Nimesulide, a Balanced Drug for the Treatment of Osteoarthritis

Nimesulide, a balanced drug for the treatment of osteoarthritis

E.C. Huskisson

Edward C. Huskisson, MD, FRCP, Consul- ABSTRACT dins that are formed mainly by COX-1, tant Rheumatologist, King Edward VII World-wide experience with nimesulide give symptomatic benefit without erod- Hospital for Officers, London, UK. c o n fi rms that it is an effe c t ive anti- ing the gastric mucosa. Address for correspondence: 14A Milford inflammatory drug in the treatment of Nimesulide at therapeutic doses prefer- House, Queen Anne Street, London W1M osteoarthritis. A review of several stud - e n t i a l ly inhibits COX-2 in man, a n d 9FD, UK ies in this condition confirms that nime - this is linked to the lower incidence of Clin Exp Rheumatol 2001; 19 (Suppl. 22): sulide is at least as efficacious as other gastrointestinal side effects compared S21-S25. commonly used compounds. The safety with common re fe rence non-cox i b © Copyright CLINICAL AND profile of nimesulide, compared to ref - compounds. Various studies, many of EXPERIMENTAL RHEUMATOLOGY 2001. erence drugs such as naproxen, etodo - recent origin, confirm the general spar- lac and diclofenac, demonstrates supe - ing by nimesulide of ga s t ric pro s t a- Key words: Osteoarthritis, rior gastrointestinal tolerability. Nime - glandin fo rm ation (1). In add i t i o n , nimesulide, AEs, GI-related AEs. sulide is therefore a good choice for the nimesulide has other pro p e rties that long-term treatment of OA. m ay contri bute to the re l at ive ly low incidence of ga s t rointestinal side ef- Introduction fects. These include the weakly acidic O s t e o a rt h ritis (OA) is both common nat u r e of nimesulide, wh i ch pre s u m- and important. It affects 15% of the ably results in relatively little gastric world's population; it is costly and a and renal accumulation, so partially ex- major cause of disability in the elderly. plaining the tolerability of nimesulide OA has been a neglected disease, be- by these organs. Most NSAIDs are cause at one time it was thought to be c o n s i d e rably more acidic than nime- an inevitable part of the ageing process. sulide, and high concentrations can ac- Ap a rt from misleading patients with cumulate within the cells of the gastric this view, we told them that OA was mucosa/submucosa where the extracel- non-inflammatory, and denied them the lular pH is low but intracellular pH is benefits of nonsteroidal anti-inflamma- higher.The acidic drugs ionise inside t o ry drugs (NSAIDs). Th e re is go o d the cells and therefore tend to be re- evidence that NSAIDs are more effec- tained.The very weakly acidic nature tive than simple analgesics such as par- of nimesulide (pKa 6.5) probably dimi- acetamol, and they have actions other nishes this retention (2). than pain relief including the relief of This chapter reviews several studies in morning stiffness. In comparison with OA with the purpose of highlighting drugs that are only analgesic, patients the efficacy and relative safety of nime- ove r wh e l m i n g ly pre fer NSAIDs. Th e s u l i d e, p a rt i c u l a rly in the long-term p ro l o n ged use of NSAIDs in this treatment of arthritis. The percentages chronic disease means that their long- quoted in the text have been rounded to term safety is particularly important. 2 significant figures. As in rheumatoid art h ritis and other i n fl a m m at o ry art h ro p at h i e s , N S A I D s World-wide experience with are the mainstay of symptomatic treat- nimesulide ment in OA. They are effective, and There is now a very large world-wide many patients with OA simply cannot experience of using nimesulide to treat manage without them. The main prob- OA. Many studies with nimesulide in lem is tolerability, in particular by the different pathologies have shown good stomach. However, efficacy and gastric efficacy, at least comparable to other intolerability are not inextricably link- NSAIDs,and relatively good tolerabili- ed. Drugs that block mainly COX-2, ty part i c u l a rly in the ga s t ro i n t e s t i n a l thus inhibiting the formation of prosta- t ract. The present rev i ew of effi c a cy glandins at sites of inflammation but and tolerability deals with 11 studies of with little effect on gastric prostaglan- nimesulide in OA. In total, there were

