Comparative Efficacy and Tolerability of Two Sustained-Release Formulations of Diclofenac

By Wagenitz, Andreas Mueller, Edgar A; Frentzel, Adrian; Cambon, Nathalie

Key words: Analgesia – Diclofenac – Non-inferiority analysis – NSAID – Osteoarthritis – Sustained-release ABSTRACT

Objective: To compare the analgesic efficacy and tolerability of a sustained-release pellet formulation of diclofenac (Olfen-100 SR Depocaps, SR-CAP, Mepha Ltd, Aesch, Switzerland) with the standard reference formulation (Voltaren retard 100, SR-TAB, Novartis Pharma AG, Basel, Switzerland), both containing 100 mg diclofenac sodium, in patients with osteoarthritis (OA) of the knee and/or hip. In addition, diclofenac’s current place in the symptomatic therapy ol OA is briefly reviewed.

Methods: In this 2-week double-blind, active-controlled, non- inferiority trial, 210 OA patients were randomised to receive either SR-CAP once daily or SR-TAB once daily (n = 105 for both groups). The primary efficacy endpoint was the change in visual analogue scale (VAS) pain score (0-100 mm) at rest at Day 14 compared with baseline. Secondary variables included the change in VAS pain score on movement and global assessments of efficacy and tolerability using verbal rating scales (VRS).

Results: Between baseline and Day 14, mean +- SD VAS pain score at rest decreased by 44.4 +- 18.5 mm in the SR-CAP group (n = 89) compared with 41.2 +- 19.8 mm in the SR-TAB group (n= 82) based on the per protocol population. Comparable changes were observed in the intention-to-treat population. The lower bound of the 1-sided 97.5% confidence interval was -2.7 mm and greater than the prespecified non-inferiority limit of -10 mm. There was a trend towards a better tolerability with SR-CAP compared with SR-TAB based on mean +- SD VRS scores (SR-CAP, 0.6 +- 0.68; SR-TAB, 0.9 +- 1.0 for assessment by patients; p = 0.063).

Conclusion: SR-CAP is as effective as and possibly better tolerated than SR-TAB in patients suffering from painful OA.

Introduction

Osteoarthritis (OA) is the most prevalent disease of the locomotory apparatus with an associated risk of mobility disability, especially in the elderly. OA can occur in any synovial joint but is most common in the hands, knees and hips1. There is no cure and current therapeutic strategies are primarily aimed at reducing pain and improving joint function. Non-steroidal anti-inflammatory drugs (NSAIDs] are among the most widely prescribed medications in the world and are frequently taken by patients with OA. NSAIDs primarily act on the cyclo-oxygenase (Cox) enzyme that converts arachidonic acid into prostaglandins. Amongst other functions, prostaglandins mediate inflammation and pain. Two principal forms of the Cox enzyme have been described; Cox I and Cox II2. Cox I is normally present in platelets, vascular endothelial cells, the stomach and the kidney whereas Cox II is usually produced in response to inflammatory stimuli2. However, Cox II can also be found in brain and kidney in the absence of inflammation3. Research results indicated that the gastrointestinal (GI) adverse events associated with the use of NSAIDs are caused by Cox I inhibition and the desired anti- inflammatory action is mediated via the inhibition of Cox II3. This led to the development of selective Cox II inhibitors (coxibs). However, they have been associated with an increased risk for cardiovascular complications and a class effect has been suggested4. Since the withdrawals of rofecoxib and valdecoxib, the benefit/risk ratio of the remaining coxibs is still under debate3,5.

Current guidelines recommend the use of a simple analgesic, paracetamol (acetaminophen), or a NSAID given either systemically or topically as first-line or second-line therapies in patients with symptomatic OA6-8. Less than 10 NSAIDs are used on a regular basis with diclofenac being the most frequently administered NSAID worldwide9. Diclofenac is regarded as one of the better tolerated NSAIDs10 and has been available for many years in various formulations for the treatment of acute and chronic rheumatic disorders. Daily dosages ranging between 75 mg and 150 mg proved to be both efficacious and well tolerated in the symptomatic treatment of OA, with a maximum effect usually reached within 2 weeks11-14. Due to its short half-life of 1-2 h, sustained release formulations of diclofenac have been developed to allow for less frequent treatment schedules and possibly improving compliance.

