The Use of Nonsteroidal Anti-Inflammatory Drugs

A 65-year-old male with stage two chronic kidney disease complains of months of right knee pain that worsens with activity. On examination of the right knee, you find a small effusion and subpatellar crepitus. You recommend quadriceps strengthening exercises and wonder about the safety and efficacy of Nonsteroidal anti-inflammatory drugs (NSAIDs) in this patient.

NSAIDs are used by millions to treat acute and chronic musculoskeletal and soft tissue-related pain and inflammation. There are at least twenty different NSAIDs available for use in the United States including two topical formulations (Table 65-1). This chapter is a brief review of NSAIDs with a focus on clinical management.

BASIC MECHANISM AND PHARMACOKINETICS

The major mechanism of action of NSAIDs is inhibition of cyclooxygenase, the enzyme that catalyzes the conversion of arachidonic acid to various molecules including prostaglandins.¹^,²^,³ Several prostaglandins are responsible for mediating pain, inflammation, and fever. Decreased production of prostaglandins leads to diminished pain and inflammation.

Cyclooxygenase comes in two isoforms, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX-1 is found in many tissues throughout the body. It produces prostaglandins that regulate normal processes like the maintenance of healthy gastrointestinal (GI) mucosa or the aggregation of platelets upon activation. COX-2 is found in fewer tissues and is induced by inflammation. Prostaglandins produced by COX-2 are especially involved in mediating pain and inflammation.¹^,³

NSAIDs vary in the degree to which they inhibit COX-1 and COX-2. Some NSAIDs inhibit COX-2 to a far greater extent than they do COX-1. These NSAIDs are referred to as “COX-2 inhibitors” or “selective NSAIDs.” All other NSAIDs are “nonselective” in that they inhibit COX-1 to an appreciable degree. The benefit of selective COX-2 inhibition is to minimize disturbance of the GI mucosa while maintaining the ability to diminish pain and inflammation.¹

Oral NSAIDs are absorbed almost completely.² Topical NSAIDs are absorbed mainly into the skin and soft tissues; only about 6% is systemically absorbed.⁴ It is important to note that most NSAIDs, once in the bloodstream, are highly bound to albumin (>95%). As a result, the free fraction of any NSAID when taken in patients with hypoalbuminemia will be higher than would be otherwise expected. Because of this, lower doses should be used in patients with cirrhosis, chronic inflammation, and other low-albumin states. NSAIDs are metabolized principally by the liver and excreted in the urine.²

TABLE 65-1 NSAIDs: Examples of Dosing and Cost

Name	Dosing	Cost (Dose, Number of Tablets)
Aspirin	325-650 mg every 4 h	$6.48 (325 mg, #90)
Celecoxib	100-200 mg twice daily	$179.76 (100 mg, #60)
Diclofenac	100-200 mg total per day, divided into two to three doses	$4.00 (50 mg, #60)
Etodolac	200-500 mg two to three times daily	$10.09 (400 mg, #60)
Ibuprofen	200-800 mg every 6 h	$5.99 (600 mg, #90)
Indomethacin	25-100 mg twice daily	$7.99 (50 mg, #60)
Meloxicam	7.5-15 mg once daily	$7.99 (7.5 mg, #30)
Nabumetone	1,000-2,000 mg total per day, as once daily or divided into two doses	$26.99 (500 mg, #60)
Naproxen	220-500 mg twice daily	$4.00 (500 mg, #60)
Salsalate	Up to 3,000 mg total per day, divided into two to three doses	$12.02 (750 mg, #60)
All NSAIDs listed are generic oral tablets except for celecoxib, which is a name-brand. Dosing from Micromedex. Cost from Goodrx.com using CVS Pharmacies within 5 miles of Philadelphia.

ACTIONS AND EVENTS

Gastrointestinal

NSAIDs harm the GI mucosa by direct irritation and by adversely affecting the mucosal perfusion, mucus production, and epithelial growth that serve to protect the GI tract from damage caused by stomach acid and digestive enzymes.

Potential GI adverse events include dyspepsia, esophagitis, gastritis, and peptic ulcers, along with the complications of obstruction, perforation, and hemorrhage. The risk of developing an adverse GI event increases about three- to fivefold with NSAID use (roughly fourfold for upper GI bleeding).¹ Higher doses are more problematic than lower doses. Longer-acting NSAIDs are thought to confer higher GI risk than shorteracting NSAIDs. One systematic review of various NSAIDs found the greatest risk of upper GI hemorrhage and/or perforation with ketorolac (rate ratio [RR] 14.54) and piroxicam (RR 9.94). The lowest risk was reported with celecoxib (RR not increased) followed by ibuprofen (RR 2.69).³

Risk factors for NSAID-related GI toxicity include a previous GI event (especially if complicated), age > 65, high-dose NSAID therapy, chronic debilitating disorders (especially cardiovascular disease), and concomitant use of anticoagulants, glucocorticoids, and other NSAIDs (including low-dose aspirin). According to an American College of Gastroenterology-published guideline, patients are considered high risk for an adverse gastrointestinal event if they have more than two risk factors or a history of a previously complicated ulcer (especially a recent one).⁵ Patients are considered moderate risk if they have one to two risk factors and low risk if they have no risk factors.

From a GI perspective, selective NSAIDs are clearly safer than nonselective NSAIDs. One meta-analysis of 14 randomized clinical trials (RCTs) reported the annual incidence rate of serious upper GI adverse events to be 0.20% in those treated with celecoxib compared to 1.68% in those treated with nonselective NSAIDs (P < 0.05).¹

Topical NSAIDs have been found to cause fewer gastrointestinal events than oral NSAIDs. In a pooled analysis of three 12-week trials of diclofenac sodium 1% gel (DSG) used in patients with knee osteoarthritis, DSG was not associated with an increased risk of adverse events, even in elderly patients with comorbidities such as diabetes and cardiovascular disease.⁶^,⁷