A randomized, multicentric, comparative evaluation of aceclofenac–paracetamol combination with aceclofenac alone in Indian patients with osteoarthritis flare-up

10.1517/14656560902781931 © 2009 Informa UK Ltd ISSN 1465-6566 727All rights reserved: reproduction in whole or in part not permitted

Original Research

Arandomized,multicentric,comparativeevaluationofaceclofenac–paracetamolcombinationwithaceclofenacaloneinIndianpatientswithosteoarthritisflare-upAnil Pareek, Nitin Chandurkar†, VD Sharma, Mohan Desai, Seema Kini & Girish Bartakke†Medical Affairs and Clinical Research, Ipca Laboratories Ltd, 142 AB, Kandivli Industrial Estate, Kandivli (West), Mumbai 400067, India

Objective: To evaluate efficacy and safety of aceclofenac–paracetamol combination against aceclofenac alone in patients with osteoarthritis (OA) flare-up. Methods: This open, randomized, comparative, multicentric, 10-day study enrolled 199 patients (aceclofenac 100 mg + paracetamol 500 mg bid: 101; aceclofenac 100 mg, bid: 98) with painful OA flare-up. Primary efficacy parameters were pain intensity difference (PID), sum of PID (SPID), and peak PID over 4 h (0.5, 1, 2, 4 h) after first dose of study medication. Secondary efficacy measurements were mean pain intensity scores from day 1 to day 10, WOMAC scores, changes in baseline signs and symptoms, and patient’s and investigator’s overall efficacy assessment. Results: Both treat-ments showed significant improvement in their baseline values in all effi-cacy parameters. The combination was superior over monotherapy in terms of PID ( -0.54 vs -0.23, -1.23 vs -0.72, -1.73 vs -1.23 and -1.94 vs -1.43 at 0.5, 1, 2 and 4 h respectively), SPID ( -5.46 vs -3.63) and peak PID ( -2.08 vs -1.56; p < 0.05). At the end of therapy, both treatments were comparable (p > 0.05) with respect to average pain intensity from day 1 to day 10, changes in WOMAC scores and resolution of baseline signs and symptoms. The combi-nation was significantly superior to monotherapy with respect to the patients’ and investigators’ overall efficacy assessments (p = 0.035 and p = 0.009 respectively). Conclusion: The findings of this open-label, com-parative study in Indian patients demonstrates that aceclofenac–paracetamol combination is effective and well tolerated in relieving OA flare-up pain. The combination showed rapid pain relief compared with monotherapy which is desirable by such patients and, hence, this combination can play an important role in the management of acute painful OA flare-up.

Keywords: aceclofenac, aceclofenac–paracetamol, osteoarthritis flare-up, pain

Expert Opin. Pharmacother. (2009) 10(5):727-735

1. Introduction

Osteoarthritis (OA) is the major cause of medical disability. It is the most common form of joint diseases and is an important public health concern [1]. Osteoarthritis of the knee and hip are common in India [2]. Community survey data in rural and urban areas of India show the prevalence of osteoarthritis to be in the range of 17 – 60.6% [3]. OA rarely occurs before the age of 40, but by the age of 75 at

1. Introduction

2. Patients and method

3. Results

4. Discussion

5. Conclusion

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least 85% of the population has either clinical or radio-graphic evidence of osteoarthritis. Its prevalence after the age of 65 is about 60% in men and 70% in women [4]. The most common presenting symptom of OA is pain, often exacerbated by joint use and usually improving with rest [5].

OA flare-up is an acute exacerbation of OA symptoms. It may occur despite daily maintenance therapy with NSAIDs or cyclo-oxygenase (COX)-2-selective inhibitors. Although the cause is unknown, it may involve transient pathophysi-ological changes that are uncontrolled by the maintenance therapy [6]. Moreover, analgesic ceiling effect, at which effi-cacy plateaus despite increasing dose, and the risk of adverse events (e.g., gastrointestinal, cardiovascular, renal) can make increasing the NSAID dose inappropriate for the manage-ment of painful OA flare-up, especially in older patients who, for example, have 3 – 4% annual risk of gastrointesti-nal bleeding compared with about 1% risk for the general population [7]. In such cases, increasing the standard anti-inflammatory or routine analgesic drug may not be practical because of an increased risk of side effects. Hence, it may be appropriate to combine two analgesic agents with different mechanisms of action to target multiple components of pain pathway, thereby providing rapid relief [8].

