Nimesulide: Pain relief beyond COX-inhibition
Sulfonanilide compound acts rapidly on various pathways
The sulfonanilide compound nimesulide is a nonsteroidal antiinflammatory drug (NSAID) that acts on various pathways to produce rapid relief of mild to moderate pain.
As an agent for the treatment of pain, the compound is notable for its wide range of activity (Magni, 1993), which includes action on both cyclooxygenase-dependent (COX-dependent) and non-COX-dependent mechanisms, making it more than simply another COX-inhibitor (coxib).
The COX-dependent mechanisms acted upon by the drug are mainly COX-2-selective (Tavares et al., 1995; Famaey, 1997); through these mechanisms, nimesulide inhibits the production of prostaglandins. This is the primary mechanism by which other coxibs such as celecoxib relieve pain. The predominantly COX-2-selective action of nimesulide results in a lower incidence of gastric complications compared with other NSAIDs, and produces a sparing effect on renal function. Unlike other coxibs, however, nimesulide has not been associated with cardiovascular events (European Medicine Agency's Committee on Medical Products for Human Use, 2005).
Apart from being an effective analgesic, nimesulide also operates as a potent antiinflammatory agent by inhibiting the synthesis and release of leukotrienes in eosinophils and neutrophils, respectively (Tool et al., 1996), and the release of histamine by basophils and tissue mast cells (Berti et al., 1990; Berti et al., 1995; Casolaro et al. 1994; Genovese et al., 1992; Marino et al., 1992). The drug also activates glucocorticoid receptors, a mechanism similar to the action of steroids in regulating inflammation.
 |
Working through other, non-COX-dependent mechanisms, nimesulide prevents tissue damage that results from the excessive production of oxygen radicals in the "respiratory burst" seen with the activation of polymorphonuclear leukocytes (PMNs) in inflammatory states. The increased metabolic activity of PMNs increases their oxygen consumption; oxygen radicals are by-products of this metabolism. While the molecules play an important part in the immune function of PMNs, an excess of free radicals is also damaging to native tissue, and has been postulated to be part of the pathogenesis of various disorders such as rheumatoid arthritis (Southorn and Powis, 1988). Nimesulide inhibits the release of superoxide anions by activated PMNs without affecting their chemotactic and phagocytic properties (Bevilacqua et al., 1988; Capecchi et al., 1993; Capsoni et al., 1997). Furthermore, the drug scavenges hydroxyl radicals and hypochlorus acid that contribute to oxidative damage to tissues (Roos, 1991; Weiss, 1989).
An additional benefit provided by nimesulide is inhibition of metalloprotease (Pellatier and Martel-Pellatier, 1993). Metalloprotease has been implicated in the degradation of cartilage matrix attending inflammation, and this inhibition results in reduced damage to affected joint tissue, a consideration in choosing an agent for relieving pain in patients with inflammatory joint diseases.
This broad range of activity results in effective analgesic, antiinflammatory. and antipyretic effects.
Nimesulide is rapidly absorbed through the gastrointestinal tract, and absorption is only minimally affected by food intake. Peak serum concentrations of the drug are achieved within one to two hours after oral administration. The drug distributes mostly into extracellular spaces, and is able to penetrate synovial tissue (Ligniere et al., 1990), where antiinflammatory activity is commonly needed by patients. These aspects of the pharmacokinetic profile allow the drug to produce pain relief that is faster-acting than other coxibs such as celecoxib and methodolac, yet with comparable efficacy.
The drug has an outstanding safety profile. As previously mentioned, use of the drug has been associated with a low incidence of gastrointestinal (GI) complications, a common problem encountered with the use of other NSAIDs and analgesics. An early postmarketing study found that the most common adverse events noted were mild GI disturbances (epigastric pain, heartburn, nausea, diarrhea, vomiting), skin reactions (rash, pruritus), and central- nervous-system (CNS) effects (dizziness, somnolence, headache). Despite a large study population (22,938 patients), no anaphylactoid reactions or severe gastrointestinal complications such as ulceration and/or bleeding were observed (Pochobradsky et al., 1991; Davis and Brogden, 1994; Rabasseda, 1996, 1997).
After the withdrawal of rofecoxib in 2004, the European Medicine Agency's Committee on Medicinal Products for Human Use assessed and reevaluated all available data, including clinical trials and epidemiological data, pertaining to the cardiovascular safety of NSAIDs, and found that no changes needed to be made to the recommendations for the use of nimesulide. The drug has not been associated with the increased cardiovascular risk seen with rofecoxib.
The drug is safe for use by elderly patients, and requires no adjustment in dose for patients under 80 years of age with normal to moderately impaired renal function (Olive and Rey, 1993), though it should be avoided in patients with moderate to severe hepatic insufficiency (Olive, 1993). Nimesulide is indicated for the treatment of acute, postoperative, and traumatic pain, and the symptomatic treatment of painful osteoarthritis and dysmenorrhea.
Nimesulide is marketed under the brand name Aulin by Schering Plough.
M
|