S-21 Nimesulide in the treatment of osteoarthritis / E.C. Huskisson

24,785 patients, usually taking nime- Table I. Reduction (%) of measured symptoms at day 90. sulide 100 mg twice daily (bid), i n o p e n , c o n t ro l l e d, or post-marke t i n g Pain at Pain on Morning Functional rest movement stiffness score surveillance studies. Therapeutic results depend on the type Nimesulide 100 mg bid 70.1** 67.0** 62.9* 36.9* of pat i e n t s , their pat h o l ogy, and the duration of treatment. This is particu- Placebo 11.1 16.9 28.1 13.0 larly so in OA, where patients tend to *p < 0.05, ** p < 0.01, with respect to the corresponding placebo value. be older, to be receiving concomitant therapies, and to show particular gastric sensitivity to NSAIDs. nimesulide group and 3 patients (25%) As expected, there was a trend for more in the 200 mg group complained of adverse events with the increasing dose Dose-finding studies ga s t rointestinal disturbances, all of of nimesulide, but interestingly the in- Two studies (3, 4) were performed to wh i ch we re mild or moderat e. One cidence in the placebo and 100 mg bid determine the optimal dosage of nime- p l a c eb o - t re ated patient (8.3%) with- groups was similar (39% and 36%, re- sulide in OA patients. The fi rs t , by drew because of severe gastralgia dur- s p e c t ive ly). Gastrointestinal side ef- D reiser (3), c o m p a red two doses in ing the wash-out peri o d. To l e rab i l i t y fects were dose-dependent, again with patients suffering from OA of the hip. was rated as excellent or good in about the placebo and nimesulide 100 mg bid Two groups of 12 patients each were 90% of patients in each tre at m e n t groups showing a similar incidence. given nimesulide 100 mg or 200 mg group. Analgesia was noted 1.5 h after taking bid for the first week, followed by pla- The second dose-finding study was a nimesulide 100 or 200 mg, but not with cebo for a 7-day wash-out period, and Fre n ch mu l t i - c e n t re trial (4) of 392 50 mg or placebo. Nimesulide is then the other dose of nimesulide. Para- patients with OA of the knee. Patients known to have a fast onset of analgesia cetamol was allowed as rescue medica- we re ra n d o m ly divided into fo u r (5, 6). tion for pain relief. groups that we re tre ated twice daily The results of this dose-finding study Classical variables (spontaneous pain, with placebo (n = 100) or with nime- confirm previous data that the optimal Lequesne Functional Index, limitation sulide 50 mg (n = 97), 100 mg (n = 98) dose with the best risk/benefit ratio for of ab d u c t i o n , and paracetamol con- or 200 mg (n = 97). This study, which the treatment of OA is nimesulide 100 sumption) were used on days 0, 7, 14 lasted one month, assessed the optimal mg bid. and 21 to assess the efficacy of treat- treatment dose for OA in terms of the m e n t , while tolerability was deter- efficacy/safety ratio. Again, evaluated Comparison with placebo mined from side-effects collected by variables (on days 0,7, 14 and 28) were Di Perri's trial (7), a double-blind study direct and indirect questioning. A glob- pain intensity (visual analogue scale, versus placebo in 40 elderly patients al assessment of efficacy and tolerabili- VAS), the Lequesne Functional Index, with OA , eva l u ated the effi c a cy of ty by patients and physicians wa s and consumption of the rescue medica- nimesulide 100 mg bid.The patients requested every week. tion paracetamol (up to 3 g/day, and were aged 60 to 88 years, with a mean Th e re was a significant reduction of excluding the first 3 hours of day one). OA duration of 76 months. Two groups pain score s , and improved art i c u l a r E ffi c a cy and tolerability assessments of 20 patients each were randomly allo- f u n c t i o n , in the nimesulide-tre at e d were rated on a 4-point scale by pa- cated to placebo or nimesulide 100 mg groups with respect to placebo,but lim- tients and physicians. bid for 3 months. Efficacy variables, itation of abduction did not change sig- The VAS scores decreased significantly measured on days 0, 30, 60 and 90, n i fi c a n t ly during tre atment in any in all