Olfen-100 SR Depocaps, Mepha Ltd, Aesch, Switzerland (SR-CAP) is a sustained-release pellet formulation containing 100 mg diclofenac sodium. A preceding unpublished multiple dose relative bioavailability study in 24 healthy male and female volunteers showed that SR-CAP delivers bioequivalent diclofenac exposure (in terms of area under the curve [AUC]) to the reference drug, Voltaren retard 100, Novartis Pharma AG, Basel, Switzerland (SR-TAB). The latter is a sustained release tablet (dragee) also containing 100 mg diclofenac sodium. The bioavailability study followed an open, randomized, crossover design and each preparation was administered once daily for 4 days. Blood samples for determination of diclofenac in plasma were collected over 24 h following morning drug intake (fasting conditions) on Day 4. The rate of diclofenac absorption was lower with SR-CAP compared to SR-TAB as reflected by an approximately 30% lower mean maximum plasma concentration (C^sub max^).

Against this background the present study was performed. We compared the efficacy and tolerability of SR-CAP (test) with that of SR-TAB (reference) in patients with painful osteoarthritis of the knee and/or hip. The main objective of the study was to demonstrate clinical non-inferiority of the analgesic effect of SR-CAP when compared with SR-TAB, thereby supporting the assumption that a lowered C^sub max^ has no impact on the efficacy of the drug.

Moreover, a reappraisal of diclofenac’s place in the symptomatic therapy of OA is provided in the light of new warnings concerning coxibs in patients with increased risk of cardiovascular thrombotic events.

Patients and methods

The study was carried out at 10 centres (general practice) in Germany as a randomised, active-controlled, double-blind clinical trial with two parallel treatments in adult male and female patients. The first patient was enrolled in June 2005 after approval of the study protocol had been obtained from independent ethics committees, and the study was completed in December 2005. All patients had given their informed consent before enrolment. The study was performed in accordance with the Declaration of Helsinki with all its amendments taking into account the principles of Good Clinical Practice (GCP). Each patient was assigned in chronological order to one of two treatment groups using a computer generated block randomisation list (allocation ratio 1:1).

Outpatients, aged 18-75 years, were eligible for enrolment if they had a confirmed diagnosis of primary OA of the knee and/or hip, based upon clinical and diagnostic radiographic (Kellgren & Lawrence Index grade II or III15) criteria. A diagnosis according to the American College of Rheumatology (ACR) was required and the patient had to be in functional class I, II or III16. Patients had to suffer from OA symptoms for at least 3 months and, in the judgement of the investigator, would need analgesic treatment for at least the duration of the study. Moreover, patients were required to present a pain intensity at rest of >/= 50 mm on a horizontal 100 mm visual analogue scale (VAS; 0 mm = no pain, 100 mm = unbearable pain).

Pregnant women and women of child-bearing potential not using effective means of contraception were excluded, as well as patients with blood coagulation/haematological disorders and patients who had known allergies to diclofenac or to ingredients of the study medication. In addition, patients with acute OA requiring additional treatment and/or arthroplastic surgery during the course of the study did not qualify for enrolment. Likewise, patients were not eligible for inclusion if they had received intra-articular corticosteroid or hyaluronic acid injections within 3 months prior to the study, underwent treatment with systemic corticosteroids or anticoagulants within 4 weeks before the trial, had a history or presence of gastroduodenal ulcer or GI bleeding, or presented with severe cardiac, hepatic, or renal disorders as well as any other concomitant severe or chronic disease. Patients with inducible porphyria or presenting with osteonecrosis/aseptic necrosis were also excluded. The use of NSAIDs (including coxibs) or any other analgesic treatment (except paracetamol for rescue) was not allowed within 3-7 days before study start, depending on the half-life of the drug. Physiotherapy was not permitted during the wash-out and treatment period. During the study, patients were instructed not to take any other NSAIDs (except study medication), anticoagulants, analgesics, corticosteroids (> 5 mg/day of prednisone), other antiarthritic drugs, immunosuppressives and drugs interacting with diclofenac. Low dose aspirin was permitted.

