For reprint orders, please contact: DRUG EVALUATION [email protected] Nimesulide for painful osteoarthritis Mauro Bianchi Osteoarthritis is one of the most common joint disorders in the world. It is costly and a major University of Milan, School of cause of pain and disability, especially in the elderly. The severity of pain often calls for Medicine, Department of Pharmacology, Via Vanvitelli, treatment with nonsteroidal anti-inflammatory drugs. Worldwide experience with nimesulide 32, 20129 Milano, Italy shows that this nonsteroidal anti-inflammatory drug has a number of pharmacological Tel.: +39 025 031 6930; properties that may make it favorable in the treatment of joint diseases. In recent years, Fax: +39 025 031 6949; several controlled studies have been carried out in order to investigate its analgesic effects in [email protected] patients with OA. The objective of this article is to review some of the features of osteoarthritis and to identify the role of nimesulide as a drug particularly tailored for the treatment of painful osteoarthritis. Osteoarthritis (OA) is one of the most common Rheumatism (EULAR) [4] and the American Col- forms of musculoskeletal disorder encountered lege of Rheumatology (ACR) Recommendations worldwide, particularly in Western populations. [11]. However, the severity of pain often requires A recent WHO report on the global burden of treatment with nonsteroidal antiinflammatory disease indicates that OA is likely to become one drugs (NSAIDs), which are the drugs preferred by of the most important causes of disability in many patients with OA [12]. Indeed, NSAIDs are both women and men [1]. The prevalence of OA the drug most commonly used by many doctors increases with age, affecting a large proportion of for the management of pain in OA patients, in elderly people [2]. It affects over 50% of the popu- comparison to simple analgesics [12,13]. In clinical lation over 65 years of age and 80% of the popu- practice, OA should be regarded as a phasic disease lation over 75 years of age [3]. Annual arthoplasty and thus the short-term administration of NSAIDs rates in Europeans over the age of 65 years are during OA flares (episodic exacerbations of inflam- around 0.5–0.7 per 1000 [4], representing a mation and pain) is a good therapeutic option for significant cost to society. the majority of patients [3,13]. A number of The main characteristic of OA is a slowly NSAIDs are available for the treatment of OA. In developing degenerative breakdown of cartilage, recent years, the pharmacological management of with episodic inflammation of the synovium. OA was dominated by highly selective cyclooxyge- OA affects all structures within a joint; patho- nase (COX)-2 inhibitors, until some compounds logical changes also occur in the synovium, of this class were withdrawn due to concerns sur- bone, and many other joint structures [5]. Pain is rounding their cardiovascular tolerability profile the most prominent and disabling symptom in [14–16]. This event was followed by a renewed inter- patients with OA [6,7], and local inflammation in est for the agents already available in the market the synovium and the cartilage may significantly before the introduction of COX-2 inhibitors. contribute to its development and joint damage. To date, no drugs have shown a clear disease- Nimesulide modifying efficacy in OA [8]. Nutritional supple- Nimesulide is a NSAID indicated for the treatment ments, in particular glucosamine and chondroitin- of acute pain, the symptomatic treatment of pain- sulfate, are frequently used by patients. However, ful OA and primary dysmenorrhea. This review the therapeutic value of these compounds in the will focus on the role of nimesulide in the treat- treatment of painful OA is still controversial [9]. ment of painful OA. The treatments currently available to alleviate OA Keywords: nimesulide, symptoms are nonpharmacological (e.g., patient Chemistry & development nonsteroidal anti- education, aerobic and muscle-strengthening exer- Nimesulide is a nonacidic NSAID with a pKa of inflammatory drugs, osteoarthritis, pain cise, lifestyle changes and weight control) and phar- 6.5. Its chemical name (4-nitro-2-phenoxymetha- macological methods [3,10]. The latter are based on nesulfonanilide) was the basis for the generic the administration of pure analgesics such as para- name of the drug – nimesulide. The chemical cetamol, which is to be considered the first-line structure, related to the sulfonanilide class, is drug according to the European League against shown in Figure 1. 