groups over time. Nimesulide was were pain at rest and on movement, group. Pa racetamol was taken by 10 better than placebo at day 7 in the 100 morning stiffness, and impairment of p atients in the nimesulide 100 mg and 200 mg groups, but the effect of 50 d a i ly activities. Lab o rat o ry ex a m i n a- group, by 9 in the 200 mg group and by mg bid was not statistically significant. tions were performed on the same days 15 patients during the wash-out period. From day 14 on, all nimesulide groups to measure routine haematological and In the third week of treatment there was showed a significant reduction of pain biochemical values. Nimesulide treat- a trend for less consumption of rescue compared to placebo. Paracetamol was ment significantly improved all param- m e d i c ation. Global effi c a cy was as- requested by 66% of patients receiving eters (Table I), as measured at day 90. sessed as good in 21%, 35% and 50% p l a c eb o , 57% of those given nime- To l e rability was eva l u ated by collec- of the groups given placeb o , n i m e- sulide 50 or 200 mg bid, and by 51% in tion of adve rse events. Th e re we re sulide 100 mg or nimesulide 200 mg, the 100 mg group. The overall physi- reports by 4 patients (20%) in the nime- re s p e c t ive ly. Nimesulide 100 mg bid cians' assessment of efficacy was excel- sulide group (2 heartburn, 1 nausea, 1 was the minimum effe c t ive dose fo r l e n t / good in 72% of patients give n dizziness) and 2 patients (10%) in the reducing pain and inflammation in OA nimesulide 100 or 200 mg bid, 59% in p l a c ebo group (1 heartbu rn , 1 dizzi- of the hip. the 50 mg group, and 42% with place- ness). All adve rse events we re mild. Two patients (16.7%) in the 100 mg bo. Laboratory tests did not reveal any ab-

S-22 Nimesulide in the treatment of osteoarthritis / E.C. Huskisson n o rmalities. This placeb o - c o n t ro l l e d nificantly in both groups. There were d i cl o fenac invo l ved 89 patients with study confirms the efficacy of nime- no significant differences in changes of OA of the hip or knee in a double-blind sulide in the treatment of OA, in this efficacy variables between the two ex- parallel-group trial. Patients were ran- case with elderly patients who often p e rimental gro u p s , but both pat i e n t s domised to receive nimesulide 100 mg s u ffer from concomitant pat h o l ogi e s and physicians gave a good/excellent bid (n = 44) or diclofenac 50 mg tid (n and receive several drugs. It is impor- assessment for nimesulide in 80% of = 45) for one month. Efficacy against tant that there is little interaction be- cases compared to 68% for etodolac. spontaneous pain, pain on passive tween nimesulide and other drugs (2). A dve rse events we re rep o rted by 39 movement, and functional impairment, patients given nimesulide, and by 34 in was equal in the two groups. Comparison with reference the etodolac gro u p , of wh i ch 59% Tolerability was investigated by labora- compounds (nimesulide) and 64% (etodolac) were tory tests (haematological, biochemical Nimesulide is effective and generally gastrointestinal. There was a significant and urine analysis) at the start and fin- safe in the management of OA when increase of SGPT, SGOT (n = 4) and - ish of tre at m e n t , by the phy s i c i a n s ' compared both to other NSAIDs and to GT (n = 2) with nimesulide, and of - overall assessment, and by endoscopy placebo. Several studies have been per- GT and bilirubin with etodolac (n = 4). at days 7 and 30. Lab o rat o ry tests formed with nimesulide against refer- These did not require withdrawal from showed an increase in serum transami- ence drugs, and below are comparisons the investigation. nases in one patient per group, and an with fl u r b i p ro fe n , e t o d o l a c, i n d o m e- C o m p a rat ive studies with dicl o fe n a c increase of alkaline phosphatase in 3 t h a c i n , d i cl o fenac (the best-selling have been performed by many groups. patients given diclofenac. Assessment NSAID in the world), and naproxen. A Chinese controlled trial (10) com- of tolerability by the physicians wa s A multi-centre Italian study (8) compared the efficacy and the tolerability excellent/good in 84% and 79% of the pared the efficacy and tolerability