Eligible patients were randomly allocated to receive either oral SR-CAP or SR-TAB, containing 100 mg of diclofenac sodium each. The study medication was ingested by the patients once daily in the morning for 14 days. Both SR-CAP and SR-TAB were to be taken with 150 mL of water in close relation to a meal. The percentage of unused study medication assessed at the end of treatment served as a measure of compliance (at least 80% of the scheduled study medication was to be taken to be compliant). Patients received their study drug at baseline (Visit 1). They had to return to the study site for efficacy and safety assessments at Day 7 (Visit 2) and Day 14 (Visit 3); a deviation of +- 2 days was permitted. Study medication (Olfen-100 SR Depocaps and Voltaren retard 100) was supplied by Mepha Ltd., Aesch, Switzerland. An independent statistician produced the randomisation list for this clinical trial and the study medication was packaged according to this randomisation list by an independent contract research organisation (CRO). Nobody else had access to the randomisation list until the database was closed. For blinding purposes, both medications were filled in identical-looking capsules and backfilled with lactose. Thus, test and reference preparations were visually indistinguishable.

Demographic characteristics, medical and drug history as well as classification of OA disease were assessed before study enrolment at the baseline examination. Patients also underwent a complete physical examination. For patients requiring a wash-out period, an additional screening visit took place within 3-7 days before baseline; at that time paracetamol rescue medication was dispensed. Vital signs were determined at all study visits. Routine haematological (erythrocyte sedimentation rate, haemoglobin, haematocrit, red blood cells, white blood cells and differential platelets) and biochemical (sodium, potassium, calcium, alanine aminotransferase [ALAT], aspartate aminotransferase [ASAT], gamma glutamyl transpeptidase [gamma-GT], alkaline phosphatase, cholesterol, glucose, uric acid, creatinine, total protein, albumin) laboratory measurements were performed before (screening or baseline) and after the study (at Visit 3). The thromboplastin time was additionally determined at baseline. All female patients of childbearing potential had a urine pregnancy test before and after the study.

Patients assessed their pain intensity at the target joint (hip or knee) both at rest and on movement at all three study visits (considering the last 24 h) using the 100 mm VAS. The primary efficacy endpoint was the change in VAS pain score at rest at Visit 3 (Day 14) compared with baseline. Secondary efficacy endpoints included the change in VAS pain score at rest at Visit 2 (Day 7) compared with baseline, the change in VAS pain score on movement at Visits 2 and 3 compared with baseline and a global efficacy assessment by patients and investigators using a 5-point verbal rating scale (VRS) (much better, better, unchanged, worse, much worse) at Visit 3.

Safety and tolerability was evaluated on the basis of adverse events and changes in laboratory parameters. In addition, patients and investigators assessed the tolerability of the study medication using a 5-point VRS (very good, good, moderate, poor, very poor) at the end of the study.

Statistical analysis

Efficacy analyses were performed for the intention-to-treat (ITT) and per protocol (PP) populations. The ITT population included all randomised patients who received at least one dose of study medication and for whom at least one efficacy assessment was performed. The PP population included all patients of the ITT population without major protocol violations, the definition of which had been prospectively defined in die statistical analysis plan before database lock. Safety was analyzed for the safety population, defined as all patients who received at least one dose of study medication.

The primary efficacy analysis (change in VAS pain score for the target knee or hip at rest between Visits 1 and 3) was based on the PP population. The robustness of these results was tested by comparison with ITT analysis results. The primary analysis (non- inferiority analysis) was an analysis of covariance (ANCOVA) including treatment and study centre as terms and the baseline VAS score (at rest) as covariate. A 1-sided 97.5% confidence interval (CI) was calculated for the between-group difference in VAS score changes (test minus reference) using least square means. Clinical non-inferiority of SR-CAP compared with SR-TAB was accepted if the lower bound of this CI was greater than -10 mm. For secondary efficacy variables on VAS, 1-sided 97.5% CIs were calculated for the differences between treatments. For statistical analysis of VRS results, ratings were allocated to figures between 0 and 4 (0 = best, 4 = worst). VRS scores were analysed according to the analysis of variance (ANOVA) procedure with treatment and study centre as factors. Safety parameters were evaluated descriptively.