Paracetamol has been recommended as the initial therapy for the treatment of pain in knee OA, primarily due to its low risk and cost [9,10], while NSAIDs are reserved for those patients who do not improve, who have severe symptoms or who have signs of joint inflammation [10-12].

Aceclofenac is effective in the treatment of painful inflam-matory diseases and has been used to treat > 75 million patients worldwide [13]. The inhibitory effects of aceclofenac on synovial levels of PGE2 have been confirmed in patients with acute knee pain and synovial effusions [14]. Controlled clinical trials have demonstrated that aceclofenac is effective and well tolerated in patients with OA, rheumatoid arthritis and ankylosing spondylitis [13-17].

Prolonged use of nonselective NSAIDs can lead to significant mortality and morbidity from gastrointestinal (GI) bleeding, ulceration and perforation, whereas paracetamol has a very low incidence of GI side effects [18]. Paracetamol acts pre-dominantly by inhibiting prostaglandin synthesis in the central nervous system and, to a lesser extent, through a peripheral action by blocking pain impulse generation [19,20]. The peak plasma concentration of paracetamol occurs in about 10 – 60 min after oral administration [21] and that of aceclofenac reaches approximately 1.25 – 3 h following ingestion [22]. The analgesic efficacy of aceclofenac 100 mg is more prolonged than that of paracetamol [23]. Addition of paracetamol to NSAIDS will increase its effects and decrease dose-dependent side effects. Combination of aceclofenac (with its peripheral effect) and paracetamol (with its central effect) will give better analgesic efficacy than individual drugs. These considerations led us to conduct a randomized comparative study to evaluate the clinical benefits of adding paracetamol to aceclofenac in the treatment of patients with osteoarthritis flare-up.

2. Patientsandmethod

2.1 StudydesignThis was a randomized, comparative, multicentric, open-label study, conducted at King George Medical University & GM & Associated Hospital, Lucknow, Seth GS Medical College & KEM Hospital, Mumbai; Topiwala National Medical College and BYL Nair Hospital, Mumbai; and BJ Medical College and Sassoon Hospital, Pune, India. The study pro-tocol was approved by the hospital ethics committee of each center. All the patients gave their written informed consent to participate in the study in accordance with the Declaration of Helsinki. The execution and monitoring of the study was conducted in accordance with the requirements of good clinical practice.

2.2 SubjectselectioncriteriaMale and female patients with OA in the age range of 40 – 70 years who were experiencing OA flare-up pain for the past 2 – 5 days were included in this study. Diagnosis of knee OA was made according to the Lequesne criteria (Lequesne score of 5 and above) [18,24]. A painful flare-up was defined as significant increase of pain (by at least a 2-point increase in the patient’s perceived pain on an 11-point numerical rating scale) during the previous 2 – 5 days, characterized by signs and symptoms suggestive of inflam-mation, morning stiffness and nocturnal pain interfering with sleep. Additional inclusion criteria were pain intensity of at least 4 on an 11-point numerical rating scale during physical activities for the past 24 h. All the eligible patients had a history of clinically confirmed symptomatic osteoarthritis for more than 3 months before study enrollment.

Exclusion criteria included previous failure with or discontinuation of aceclofenac or paracetamol therapy owing to an adverse event, history of hypersensitivity to any of the study medications or similar drugs from the same class, history of asthma, history or diagnosis of fibromyalgia, rheumatoid arthritis, ankylosing spondylitis, active gout, active pseudogout, anserine bursitis or other inflammatory arthritic disorder, drugs affecting platelet functions and coagulation, surgery involving the target joint within the past year, use of steroids within 4 weeks before study entry, ancillary physiotherapy or massages within 48 h of study entry, history of peptic ulcers, duodenal ulcers, gastro-intestinal bleeding or bleeding disorders, abnormal renal or liver functions, or any other significant medical illness. Pregnant and lactating women or females of childbearing potential not practicing contraception were not enrolled in this study.