of of nimesulide and diclofenac in OA of nimesulide and diclofenac groups re- nimesulide versus flurbiprofen in 199 the knee. Nimesulide 100 mg bid was spectively. The incidence of gastroin- patients with rheumatic diseases treat- given to 60 patients, and diclofenac 50 testinal side effects was part i c u l a rly ed for 9-13 days. The medications in mg three times daily (tid) was given to high with diclofenac (68% versus 43% this case we re suppositories (nime- 63 patients for 3 weeks. Efficacy was with nimesulide). Endoscopies we re sulide 200 mg bid, n = 99; flurbiprofen evaluated on days 7 and 21 regarding normal in all patients at the start of 100 mg bid, n = 100). Typical variables pain (at rest, on active movement and treatment, but ulcers developed in one of pain (spontaneous and provo ke d ) on palpation), joint swelling and walk- patient given nimesulide (2.4%) and in were measured by a VAS, body temper- ing.Tolerability was determined from three given diclofenac (7.3%). ature was recorded, and haematological re c o rded adve rse eve n t s , l ab o rat o ry L o n g - t e rm therapy is needed in OA , and biochemical tests were performed. t e s t s , and ove rall assessment by pa- and more recently studies have exam- All va ri ables improved signifi c a n t ly tients and investigators. ined the effi c a cy and tolerability of with either treatment, and there was an Both treatments showed efficacy, but drugs over an extended period. An 'ac- ove rall go o d / excellent assessment by nimesulide was better than diclofenac tive control equivalence study' by the both patients and physicians in more (p < 0.01 at day 7; p < 0.05 at day 21). author (12) was performed with nime- than 80% of cases. Measurement of Nimesulide was clearly more effective sulide and diclofenac in 279 patients anti-inflammatory activity against leu- than dicl o fenac according to assess- with OA of the hip or knee. For 24 cocytosis, increased ESR and C-reac- ments by the investigators (good/excel- weeks 135 patients received nimesulide t ive pro t e i n , i n d i c ated a signifi c a n t lent, 95% for nimesulide versus 46% 100 mg bid, and 144 patients received s u p e ri o rity of nimesulide over fl u r- for dicl o fenac) and by the pat i e n t s 50 mg diclofenac tid. Primary efficacy biprofen. Nimesulide induced a signifi- (good/excellent, 85% versus 42%). measures were the patients' global eval- cantly faster antipyretic action, consis- The safety profile was again in favour uation of efficacy on the scale of excel- tent with its known fast onset of anal- of nimesulide, with significantly fewer lent, good, fair, poor or useless, and by gesia (5, 6). There were no withdrawals patients complaining of side effects in the Lequesne Functional Index. Sec- from the study, and relatively few ad- general (13% versus 29% for nimesu- o n d a ry cri t e ria included global pain verse events occurred (7% with nime- lide and diclofenac, respectively). Fur- measurement, morning stiffness, stiff- sulide and 9% with flurbiprofen). thermore, there were even fewer gas- ness after sitting, pain at night, and the In a 3-month German mu l t i - c e n t re trointestinal adverse events with nime- Doyle Articular Index. Adverse events study (9), nimesulide 100 mg bid was sulide than dicl o fenac (6.7% ve rs u s were recorded, and haematological and compared with etodolac 300 mg bid in 30% of total adverse events, p < 0.01). b i o chemical blood tests we re carri e d 199 patients with OA of the knee (n = Th e re we re few lab o rat o ry ch a n ge s out at the beginning, in the middle, and 1 0 0 , nimesulide; n = 99, e t o d o l a c ) . outside the normal ra n ge in either at the end of the study. Spontaneous pain and the Lequesne group,and none were of clinical impor- A complex statistical method (13) Functional Index, measured at baseline tance. found that the drugs were equally effi- and weeks 2, 4,8 and 12, improved sig- Another comparative study (11) with cacious, but gastrointestinal tolerability

