NSAID's

Nonsteroidal antiinflammatory agents are used for chronic pain mangement in arthritic and inflammatory conditions, and as adjuvants in cancer pain mangement. Unlike narcotics, these agents do have a ceiling effect to their analgesic potency. Higher dose ranges increases the incidence of side effects without major increases in pain relief. There are now a plethora of agents on the market, with claims of better pain control. However, controlled studies have failed to demonstrate significant differences in analgesic efficacy among the variety of agents. Choice of agents therefore, is dependent upon interpatient variability, and the american college of rheumatology recommends a rotational trial of NSAID's if one's initial choice appears ineffective, before abandoning the therapy.

NSAID's act by inhibiting the production of nociceptive substances in the periphery, and may have central analgesic effects as well. The arachadonic acid cascade starts with the liberation of phospholipid from injured cell membranes. This is in turn converted by phospholipase to arachidonic acid, which can then be acted on by cyclooxygenase or lipoxygenase, and produce prostaglandins, prostacyclins, thromboxane, and leukotrienes. All the nonsteroidals inhibit cyclooxygenase, and some also inhibit lipooxygenase, thus arresting the production of these inflammatory mediators. The arachadonic acid cascade is illustrated below.

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Toxicity of these agents is one the major concerns with long term administration. Recently, one agent, bromfenac, was withdrawn from clinical use secondary to severe hepatotoxocity, resulting in liver failure and even death.

GI toxicity manifests in the form of peptic ulcer disease. By inhibiting prostaglandin synthesis, the protective role these agents play is removed. Unfortunately, clinically significant GI ulceration is often silent. Risk factors include age over 60, history of coexisting ulcer disease, and multiple nonsteroidal use.

Prostaglandin inhibition by NSAID's can result in decreased renal blood flow, but is clinically significant in those patients already at risk for renal dysfunction, such as the hypovolemic patient, the patient with coexisting renal insufficiency, and with congestive heart failure. Toradol is associated with a higher incidence of renal dysfunction, but this is primarily due to the fact that it is the only available parenteral NSAID, and is used quite commonly in the perioperative period in hypovolemic patients

Hematologic dysfunction manifests predominantly as transient impairment of platelet function. The exceptions are choline magnesium trisalicylate and salsalate. Aspirin inhibits platelet function for the life of the platelet, while the other NSAID's cause a transient inhibition.

Hepatic toxicity has been reported to occur in 3% of patients on NSAID's. The mechanism of action is not well defined, but it is recommended to determine LFT's for patients on long term therapy. As mentioned above, bromfenac was withdrawn from the market secondary to severe toxicity with long term use.

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