The clinically relevant non-inferiority margin (delta) for the primary efficacy variable was defined as 10 mm on the VAS pain scale (0-100 mm). Such a non-inferiority margin has been previously applied for these types of studies17-19. Standard deviations (SD) for VAS assessments between 18 mm and 27 mm have been reported17,20,21. A sample size of 100 patients per group was determined to conclude non-inferiority of SR-CAP to SR-TAB based on the following assumptions: delta = 10 mm, SD = 23 mm, level of significance alpha = 2.5% (1-sided t-test), power (1-beta) = 80%, dropout/non-valid patient rate = 15%.

Table 1. Demographic and clinical characteristics of patients at baseline (ITT population)

Results

In total, 210 patients (105 per treatment group) were randomised to treatment groups. Twenty-five patients (10 SR-CAP, 15 SR-TAB) discontinued the study prematurely. Of these, 20 discontinued for adverse events (8 SR-CAP, 12 SR-TAB); a further 2 patients (1 per group) were withdrawn because of serious adverse events. Other reasons were unsatisfactory therapeutic response (n = 1) and protocol violation (n = 1), both in the SR-TAB group. One SR-CAP patient withdrew consent; this subject never took study medication and was, therefore, excluded from the ITT population. Hence, the ITT population comprised a total of 209 patients (104 SR-CAP, 105 SR- TAB).

For the definition of the PP population, the 25 patients discontinuing the study prematurely were excluded. A further 14 patients were excluded because of pain intensity at rest of < 50 mm on VAS at time of randomisation (n = 3), no return of study medication rendering judgement of compliance impossible (n = 3), intake of study medication > 16 days (n = 3), documented non- compliance (n = 2), missing pain assessment at Visit 3 (n = 1) or intake of disallowed concomitant medication (n = 2). Therefore, the PP population consisted of 171 patients (89 SR-CAP, 82 SR-TAB). The ITT population and the population analysed for safety were identical in this clinical trial.

Demographic and clinical characteristics were well balanced between treatment groups and typical for the population investigated. This applies to both the ITT population (Table 1) and the PP population (data not shown). The majority of patients (88.5%) had multiple joints affected by OA, whereas OA localized to specific joints (hip or knee) was reported in 17.7% of patients. Moreover, medical and surgical history was comparable between treatment groups, and there was no difference in baseline VAS scores.

Analgesic efficacy

Both SR-CAP and SR-TAB markedly reduced pain at rest without notable differences between groups at any time during the treatment period (Figure 1). The mean VAS pain scores at rest assessed during the study and the mean changes from baseline are summarised in Table 2, for both the ITT and PP population. Between baseline and Day 14, mean VAS pain score at rest decreased by 44.4mm in the SR-CAP group compared with 41.2 mm in the SR-TAB group based on the PP data set. The lower bound of the 97.5% CI for the between-group difference was -2.7mm and thus greater than the prespecified non-inferiority limit of -10 mm. The results for the ITT population were supportive for claiming non-inferiority of SR-CAP to SR-TAB. For the ITT population, mean VAS pain score at rest decreased between baseline and Day 14 by 43.7mm in the SR-CAP group compared with 36.6mm in the SR-TAB group with a lower bound of the 97.5% CI for the between- group difference of 1.5 mm (indicating possible superiority of SR- CAP in this particular analysis).

Table 2 and Figure 1 also show the reduction in VAS pain scores at rest between baseline and Day 7 (Visit 2). For both, the ITT and PP population, the lower limits of the 97.5% CI for the between- group differences were again greater than -10 mm.

The mean VAS pain scores on movement and the mean changes from baseline are summarised in Table 3 (ITT and PP populations). Both diclofenac formulations, SR-CAP and SR-TAB, markedly reduced pain on movement without notable differences between groups at any time during the treatment period. All analyses yielded lower limits of the 97.5% CI for between-group differences greater than -10mm.