S-23 Nimesulide in the treatment of osteoarthritis / E.C. Huskisson was better for nimesulide. Completion ity of nimesulide over 3 months. The effects are generally less frequent and by patients of long studies is often 132 OA patients took 100 mg nime- m i l d e r. The re l at ive ly good ga s t ro i n- poor, but surprisingly 65% and 69% in sulide granules twice daily, and were testinal safety of nimesulide is consis- the nimesulide and diclofenac groups assessed for pain and side effe c t s . tent with studies on human gastric mu- completed the 24 weeks. This is consis- Haematological and biochemical anal- cosa that show at most a weak inhibi- tent with good long-term efficacy and yses were made at the start and finish tion of pro s t aglandin synthesis (1). t o l e rab i l i t y. The ove rall incidence of of the study, and the inve s t i gat o rs Nimesulide has been given to ab o u t adverse events was similar in the two assessed tolerability at the end of the 200 million patients, so that its safety groups: 65% of patients given nime- s t u dy. VAS values indicated a pain and tolerability are well known. In s u l i d e, and 68% given dicl o fe n a c, reduction of 54% during the observa- a ddition to pre fe rential inhibition of reported one or more adverse events. tion period, and the physicians judged COX-2,nimesulide has a range of other However, more patients in the diclo- the treatment as excellent/good in 77% p h a rm a c o l ogical effe c t s , i n cl u d i n g fenac group had adverse gastrointesti- of cases. The gastrointestinal, skin and inhibition of various mediators of in- nal events (47% versus 36% with nime- n e rvous system adve rse events that fl a m m ation and cart i l age degra d at i o n sulide, p < 0.05), and they were more occurred in 33% of patients were most- (2). It seems likely, but not yet proven, likely to be worse (moderate or severe) ly (80%) mild or moderate. Results of that at least some of these non-prosta- with dicl o fe n a c. The inve s t i gat o rs ' laboratory analyses were normal. glandin actions contribute to the clini- global evaluation of tolerability using Po s t - m a rketing surveillance gives a cal effectiveness of nimesulide. the same scale as for efficacy showed ' p ractical' eva l u ation of effi c a cy and References more patients with excellent tolerance t o l e rability in a more heteroge n e o u s 1. S H A H A A , M U R R AY FE, FITZGERALD DJ: to nimesulide (37% versus 24%). No p o p u l ation. In ch ronic OA , 2 2 , 9 3 8 The in vivo assessment of nimesulide cyclo- serious haematological or biochemical patients (16) took nimesulide tablets or oxygenase-2 selectivity. Rheumatology 1999; abnormalities occurred in either treat- granules 100 or 200 mg bid for up to 38 (Suppl. 1): 19-23. 2. BENNETT A , VILLA G: N i m e s u l i d e : A n ment group. Of particular intere s t , t h ree weeks. Effi c a cy was rated as NSAID that pre fe re n t i a l ly inhibits COX - 2 , there was a substantial fall in serum good or excellent in 76%, and the side and has various unique pharmacological ac- uric acid in the nimesulide group (p < effects that occurred in 9.4% were gen- tivities. Exp Opinion Pharmacother 2000; 1: 277-86. 0.01), but not in those given diclofenac. erally mild and rarely required a de- 3. DREISER RL: Nimesulide in the treatment of Nimesulide might therefore be useful crease in dosage or withdrawal from o s t e o a rt h ritis of the hip: A dose-fi n d i n g for tre ating gout. A z ap ro p a zone has treatment (3.5% drop-out). study. Helsinn, Internal Report, 1991. 4. BOURGEOIS P, DREISER RL, LEQUESNE MG this same effect on serum uric acid and Nimesulide was also used by 135 asth- et al. : M u l t i - c e n t re doubl e - blind study to is currently considered by many to be m atic patients (0.6%) in the lat t e r d e fine the most favo u rable dose of Nime- the most useful anti-inflammatory drug study, and only one complained of dys- sulide in terms of efficacy/safety ratio in the in gout. pnea. This is consistent with the well- treatment of osteoarthritis. Eur J Rheum In - flam 1994; 14: 39-50. A one-year active control equivalence e s t ablished ge n e ral safety of nime- 5. RAGOT PJ, MONTI T, MACCIOCCHI A: Con- s t u dy (14) compared nimesulide and sulide in patients with respiratory dis- t rolled clinical inve s t i gation of acute anal- naproxen in 370 patients with OA of e a s e s , i n cluding many of those wh o gesic activity of nimesulide in pain after oral the hip or knee who re c e ived either d evelop asthma with other NSAIDs surgery. Drugs 1993; 46: 162-7. 