In general, pain is first treated with the nonopioid anal-gesics. These drugs are useful for treatment of pain, fever, and inflammation and for reduction of platelet aggregation. Although the NSAIDs are less effective than the opioids in providing pain relief, they do not produce tolerance and physical dependence, as do the opioids. The mechanism of action of traditional NSAIDs involves blockade of the production of prostaglandins by inhibition of the enzyme cyclooxygenase (COX) at the site of injury in the periphery, thus decreasing the forma-tion of mediators of pain in the peripheral nervous sys-tem. COX was originally thought to be a single enzyme that was responsible for the conversion of arachidonic acid to a variety of prostanoids. The prostanoids pro-duced by COX activity include those that are involved in inflammatory responses in tissue leading to detri-mental effects and those that are critical to the mainte-nance of the gastric mucosal lining and certain renal functions. Thus, inhibition of COX by the NSAIDs may be accompanied by ulceration of the stomach lining and renal damage. In 1991 it was discovered that the COX system consisted of two enzymes, COX-1 and COX-2. COX-1 appears to remain constitutively active and is the site of action of the NSAIDs used prior to the early 1990s. However, COX-2 is not constitutively active and is induced by traumatic tissue injury, although some ev-idence of low levels of COX-2 constitutive activity ex-ists for certain regions, such as the brain. The discovery of COX-2 led to the hypothesis that the major thera-peutic benefit of the COX inhibitors was due to the block of inducible COX-2, while the major problematic side effects of the NSAIDs were due to COX-1 inhibi-tion. Although this hypothesis has undergone several it-erations, it does appear that the COX-2 inhibitors can at the very least be described as gut sparing. The original NSAIDs appear to be nonselective for COX-1 and COX-2. Development of novel COX-2 inhibitors has led to the discovery of a class of NSAIDs largely devoid of the gastrointestinal (GI) and renal problems associ-ated with the older NSAIDs. Although the COX-2 drugs are no more efficacious than the older nonselec-tive COX inhibitors, the decrease in side effect profile has provided a new mechanism of long-term antiinflam-matory treatment.
Aspirin is one of the most important NSAIDs be-cause it decreases pain at predominantly peripheral sites with little cortical interaction and thus has few CNS effects. The prototypical COX-2 inhibitors are celecoxib (Celebrex) and its chemical cousin, rofecoxib (Vioxx). In addition to a role in inflammatory processes, COX-2 seems to play a role in colon cancer and Alzheimer’s disease, providing potential additional uses for COX-2-selective drugs.