In the investigator’s overall assessment of efficacy at the end of the study, a comparable proportion of patients in both treatment groups were recorded with ‘much better’ or ‘better’ with regard to their current OA status (SR-CAP, 91.0%; SR-TAB, 89.0%). The patient’s assessment of efficacy revealed almost identical results (SR-CAP, 92.1%; SR-TAB, 86.6%). In each group there was one patient who judged his/her OA status as ‘worse’. These assessments are reflected by mean +- SD VRS scores which showed no statistically significant difference (based on ANOVA) between treatment groups for both the investigator’s rating (SR-CAP, 0.6 +- 0.6; SR-TAB, 0.7 +- 0.7) and patient’s rating (SR-CAP, 0.7 +- 0.6; SR-TAB, 0.8 +- 0.7).

Table 2. Pain visual analogue scale (VAS) score* at rest in patients treated with SR-CAP and SR-TAB (PP and (PP and ITT population) Figure 1. Visual analogue scale (VAS) pain scores at rest (mean +- standard deviation) at baseline and during treatment with SR-CAP (n = 89) and SR-TAB (n = 82); per protocol population

Table 3. Pain visual analogue scale (VAS) score* on movement in patients treated with SR-CAP and SR-TAB (PP and ITT population)

Tolerability

Overall, both treatments were well tolerated, with a numerically lower proportion of patients reporting at least one adverse event in the SR-CAP group (30.8%) than in the SR-TAB group (39.0%). Most of the adverse events were considered drug-related and of mild to moderate severity; all patients recovered without sequelae. The most frequently reported adverse events were related to the GI tract (primarily diarrhoea, abdominal pain and nausea), occurring in 25.0% and 32.4% of patients in the SR-CAP and SR-TAB group, respectively (Table 4). Non-GI adverse events occurred in a similar frequency in both groups. One patient in each group experienced a serious adverse event. Both subjects had signs of bleeding in the GI tract (bloody stool and black stool) which resolved upon discontinuation of the study medication. Overall, 20 patients discontinued the study for adverse events (8, SR-CAP, 12, SR-TAB). Except for one case of hypertension, these adverse events were all related to the GI tract (primarily diarrhoea and abdominal pain).

The overall tolerability was assessed as ‘very good’ or ‘good’ by 85.4% of the patients in the SR-CAP group compared with 78.1% in die SR-TAB group (Table 4). The investigator’s assessment of tolerability yielded similar results, whereas tolerability was reported to be ‘poor’ in 1 (1.1%) SR-CAP patient compared with 8 (9.8%) patients in the SR-TAB group. The mean VRS scores for tolerability were lower for the SR-CAP group. Although this difference did not achieve significance, a statistical trend was apparent (p = 0.063 and p = 0.090 for assessment by patients and investigators, respectively).

No clinically relevant changes in vital signs were noted during the study. Likewise, haematological and biochemical variables revealed no statistical or clinically meaningful differences between treatment groups during the course of the study. Two patients in the SR-TAB group had increased liver transaminases which were reported as adverse events.

Discussion

This randomised, active-controlled, double-blind clinical trial was designed to compare the analgesic efficacy and tolerability of two sustained-release 100 mg formulations of diclofenac, SR-CAP (test) and SR-TAB (reference). The results demonstrate non- inferiority of the analgesic effect of SR-CAP when compared with SR- TAB in OA patients. Moreover, SR-CAP shows a trend towards better tolerability than SR-TAB.

Table 4. Number (%) of patients with adverse events during treatment with SR-CAP and SR-TAB, irrespective of cause (safety population)*, and global tolerability assessments by investigators and patients (PP population)

