maximal plasma concentrations quickly, and clinical responses may be delayed. Plasma concentrations can vary widely owing to 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 (Table 15-3). Although drugs have been developed with long half-lives to improve the compliance of patients, the fact that piroxicam has such a long half-life is not that attractive for the elderly patient at risk for specific NSAID-induced toxic effects. In the older patient, it is sometimes preferable to use drugs of shorter half-life so that the unwanted effects may more rapidly disappear when the drug is discontinued.

Sulindac and nabumetone are “prodrugs” in which the active compound is produced after first-pass metabolism through the liver. Prodrugs were developed to decrease the exposure of the gastrointestinal mucosa to the local effects of the NSAIDs. Unfortunately, as noted before, with adequate inhibition of COX-1, the patient is placed at substantial risk for an NSAID-induced upper gastrointestinal tract event as long as COX-1 activity is inhibited. This is true for drugs such as ketorolac given by injection, indomethacin given rectally, and for these prodrugs when they are given in adequate therapeutic doses.⁷¹^,⁷²

Once steady state has been achieved, synovial fluid concentrations of NSAIDs do not vary much. Although theoretically important for clinical effect, this has not been shown in vivo.²⁹^,³⁰ Thus, choices to prescribe specific NSAIDs are largely based on issues of safety, convenience, and compliance.

Miscellaneous

Other pharmacologic properties may be important clinically. NSAIDs that are highly lipid soluble in serum will penetrate the central nervous system more effectively and may occasionally produce striking changes in mentation, perception, and mood.⁷³^,⁷⁴ Indomethacin has been associated with many of these side effects, even after a single dose, particularly in the elderly.

TABLE 15-3 PLASMA HALF-LIVES OF THE NSAIDS AND THE COXIBS

Chemical Class	Drug Name	Plasma Half-Life (hr)
Carboxylic acids	Acetylsalicylic acid	4-15
	Choline magnesium trisalicylate	4-15
	Salsalate	4-15
	Diflunisal	7-15
Propionic acids	Ibuprofen	1.5–2
	Naproxen	13
	Fenoprofen	3
	Ketoprofen	2
	Flurbiprofen	3-9
	Oxaprozin	36-40
Acetic acids	Indomethacin	3-11
	Tolmetin	1-1.5
	Sulindac	13-16
	Diclofenac	1-2
	Etodolac	2-4
	Ketorolac	2
Fenamic acids	Mefenamic acid	2
Fenamic acids	Meclofenamic acid	2-3
Enolic acids	Piroxicam	30-86
Naphthylkanones	Nabumetone	19-30
Coxibs	Celecoxib	11
Coxibs	Rofecoxib	17

Adverse Effects

Mechanism-Based Adverse Effects

Risk for Anaphylaxis and Pulmonary Effects. Many adverse reactions attributed to NSAIDs are due to inhibition of prostaglandin synthesis in local tissues (Table 15-4). Patients with allergic rhinitis, nasal polyposis, or a history of asthma are the broadest example; in these patients, all NSAIDs effectively inhibit prostaglandin synthase and increase their risk for anaphylaxis. In high doses, even nonacetylated salicylates may sufficiently decrease prostaglandin synthesis to induce an anaphylactic reaction in sensitive patients.⁷⁵ Although the exact mechanism for this effect remains unclear, it is known that E prostaglandins serve as bronchodilators. When cyclooxygenase activity is inhibited in patients at risk, a decrease in synthesis of prostaglandins that contributes to bronchodilation results. Another explanation implicates other enzymatic pathways that use the arachidonate pool after it is converted from phospholipase, whereby shunting of arachidonateinto the leukotriene pathway occurs when cyclooxygenase is inhibited. The leukotriene pathway converts arachidonate by 5-lipoxygenase, leading to products such as leukotriene B₄ and others, which are clearly associated with anaphylaxis. This explanation implies that release
of large stores of arachidonate in certain inflammatory situations leads to excess substrate for leukotriene metabolism. This results in release of products that are highly reactive, leading to increased bronchoconstriction and the risk for anaphylaxis in the right patient.⁷⁶ Whether the main mechanism of effect is inhibition of prostaglandin synthesis or shunting of arachidonate into conversion by 5-lipoxygenase or a combination of the two, it is clear that patients who are sensitive are at great risk when NSAIDs are used.

