Nimesulide for Painful Osteoarthritis

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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.

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 period of 3 months [32]. In this hepatic impairment. multicenter study, both the beneficial and unwanted effects of the two drugs were generally Efficacy & safety in osteoarthritis comparable, although overall judgements of the Data from the most relevant studies in which the efficacy by both the physicians and the patients effects of nimesulide have been compared with were in favor of nimesulide. those of active comparator drugs in patients with A meta-analysis of 6 trials with OA patients OA will now be reviewed. was carried out to evaluate the efficacy and safety A multicentric dose-finding study was carried of nimesulide in comparison with placebo and out in 329 patients with OA divided into four other NSAIDs (diclofenac, naproxen, piroxicam, groups, who received nimesulide 50, 100 or ketoprofen and etodolac). Results showed that 200 mg twice daily or placebo, for 1 month [27]. the efficacy of nimesulide was superior to pla- This study showed a dose–effect relationship for cebo and at least comparable to that of the other nimesulide and supported the view that the opti- NSAIDs, with a trend of better tolerability [33]. mal dose of nimesulide for efficacy is 100 mg Based on the evidence that nimesulide is an twice daily. effective NSAID and could be considered as a Huskisson and colleagues compared drug of choice for the symptomatic treatment of nimesulide with diclofenac in an active control OA, a prospective, randomized, double-blind equivalence study during a 24-week period [28]. study has been performed to specifically com- A total of 279 patients with OA of the hip or pare the analgesic efficacy of nimesulide, knee received either nimesulide 100 mg celecoxib and rofecoxib in 30 patients with knee twice daily or diclofenac 50 mg three-times OA, over a period of 3 weeks [34]. daily. Global efficacy and the Lequesne Func- Using this design, each drug was tested against tional index were the primary efficacy meas- all the others and was administered equally ures. At the end of the treatment period, either as first, second or third in the sequence to nimesulide proved to be at least as effective as the same number of patients. Enrolled patients diclofenac, but with a statistically significant were randomly assigned to treatment with single superiority for GI tolerability. oral doses of nimesulide 100 mg, celecoxib By evaluating pain and functional parameters, 200 mg or rofecoxib 25 mg. Each drug was Porto and colleagues found nimesulide 100 mg given daily for 7 days. As patients with OA have twice daily and diclofenac 50 mg three-times pain that typically increases with activity and is daily for 1 month equally effective in a parallel particularly evident after a period of inactivity, group study in 89 patients with OA of the hip or special attention was devoted to the onset of the knee [29]. At the end of the study period, the action on pain connected with movement after endoscopic evaluation proved normal in the the drug administration in the morning. The majority of patients, although three patients in main efficacy criterion was pain intensity assess- the diclofenac group developed ulcers, compared ment by using the visual analog scale (VAS) with only one in the nimesulide group. measured on a scale of 0–100 mm. In addition, Kriegel and colleagues compared nimesulide at the end of each week of treatment patients (100 mg twice daily) with naproxen (250 mg in answered questions about analgesic efficacy on a the morning and 500 mg at night) in a double- five-point categorial scale: none, mild, moderate, blind study lasting 1 year [30]. While efficacy was good and very good. At the end of the study, rated similarly as good/excellent by investigators each patient was asked about which of the three for both drugs (59.3% for nimesulide and forms of treatment he or she would opt for as a 56.4% for naproxen), patients treated with continuation of the therapy. nimesulide showed a lower incidence of GI Although all the drugs induced a reduction in adverse events. pain intensity, the analgesic efficacy of Similar results were obtained by Quattrini and nimesulide was clearly superior to that of the Paladin, in a study comparing nimesulide other two NSAIDs. In addition, it is particularly 100 mg twice daily with naproxen 500 mg worth underlining that the analgesic action of twice daily, where both drugs demonstrated nimesulide was more rapid than that exerted by equal effectiveness after 4 weeks of treatment [31]. the other drugs tested. In fact, only the patients www.futuremedicine.com 535 DRUG EVALUATION – Bianchi