In a preceding multiple dose relative bioavailability study in healthy volunteers, it was shown that SR-CAP is bioequivalent to SR- TAB (in terms of AUC) but diclofenac C^sub max^ was approximately 30% lower. A post-hoc analysis of that study investigated the time above minimum effective diclofenac plasma concentrations of 50-100 ng/mL previously suggested22,23. There was no statistical difference between SR-CAP and SR-TAB widi respect to tiiat parameter indicating the potential for equal analgesic efficacy of both formulations (unpublished data). The present study confirms the assumption that the lowered C^sub max^ of diclofenac has no impact on the efficacy of SR-CAP by demonstrating non-inferiority to the reference drug in a population for whom diclofenac use is very common. In fact, there was a rapid reduction in VAS pain scores at rest (primary efficacy variable) in both per protocol treatment groups, indicating a rapid analgesic effect of both diclofenac preparations. Analyses of secondary efficacy parameters (VAS pain scores on movement and VRS scores) consistendy supported non-inferiority of SR-CAP to SR-TAB. Moreover, the robustness of study results was demonstrated by results from ITT analyses, which were in good agreement with those assessed in the PP population. The reductions in VAS pain scores observed in the present study are in line witii previous investigations on the efficacy of diclofenac in OA patients using the same daily diclofenac dose and a similar trial design20,24. In the study performed by Goei The and colleagues24, the reduction in VAS pain scores on movement at 2-3 weeks was less pronounced compared to our study, which can be explained by the lower mean baseline VAS score on movement of 59.7mm compared to approximately 70mm in this trial.

The use of NSAIDs is traditionally associated with several adverse events, particularly those involving the GI tract. This was also seen in our study, in which most adverse events were GI- related. Overall, both diclofenac formulations were well tolerated with only two serious adverse events reported. It is noteworthy that there were numerically fewer adverse events with SR-CAP than with SR- TAB. Furthermore, the global tolerability assessments showed that patients and physicians had similar perceptions of the tolerability of both formulations, but better VRS scores were obtained with SR- CAP. This was supported by statistical analysis results showing a trend towards a better tolerability with SR-CAP compared to SR-TAB based on VRS scores. The latter observation may be related to the fewer GI adverse events seen in the SR-CAP treatment group. The lower diclofenac C^sub max^ could be the underlying reason for the better GI tolerability with SR-CAP. Although local irritation by orally administered diclofenac allows back diffusion of acid into the gastric mucosa and induces tissue damage, parenteral administration also can cause gastric damage25. Hence, lower maximum diclofenac plasma concentrations might be beneficial to patients in terms of GI tolerability.

Our study has a potential limitation in the fact that placebo control is lacking. However, since numerous previous studies have shown that NSAIDs (including diclofenac) are more effective than placebo in the symptomatic short-term treatment of OA patients, the inclusion of a placebo arm was not considered necessary or ethical26,27.

Place of diclofenac in therapy

For decades, NSAIDs have been frequently taken by patients with symptomatic OA. Many studies and meta-analyses thereof demonstrated the efficacy of oral NSAIDs in the management of pain associated with that disorder26,27. NSAIDs effectively relieve pain by about half and increase mobility in about 60% of subjects with OA as demonstrated by a meta-analysis of two Cochrane reviews28. However, the use of NSAIDs can cause GI toxicity which is dose dependent as evidenced by several systematic reviews8. The identification of Cox II and the subsequent introduction of the selective Cox II inhibitors (coxibs) were thought to be a major breakthrough with the expectation of an analgesic efficacy similar to NSAIDs but a reduction in GI side-effects. In fact, two systematic reviews concluded a significant reduction of GI toxicity with coxibs whilst there was no evidence that coxibs are more effective than traditional NSAIDs29,30. There is, however, a major concern over potential cardiovascular complications (e.g., myocardial infarction or stroke) with the use of coxibs. In 2005, the scientific committee of the European Medicinal Products for Human Use (EMEA) decided to impose restrictions on the use of coxibs. They should no longer be used in patients who have established ischemic heart disease and/or cerebrovascular disease, or in patients with peripheral artery disease. Furthermore, healthcare professionals should exercise caution when prescribing such drugs to patients with risk factors for heart disease. Meanwhile, rofecoxib and valdecoxib have been withdrawn from the market; for the remaining coxibs the benefit/ risk ratio is still under debate3,5.