6. P U L K K I N E N M O: E ffect of nimesulide on nimesulide 100 mg bid (n = 183), or (17, 18). intrautine pressure and menstrual pain in dys- naproxen 250 mg in the morning and A meta-analysis performed by Wober m e n o rrheic women. D rugs Exp Clin Res 500 mg at night (n = 187). The primary (19), which included some of the stud- 1984; X (8-9): 599-606. 7. BLARDI P, GATTI F,AUTERI A, DI PERRI T: endpoint was pain on the WOMAC OA ies discussed ab ove, c o n fi rmed that Effectiveness and tolerability of Nimesulide index after six months. Other measures nimesulide 100 mg bid for 2 weeks is at in the treatment of osteoarthritic elderly pa- i n cluded the Lequesne Functional least as efficacious as other NSAIDs tients. Int J Tiss Reac 1992; 14: 263-8. Index, global assessment, paracetamol (piroxicam, ketoprofen, naproxen, eto- 8. R E N Z I G, DELLA MARCHINA M: N i m e s u- lide:Comparative, multi-centre, double-blind consumption, and adverse events. The dolac and diclofenac) in treating OA. evaluation versus Flurbiprofen concerning its two drugs were similar in efficacy, and Furthermore, nimesulide was shown to therapeutic potential in rectal form in osteo- tolerability was relatively good particu- have a superior benefit-risk ratio since articular diseases. Helsinn, Internal Report (TSD 5438), 1989. l a rly considering the patients' age it is generally about equal to placebo in 9. LÜCKER PW, PAWLOWSKI C, FRIEDERICH I (mean 64 ± 8.5 years), but again gas- s a fety and tolerab i l i t y, e s p e c i a l ly re- et al.: Double-blind, randomised, multi-cen- t rointestinal side effects we re some- garding gastrointestinal adverse events. tre clinical study evaluating the efficacy and what less with nimesulide. tolerability of Nimesulide in comparison with Etodolac in patients suffering from osteoarth- Open studies have examined the effect Conclusions ritis of the knee. Eur J Rheum Inflam 14 (2), of nimesulide in 'real life' rather than in Nimesulide 100 mg bid is at least as 29-38, 1994. the somewhat structured conditions of e ffe c t ive as other NSAIDs such as 10. GUI-XIN Q, MACCIOCCHI A: Trial on the efficacy and tolerability of Nimesulide versus controlled trials. A French open study diclofenac and naproxen in OA, but is Diclofenac in the treatment of osteoarthritis (15) assessed the efficacy and tolerabil- better tolerated by the stomach and side of the knee. Helsinn, Internal Report, 1997.

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11. PORTO, REIS C, PERDIGOTO R et al.: Gas- mesulide (tablets) in patients suffering from E ffi c a cy and tolerability of nimesulide in troduodenal tolerability of nimesulide and di- osteoarthritis of the knee or of the hip. Hel- asthmatic patients intolerant to aspirin. Drugs clofenac in patients with osteoathritis. Curr sinn, Internal Report, 2000. 1993; 46: 115-120. Ther Res 1998; 59; 654-65. 15. FAMAEY JP,VANDEKERCKHOVE K, GÉCZY 18. BRUSASCO V, CRIMI E, SCARICABAROZZI I: 12. H U S K I S S O N E C , M ACCIOCCHI A , R A H L F S J, BRUHWYLER J: A large, open-label trial of Nimesulide does not interfe re with airway VW et al.: Nimesulide versus diclofenac in nimesulide in patients with osteoart i c u l a r re s p o n s iveness in allergic asthma. D ru g s the treatment of osteoarthritis of the hip or conditions treated in a general practice set- 1993; 46: 121-3. knee:An active controlled equivalence study. ting. Curr Ther Res 1998; 59: 467-82. 19. WOBER W: Comparative efficacy and safety Curr Ther Res 1999; 60; 253-65. 16. POCHOBRADSKY MG, MELE G, BERETTA A, of nimesulide and diclofenac in patients with 13. WEI LJ, LACHIN JM: Two-sample asympto- MONTAGNANI G:Post-marketing survey of acute shoulder, and a meta-analysis of con- tically distribution-free tests for incomplete Nimesulide in the short - t e rm tre atment of trolled studies with nimesulide. Rheumatolo - multivariate observations. J Am Stat Assoc osteoarthritis. Drugs Exptl Clin Res 1991; 17: gy 1999; 38: 33-8. 1984; 79: 653-61. 197-204. 14. SEILER K-U: Efficacy and tolerability of ni- 17. BIANCO S,ROBUSCHI M, PETRIGNI G et al.:

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