10.2217/17460816.1.5.533 © 2006 Future Medicine Ltd ISSN 1746-0816 Future Rheumatol. (2006) 1(5), 533–539 533 DRUG EVALUATION – Bianchi Figure 1. Nimesulide. The ability of nimesulide to affect so many mediators involved in the inflammatory process provided it with a rather unique role of multi- NHSO2CH3 acting drug in several inflammatory pain condi- O tions. In addition, the sparing of inhibition of the physiologically important COX-1 prosta- noids in the gastrointestinal (GI) tract has been NO2 shown to be related to the low incidence of seri- Nimesulide differs from other nonsteroidal ous GI adverse events associated with the use of anti-inflammatories in that its chemical structure this drug [20–23]. contains a sulfonanilide moiety as the acidic group. It is known as: methane-sulfonamide, Pharmacokinetics & metabolism N-(4-nitro-2-phenoxyphenyl)-, or The pharmacokinetic properties of nimesulide 2-phenoxyl-4-nitro-methanesulfonanilide, have been largely investigated [24,25]. The drug or 4-nitro-2-phenoxymethanesulfonanilide. has a fast rate of oral absorption and the presence of food did not reduce either the rate or extent of The discovery of this compound (originally nimesulide absorption. After administration of named R-805) arose from investigations per- 50–200 mg tablets to healthy volunteers, mean formed at Riker Laboratories Inc. (Northridge, maximum plasma concentration (Cmax) values CA, USA), later part of the 3M Company at St ranging 1.98–9.85 mg/l were achieved within Paul, MN, USA. The molecule was synthesized 1.67–3.17 h (tmax). Similar Cmax values were in early 1971. It is interesting to note that the observed for nimesulide 100–200 mg in granule synthesis of nimesulide slightly preceded the (sachets) or suspension formulation, whereas the first hypothesis suggested by Sir John Vane and tmax was shorter (1.22–2.08 h) for these formula- his colleagues on the mechanism of action of tions in comparison with tablets. After repeated aspirin and related drugs. In 1980, Helsinn oral administration of 100 mg tablets twice daily Healthcare (Switzerland), acquired the world- for 10 days, the mean Cmax and tmax at steady- wide licensing rights for nimesulide. The drug state were similar to those observed after a single was first marketed in Italy in 1985. dose. All oral formulations demonstrate high and equivalent bioavailability. Elimination is Pharmacodynamics progressive, with the half-life in plasma being As expected for a NSAID, the therapeutic 2–5 h for the parent drug and 3–9 h for its main effects of nimesulide are largely related to its metabolite (4-hydroxynimesulide, M1); this ability to reduce prostaglandin synthesis by inhib- allows for convenient twice-daily dosage without iting COX enzymes. With regard to this mecha- any evidence of accumulation with the nism of action, evidence exists indicating that recommended 100 mg dose. nimesulide may be defined as a preferential inhib- Like other NSAIDs, nimesulide is extensively itor of COX-2; indeed, at therapeutic concentra- bound to plasma proteins (albumin); the tions, nimesulide shows a five- to 50-fold unbound fraction in plasma is approximately selectivity for COX-2 over COX-1 [14–18]. Moreo- 1%. The drug is rapidly distributed into the syn- ver, nimesulide displays several pharmacodynamic ovial fluids and accumulates there at effective properties, which may explain the anti-inflamma- concentrations [26]. tory and analgesic effects of this drug [19]; these It is metabolized via liver cytochrome P450 properties include reduced generation of super- (CYP)2C9, 2C19 and possibly 1A2, principally oxide anions by stimulated polymorphonuclear to the 4-hydroxy-metabolite, which has leukocytes (PMN), inhibition of histamine pharmacological properties similar to those of release from mast cells and basophils, inhibi- the parent drug. All metabolites are then tion of phosphodiesterase (PDE) IV, inhibition excreted in the urine (∼70%) and feces (∼20%). of the production of platelet-activating factor No interactions of clinical relevance between (PAF), scavenging of hypochlorus acid, reduc- nimesulide and other drugs, such as glibencla- tion of the synthesis of matrix metalloproteases mide, cimetidine, antacids, furosemide, theo- (MMPs), reduction of apoptotic processes in phylline and digoxin, have been observed; chondrocytes and other connective tissue cells, however, as for other NSAIDs, the concomitant and reduction of the activity of nitric oxide administration of nimesulide and warfarin as synthases (NOS). well as other NSAIDs is not recommended. 534 Future Rheumatol. (2006) 1(5) Nimesulide – DRUG EVALUATION Age, gender or moderate renal impairment do The efficacy and tolerability of nimesulide not influence the elimination of the drug: dosage (200 mg/day) was also compared with those of adjustment is not necessary in these categories. etodolac (600 mg/day) in 199 patients with OA Nimesulide is contraindicated in patients with of the knee over a