2.3 TreatmentproceduresEnrolled patients who had received painkillers within 8 h of study entry had undergone a placebo washout for 24 – 48 h. Patients were then randomly assigned to either aceclofenac (100 mg)–paracetamol (500 mg) fixed dose

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combination b.i.d, or aceclofenac (100 mg) alone b.i.d for a maximum of 10 days.

2.4 EfficacycriteriaThe primary efficacy outcome measures included pain intensity difference (PID), sum of pain intensity difference (SPID/4) and peak pain intensity difference (peak PID) over 0 – 4 h after first dose of study medication.

The pain intensity was captured on an 11-point numerical rating scale (PI-NRS) ranging from 0 to 10, where a score of 0 represents ‘no pain’ and 10 represents ‘worst possible pain’. Pain intensity difference was calculated as a subtraction of pain intensity score of each time point from baseline. The sum of pain intensity difference (SPID/4) is sum of pain intensity differences relative to baseline over 4 h; and peak pain intensity difference is the maximum difference in peak pain intensity score from baseline recorded over 4 h.

The secondary efficacy variables included pain intensity scores on day 1 to day 10; symptoms of OA and flare-up and patients’ and investigators’ overall assessment of flare-up.

Symptoms of OA were measured using Western Ontario and McMaster (WOMAC) universities osteoarthritis index questionnaire (pain, joint stiffness, and physical function). Responses to the WOMAC questionnaire, based on a five-point scale where 0 = none, 1 = mild, 2 = moderate, 3 = severe and 4 = extreme, were evaluated on day 1 and at the final visit. Flare-up symptoms like morning stiffness, nocturnal pain and swelling/inflammation were also evalu-ated on day 1 and at the final visit. The patients’ and inves-tigators’ overall assessments of study medication were recorded at the final visit using a four-point scale (0 = poor, 1 = no change, 2 = good, 3 = excellent).

Patients were evaluated for pain intensity difference at 30 min, 1 h, 2 h, 4 h and 24 h after first dose of adminis-tration and then every 24 h for the next 10 days. Patients used daily pain diaries to record their pain intensity scores.

2.5 SafetycriteriaPatients who received at least one dose of the study medication were evaluable for the safety assessment. Safety evaluation was based on the adverse events reported during the study.

Table1.Demographyanddiseasecharacteristicsofpatientsatbaseline.

Parameters Aceclofenac(n=98) Aceclofenac–paracetamol(n=101) pvalue

Males (%) 32 (33) 22 (22) 0.085

Females (%) 66 (67) 79 (78)

Mean age (years)(range) 53.87 (40–70) 54.62 (40–70) 0.528

Mean weight (kg) ±SD 64.30 ± 10.77 61.88 ± 8.21 0.078

Mean height (cm) ± SD 157.68 ± 8.89 157.80 ± 7.91 0.922

Body mass index(Kg/m2) (mean ± SD) 25.89 ± 4.07 24.90 ± 3.29 0.061

Pulse rate (beats/min) ± SD 79.28 ± 6.16 80.19 ± 5.72 0.281

Body temperature (0F) (mean ± SD) 98.17 ± 0.73 98.31 ± 0.72 0.173

Respiration rate (breaths/min) (mean ± SD) 17.41 ± 3.78 17.57 ± 4.35 0.788

Systolic blood pressure (mmHg) (mean ± SD) 126.70 ± 9.96 125.74 ± 11.15 0.524

Diastolic blood pressure (mmHg) (mean ± SD) 82.26 ± 7.32 81.84 ± 7.36 0.685

Disease duration (months) (median) 12 12 0.867

Pain intensity (PI-NRS) (mean ± SD) 6.90 ± 1.16 6.98 ± 1.39 0.650

Lequesne Index 9.53 ± 2.27 9.13 ± 2.58 0.245

Pain intensity (frequency count)

Worst (%) 4 (4.8) 5 (4.9) 0.768

Severe (%) 58 (59.1) 55 (54.4) 0.501

Moderate (%) 36 (36.7) 41 (40.59) 0.576

WOMAC scores (mean ± SD) 36.02 ± 12.17 33.71 ± 11.51 0.171

Morning stiffness (%) 70 (71) 75 (74) 0.654

Nocturnal pain (%) 61 (62) 59 (58) 0.581

Swelling/inflammation (%) 51 (52) 52 (51) 0.937

PI-NRS: Pain intensity numerical rating scale.