TABLE 15-4 ADVERSE REACTIONS OF THE NSAIDS

Gastrointestinal	Nausea, vomiting, dyspepsia, diarrhea, constipation
	Gastric mucosal irritation, superficial erosions, peptic ulceration, increased fecal blood wasting
	Major gastrointestinal hemorrhage, penetrating ulcers
	Small bowel erosions; induce “diaphragm” development in small bowel
	Hepatotoxicity, hepatitis, fulminant hepatic failure
Renal	Glomerulopathy, interstitial nephritis, alterations in renal plasma flow leading to fall in glomerular filtration rates; interfere with natriuresis induced by diuretics; inhibit renin release; induce edema
Renal	Alterations in tubule functions
Central nervous system	Headaches, confusion, hallucinations, depersonalization reactions, depression, tremor
Central nervous system	Aseptic meningitis, tinnitus, vertigo, neuropathy, toxic amblyopia, transient transparent corneal deposits
Hematologic	Anemia, marrow depression, Coombspositive anemia
Hematologic	Decrease platelet aggregation
Hypersensitivity	Asthma, asthma/urticaria syndrome, urticaria, rashes, photosensitivity, Stevens-Johnson syndrome
Other	Drug interactions, such as displacement of oral hypoglycemics and warfarin from protein binding sites and from sites of metabolism
Other	Interference with the actions of β-blockers and some diuretics

The nonacetylated salicylates as a group have been considered a safe choice in these patients because they are known to possess anti-inflammatory activity but are relatively weak cyclooxygenase inhibitors. Stevenson and associates⁷⁷ have demonstrated that in general, this continues to be true; however, their study suggests a bit of caution. They studied ten ASA-sensitive patients who had developed asthma previously when treated with ASA. In a double-blinded, placebo-controlled, crossover oral challenge, these patients received either ASA or 2 g of salsalate (a nonacetylated condensation product of two salicylate moieties). All but two patients tolerated the salsalate dose well; in these two patients, an increase in airway resistance with salsalate therapy was demonstrated. When they were desensitized to ASA, the two patients who were previously intolerant showed improvement in tolerance to the salsalate, which suggests crossover in the mode of action. Thus, not all patients who develop bronchospasm to NSAIDs are safe when they are prescribed a nonacetylated salicylate, and if it is absolutely required, the patient should be monitored carefully, perhaps with an airflow meter after a single dose of the chosen drug to determine whether bronchospasm develops. Alternatively, the patient should be desensitized before the start of therapy.

We know little about the importance of the activities of either of the two cyclooxygenase isoforms in the lung parenchyma.⁴⁹

Platelet Effects. Platelet aggregation and thus the ability to clot are primarily induced through stimulating thromboxane production with activation of platelet COX-1. There is no COX-2 in the platelet. NSAIDs and ASA inhibit the activity of COX-1, but the COX-2-specific inhibitors have no effect on COX-1 at clinically effective therapeutic doses.⁴⁹

The effect of the nonsalicylate NSAIDs on platelet function is reversible and related to the half-life of the drug, whereas the effect of ASA is to acetylate the COX-1 enzyme, thereby permanently inactivating it. Because platelets cannot synthesize new cyclooxygenase enzyme after exposure to ASA, the platelet does not function appropriately for its life span. Therefore, the effect of ASA on the platelet does not wear off as the drug is metabolized, as with the nonsalicylate NSAIDs. Patients awaiting surgery should therefore stop their NSAIDs at a time determined by four to five times the serum half-life; ASA needs to be discontinued 1 to 2 weeks before the planned procedure to allow repopulation of platelets that have been unexposed to ASA.

There is also little information about the use of the COX-2-selective inhibitors in patients at risk for thrombosis.⁴⁹ The randomized clinical trials of the COX-2-selective inhibitors were not designed to address this question; thus, we have to await postmarketing surveillance to help resolve this problem. Furthermore, there is little information demonstrating that the traditional NSAIDs are safer or more useful than the COX-2-selective inhibitors in this regard. Only ASA has been studied prospectively, and low-dose ASA should be given concomitantly with either NSAIDs or selective COX-2 inhibitors in patients at risk for thrombosis. Given the additive ulcerogenic potential associated with the use of multiple NSAIDs, it is advisable to use selective COX-2 inhibitors with ASA when combination cardioprotective and anti-inflammatory therapies are considered. It is recommended that frail patients who are at increased risk for gastrointestinal (GI) complications when prescribed a COX-2 selective inhibitor combined with low-dose aspirin should also receive a proton-pump inhibitor as well.

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