In view of the safety concerns with coxibs, traditional NSAIDs experienced a renewed interest and strategies were explored for their use in patients at risk for NSAID-related GI complications. A number of strategies have been used to minimise the GI risk due to NSAIDs. Several systematic reviews provided evidence to support the co-administration of NSAIDs with gastroprotective agents such as misoprostol, H^sub 2^ blockers or proton pump inhibitors (PPIs)8. Cost-effective analyses indicated that the addition of a PPI to a conventional NSAID is the most cost-effective option in patients at risk for GI toxicity or cardiovascular event, and hence it was proposed that this strategy is preferable to the use of a coxib31. Recently, a moderate increase in the risk of serious vascular events was suggested also for certain traditional NSAIDs32. Another analysis of a large data set (74 838 users of NSAIDs) found no additional cardiovascular risk from NSAID use33. So far, no placebo- controlled randomised trial has studied the risk of cardiovascular events for NSAIDs.

There is insufficient information to rank the pain-relieving efficacy of different NSAIDs in the treatment of OA34, but it was suggested that diclofenac (100-150 mg) and naproxen (500-750 mg) are more effective than low doses of ibuprofen, and more effective than paracetamol28. In terms of safety, diclofenac is regarded as one of the better tolerated NSAIDs as far as GI toxicity is concerned10. In one meta-analysis, high-dose diclofenac has been associated with a moderately increased risk of thrombotic cardiovascular events32 but this could not be confirmed by others, and, in contrast to coxibs, has never been substantiated by placebo-controlled randomised trials33.

Current treatment guidelines recommend the use of paracetamol or a NSAID as first-line or second-line therapies in patients with symptomatic OA6-8. Two surveys in which patients with OA were asked to rate medications based on their previous experiences provided similar results. The majority of patients preferred NSAIDs to paracetamol because of their better efficacy35-37. Out of the NSAIDs, diclofenac is currently the most widely prescribed NSAID in the world9. Despite the recent debate concerning its potential cardiovascular toxicity, diclofenac has still to be considered as one of the most important drugs in the treatment of painful OA. It should be prescribed at the lowest effective dose for the minimum requisite period of time. Long-term use, if needed, requires regular safety monitoring, especially for blood pressure. Like other NSAIDs, diclofenac should be combined with a gastroprotective agent in patients at high-risk for GI adverse events. Available data support its use, alone or in combination witii a gastroprotective agent, rather than of a coxib; an assessment which is shared by others3,37,38. Conclusion

The results of this study demonstrate the clinical noninferiority of SR-CAP compared with SR-TAB in reducing pain in patients suffering from painful OA of the knee and/or hip. Moreover, SR-CAP shows a trend towards better tolerability than SR-TAB in this patient population. Diclofenac is still one of the most important drugs allowing osteoarthritic patients to live with an acceptable quality of life.

Acknowledgements

Declaration of Interest: Mepha Ltd, Aesch, Switzerland provided the study medication and funded the study. Drs. A. Frentzel and N. Cambon are employees of Mepha Ltd.

We would like to acknowledge the collaboration and commitment of the local investigators and their staff (all located in Germany): Dr. Andreas Wagenitz, Berlin; Dr. Gert Voss, Berlin; Dr. Thomas Burghardt, Munchen; Dr. Volkmar Herkt, Dresden; Dr. Johannes Hettwer, Bad Hersfeld; Dr. Axel Hoist, Hamburg; Dr. Axel Kaden, Hamburg; Dr. Georg Kovacs, Frankfurt; Dr. Jurgen Roch, Dresden; Dr. Dieter Veith, Emmendingen.

* Clinical trial registration number: 2005-000799-42

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CrossRef links are available in the online published version of this paper: http ://www. cmrojournal.com

Paper CMRO-3997_2, Accepted for publication: 20 June 2007

Published Online: 12 July 2007

doi: 1 0. 1 1 85/030079907X223251

Andreas Wagenitz(a), Edgar A. Mueller(b), Adrian Frentzel(c) and Nathalie Cambon(c)

a Clinical practice for orthopaedics, Berlin, Germany

b Institute for Clinical Pharmacology, Medical Faculty, Technical University, Dresden, Germany

c Medical Department, Mepha Ltd, Aesch, Switzerland

Address for correspondence: Dr. Andreas Wagenitz, Praxis fur Orthopadie, Leonorenstr. 96-98, 12247 Berlin, Germany. Tel.: +49 307 744 342; fax: +49 307 732 7127; e-mail: dr.andreas@wagenitz- berlin.de

Copyright Librapharm Aug 2007

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