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Figure1.Meanpainintensitydifferencesateachtimepoint.*p < 0.05.

Adverse events were categorized by the investigator as to their intensity as mild, moderate or severe and the relation-ship to the study drug as none, probably not, possible, probable or definite. At every visit during the entire study period, the reported adverse events, clinical state of the patients and details of concomitant medication, if any, were captured. An adverse event was defined as an unfavorable and unintended sign, including an abnormal laboratory finding, symptoms or disease temporarily associated with the use of study drugs. Patients were encouraged to report adverse events spontaneously or in response to a general nondirected questionnaire. The incidence of reported adverse events was summarized by treatment group and classified according to body systems.

Changes in the laboratory parameters were assessed by obtaining blood samples at the baseline and at the end of the therapy to perform routine hematology and biochemistry.

2.6 StatisticalplanThe baseline characteristics of the two treatment groups were described for the intent to treat (ITT) population. Descriptive statistics, including frequency counts for cate-gorical variables and measures of central tendency and dis-persion for continuous variables were calculated to summarize the data. The two treatment groups were compared at baseline for homogeneity using a t-test for continuous variables and the Chi-square test for categorical variables.

For the primary efficacy criteria, the differences between the two groups in SPID, PID and peak PID for 4 h after the first dose were analyzed using the student’s t-test in the ITT population. Comparison of change in PI-NRS score from baseline to day 1 to day 10 was done by an analysis of covariance model using baseline score as covariate. The WOMAC was analyzed for the three subscales and for the total score by an analysis of covariance model using baseline score as covariate. Efficacy analyses were based on the ITT population, which included all randomized patients who

received at least one dose of study medication and had post-randomization efficacy data. If a patient dropped out of the study, a last observation carried forward approach was used to impute missing assessments.

Safety evaluation was done for all randomized patients who took at least one dose of study medication. No significant laboratory changes were observed between both the treat-ment groups. All statistical tests were conducted at a two-sided 5% significance level. Statistical analyses was performed using MINITAB 14.

3. Results

Between September 2007 and July 2008, 199 patients were randomized to receive either aceclofenac–paracetamol (n = 101) or aceclofenac alone (n = 98) and were followed for 10 days.

Out of 199 patients, 196 patients completed the study. Two patients from the aceclofenac group and one patient from the aceclofenac–paracetamol group were lost to follow-up. Both the treatment groups were comparable with respect to demography and baseline disease characteristics (Table 1).

This study enrolled 54 males (27.13%) and, predominantly, 145 females (72.86%), with age ranging from 40 to 70 years with an average age of 54.25 ± 8.31 years and average weight 63.07 ± 9.61 kg. Patients in both the treatment groups had OA for about 2.5 years. The mean PI-NRS scores at baseline were 6.93 ± 1.27 and mean WOMAC score was 34.84 ± 11.86 in the study population.

3.1 Primaryoutcome3.1.1 Pain intensity difference from baseline to all subsequent time points over 4 hFigure 1 shows the difference in pain intensity relative to baseline as calculated from the PI-NRS scores at each time point for up to 4 h. The fall in pain intensity was signifi-cantly better in combination compared with monotherapy at 0.5 (p = 0.008), 1 (p = 0.002), 2 (p = 0.012), and 4 (p = 0.028) h after the first dose administration.

3.1.2 Sum of pain intensity differences over 4 h between the treatments (SPID/4)The overall pain intensity reduction was assessed by sum-ming all the differences relative to baseline at all the time points. Aceclofenac–paracetamol was significantly more effective than aceclofenac at reducing the overall pain intensity (p = 0.005) (Figure 2).

3.1.3 Peak pain intensity difference over the 4 h time periodThe maximum change in pain intensity (over the 4-h period) recorded for each patient varied significantly between the treatment groups. Statistical analysis using the student’s t-test between the treatment groups

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Figure 2. Sum of pain intensity difference (SPID) (mean)over4h.p = 0.005.

showed that the combination ( -2.08 ± 1.52) was signifi-cantly more effective than monotherapy ( -1.56 ± 1.44; p = 0.014) (Figure 3).