treated with nimesulide recorded mean VAS val- Regulatory affairs ues measured 15 and 30 min after drug intake, Nimesulide is available as tablets, granules which differed significantly from those measured (sachets), suppositories, oral suspension, drops in basal conditions. and topical gel. Original nimesulide is marketed This observation appears to be of particular worldwide in more than 50 countries, mainly in importance if we consider that a rapid decrease Europe, Central and Latin America and Asia, in pain intensity will make a considerable diffe- with the following authorized tradenames: rence in the ability of patients with OA to carry Ainex®, Aulin®, Donulide®, Eskaflam®, Heu- out their normal everyday activities. gan®, Mesulid®, Nexen®, Nimed®, Nimedex®, The percentage of patients who reported good Nisulid®, Scaflam® and Scaflan®. or very good analgesic efficacy were 53.4% in the According to the last Summary of Product nimesulide group, 46.7% in the celecoxib group, Characteristics (2003), nimesulide is approved and 50.0% in the rofecoxib group. The percentage for use in the treatment of acute pain, in the of patients who reported good or excellent tolera- symptomatic treatment of painful osteoarthritis bility were 76.7% in the nimesulide-treated group, and in primary dysmenorrhoea. 70.0% in the celecoxib-treated group and 76.7% As for other NSAIDs, the use of nimesulide is in the group of patients treated with rofecoxib. recommended for the shortest time needed to In conclusion, this personal experience with solve the symptoms of inflammation. nimesulide in patients with knee OA has proved the suitability of this drug in this clinical set- Conclusion ting, where a fast onset of analgesic activity is OA is the most common form of arthritis. Typ- also desirable. ical symptoms of OA are pain and functional Further details on the efficacy and tolerability limitation. Treatment of symptomatic OA is of nimesulide in clinical trials may be found in a focused on controlling the pain and improving comprehensive monograph published recently the patient quality of life. There is abundant (see: Information resources). evidence that anti-inflammatory drugs are more effective than simple analgesics; this is Postmarketing surveillance not surprising since there is also considerable A postmarketing survey was carried out in Italy in evidence for the role inflammation plays in 22,938 patients to assess the efficacy and OA. Indeed, very often, the joints of patients tolerability of nimesulide in the short-term treat- affected by OA show cardinal signs of inflam- ment of OA [35]. The treatment period ranged mation like warmth and swelling. There is a from 1 to 3 weeks. At the end of the study, physi- very large experience of the use of the NSAID cian’s overall evaluation indicated that 76% of nimesulide in OA from around the world. A patients showed good/optimal response to the considerable number of studies clearly show treatment. Patients’ evaluations were similarly pos- that nimesulide in its convenient dosing sched- itive: 69% of patients evaluated their condition as ule of 100 mg twice daily is at least as effective good/excellent. as other NSAIDs with which it has been Adverse reactions (ARs), presumably related directly compared. A comprehensive analysis of to nimesulide, occurred in 8% of patients; dys- these data suggest that nimesulide represents an pepsia, pyrosis and nausea accounted for approx- effective agent for the treatment of OA pain, imately 90% of events, and no serious with particular reference to the rapid onset of complications such as peptic ulceration and/or its analgesic effect. This aspect is of particular gastrointestinal bleeding were observed. importance if one considers that a rapid The safety profile of the drug is constantly decrease in pain intensity will contribute assessed through an accurate postmarketing sur- importantly to the ability of patients with OA veillance (PMS), critically followed up at to carry out their normal everyday activities. In Helsinn Healthcare (Switzerland). From 1985 addition, the good tolerability profile, with to June 2006, over 480 million patients have special regard to gastrointestinal effects, may been treated with nimesulide worldwide; the offer a significant advantage over other features of the events recorded by the PMS, NSAIDs. It is clear, however, that even with a together with the evidence from clinical studies, well-tolerated drug like nimesulide, caution is suggest that the benefit/risk profile of required to ensure the safety of patients who are nimesulide remained favorable and unchanged more vulnerable, such as the elderly and those over time. with hepatic impairment.

