Piroxicam, an oxicam (Figure 36–1), is a nonselective COX inhibitor that at high concentrations also inhibits polymorphonuclear leukocyte migration, decreases oxygen radical production, and inhibits lymphocyte function. Its long half-life (Table 36–1) permits once-daily dosing.
Piroxicam can be used for the usual rheumatic indications. When piroxicam is used in dosages higher than 20 mg/d, an increased incidence of peptic ulcer and bleeding (relative risk up to 9.5) is encountered (see common adverse effects above).
Sulindac is a sulfoxide prodrug. It is reversibly metabolized to the active sulfide metabolite and has enterohepatic cycling; this prolongs the duration of action to 12–16 hours.
In addition to its rheumatic disease indications, sulindac suppresses familial intestinal polyposis and it may inhibit the development of colon, breast, and prostate cancer in humans. Among the more severe adverse reactions, Stevens-Johnson epidermal necrolysis syndrome, thrombocytopenia, agranulocytosis, and nephrotic syndrome; all have been observed. It is sometimes associated with cholestatic liver damage.
Tolmetin is a nonselective COX inhibitor with a short half-life (1–2 hours) and is not often used. It is ineffective (for unknown reasons) in the treatment of gout.
Azapropazone, carprofen, meclofenamate, and tenoxicam are rarely used and are not reviewed here.
All NSAIDs, including aspirin, are about equally efficacious with a few exceptions—tolmetin seems not to be effective for gout, and aspirin is less effective than other NSAIDs (eg, indomethacin) for AS.
Thus, NSAIDs tend to be differentiated on the basis of toxicity and cost-effectiveness. For example, the GI and renal side effects of ketorolac limit its use. Some surveys suggest that indomethacin and tolmetin are the NSAIDs associated with the greatest toxicity, while salsalate, aspirin, and ibuprofen are least toxic. The selective COX-2 inhibitors were not included in these analyses.
For patients with renal insufficiency, nonacetylated salicylates may be best. Diclofenac and sulindac are associated with more liver function test abnormalities than other NSAIDs. The relatively expensive, selective COX-2 inhibitor celecoxib is probably safest for patients at high risk for GI bleeding but may have a higher risk of cardiovascular toxicity. Celecoxib or a nonselective NSAID plus omeprazole or misoprostol may be appropriate in patients at highest risk for GI bleeding; in this subpopulation of patients, they are cost-effective despite their high acquisition costs.
The choice of an NSAID thus requires a balance of efficacy, cost-effectiveness, safety, and numerous personal factors (eg, other drugs also being used, concurrent illness, compliance, medical insurance coverage), so that there is no best NSAID for all patients. There may, however, be one or two best NSAIDs for a specific person.
RA is a progressive immunologic disease that causes significant systemic effects, shortens life, and reduces mobility and quality of life. Interest has centered on finding treatments that might arrest—or at least slow—this progression by modifying the disease itself. The effects of disease-modifying therapies may take 2 weeks to 6 months to become clinically evident.