536 Future Rheumatol. (2006) 1(5) Nimesulide – DRUG EVALUATION

Future perspective Information resources Two main objectives of the pharmacological Relevant further reading management of OA are the resolution or the Rainsford KD: Nimesulide. Actions and Uses. relief of pain, and the prevention of the progres- Birkhäuser Verlag, Basel, CH, Switzerland (2005). sion of the disease by reducing the degradation • Comprehensive monograph on nimesulide of joint cartilage. NSAIDs are very useful in the recently published. treatment of symptomatic OA. Nimesulide proved to be more rapid and effective in provid- Relevant websites ing symptomatic relief than did some COX-2 • Nimesulide Information selective inhibitors [27,34,36]. www.nimesulide.net However, NSAIDs are considered as lacking a • The arthritis foundation structure-modifying effect. This means that they www.arthritis.org can reduce pain and functional limitation, but • Bone and Joint decade online not the progression of joint deterioration. www.boneandjointdecade.org Recent data demonstrate that nimesulide has a favorable effect on the metabolism of joint carti- • The European League Against Rheumatism www.eular.org lage that is unrelated to COX-inhibition [37,38], suggesting that this drug may also positively • National Institute of Arthritis and affect the natural course of OA. Further studies Musculoloskeletal and skin diseases are needed to clarify the possible differences www.nih.gov/niams among the various NSAIDs with reference to • American College of Rheumatology this particular action. www.rheumatology.org

Executive summary Mechanism of action • Nimesulide prevents the generation of prostaglandins by inhibiting cyclooxygenase (COX) enzymes, with preferential action on COX-2. • Moreover, it inhibits the production, release or activity of a number of mediators of inflammatory pain. • Recent data suggest that nimesulide may positively affect the metabolism of joint cartilage. Pharmacokinetic properties • Following oral administration, nimesulide (50–200 mg) is rapidly and extensively absorbed. Mean maximum plasma concentration

(Cmax) values ranging 1.98–9.85 mg/l are achieved within 1.67–3.17 h (tmax ) from drug intake (tablets); similar Cmax values, but lower tmax are reached with granule formulation. • The half-life in plasma is approximately 2–5 h for the parent drug and 3–9 h for its main metabolite, thus enabling convenient twice-daily dosage. • Metabolism involves the liver cytochrome P450 (CYP) system. The drug is metabolized by CYP2C9 and CYP2C19 (and possibly CYP1A2), principally to the 4-hydroxy-metabolite (M1). This metabolite has similar pharmacological properties to the parent drug, although with lower efficacy. • Excretion in the urine and feces accounts for approximately 70% and 20% of the administered dose, respectively. • Age, gender or moderate renal impairment do not influence the elimination pattern of the drug. • The use of nimesulide is contraindicated in patients with hepatic impairment. Clinical efficacy & safety • Nimesulide has been directly compared with the most widely used drugs for the treatment of painful osteoarthritis (OA). • The most convenient dosing schedule is 100 mg twice daily. • Nimesulide proved to be a valid alternative to other nonsteroidal anti-inflammatory drugs (NSAIDs) with a similar or even superior analgesic efficacy characterized by a fast onset of action. • Nimesulide demonstrated a good safety profile in OA patients, at least comparable to that of the most used NSAIDs, with evidence of a better gastrointestinal tolerability. Drug interaction • No interactions of clinical relevance between nimesulide and many other drugs have been observed; the concomitant administration of nimesulide and warfarin as well as other NSAIDs is not recommended. Dosage & administration • Nimesulide is available in tablets, granules (sachets), suppositories, oral suspension, drops and topical gel. • Recommended dosing schedule (adults and children >12 years old) for tablets/granules: 100 mg twice daily. • Recommended dosing schedule for suppositories: 200 mg twice daily. • The presence of food does not influence either the rate or extent of nimesulide absorption. www.futuremedicine.com 537 DRUG EVALUATION – Bianchi

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