3.2 Secondaryoutcomes3.2.1 Pain intensity on day 1 to day 10The improvement in average pain intensity score was also analyzed after repeated doses over 10 days of treatment. The two treatments showed significant fall in pain intensity from baseline to the end of therapy (Figure 4).

The PID was significantly more in patients treated with combination therapy during the first 4 days of the therapy (p < 0.05). However, both the treatments reduced the pain intensity to a similar extent from day 5 to day 10 (p > 0.05; Figure 5).

3.2.2 Osteoarthritis symptoms measured using WOMAC at the end of studyThere was statistically significant improvement in WOMAC overall score and subscores like pain, joint stiffness and physical function at the end of therapy from baseline for both treatment groups. However, both treatment groups were comparable with respect to change in WOMAC scores at the end of therapy (p > 0.05; Table 2).

3.2.3 Resolution of clinical signs and symptoms of osteoarthritis flare-upThere was significant resolution of clinical signs and symptoms in both the treatment groups from baseline (p < 0.05). At the end of therapy, baseline signs and symp-toms of OA flare-up were resolved in a greater proportion of patients on combination therapy compared with those on monotherapy, with no significant difference between them (p > 0.05; Table 3).

3.2.4 Patient’s overall efficacy assessment for treatmentThe overall efficacy was rated as good to excellent in significantly more patients from the combination group (65.34%) compared with the monotherapy group (48.97%, p = 0.035; Figure 6).

3.2.5 Investigators’ overall efficacy assessment for treatmentThe investigators’ overall efficacy assessment was significantly better in the aceclofenac–paracetamol group than in the aceclofenac group (p = 0.009). Aceclofenac–paracetamol was rated as good to excellent in 62.37% of patients compared with 41.83% of patients on aceclofenac only (Figure 7).

3.2.6 SafetyThose patients who received at least one dose of study medication were included in the safety analysis. A total of 199 patients were analyzed. Twenty patients (10.05%) reported twenty adverse events during this study. The adverse events reported in this study are tabulated in Table 4. The commonly reported adverse events were nausea and gastritis. The less common adverse events were vomiting, dizziness, dyspepsia, itching and swelling and generalized puffiness. In the investigators’ judgment, the reported adverse events were of mild to moderate intensity and possibly related to the study drugs. The incidence of adverse event with aceclofenac–paracetamol combination was similar to that of aceclofenac alone. All the adverse events subsided on their own. The

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Figure 3. Mean peak pain intensity difference (PID) over4h.*p =0.014.

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Figure5.Painintensitydifferencefromday1today10.*p < 0.05.

Table2.MeanscoreoftheWesternOntarioandMcMasterUniversities(WOMAC)OsteoarthritisIndexQuestionnaireatbaselineandendoftherapy.

Category Aceclofenac(n=98) Aceclofenac–paracetamol(n=101)

Subscales Baseline visit Final visit Change* Baseline visit Final visit Change*

Pain (± SD) 7.91 ± 2.74 4.11 ± 2.78 -3.80 ± 3.37 7.60 ± 2.55 3.76 ± 2.60 -3.84 ± 2.81

Joint stiffness (± SD) 2.33 ± 1.80 1.08 ± 1.51 -1.25 ± 1.76 1.79 ± 1.71 0.75 ± 1.35 -1.04 ± 1.60

Physical function (± SD) 25.76 ± 8.53 14.85 ± 9.81 -10.91 ± 10.47 24.31 ± 8.49 13.68 ± 9.40 -10.63 ± 9.99

Total score (± SD) 36.02 ± 2.17 20.05 ± 13.5 -15.97 ± 14.85 33.71 ± 11.51 18.20 ± 2.65 -15.51 ± 3.47

*p > 0.05

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Figure4.Evaluationoftheaveragepainintensity(PI)during10daysoftreatment.

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Table3.Resolutionofclinicalsignsandsymptomsofosteoarthritisflare-up.

Signsandsymptoms Aceclofenac(n=98) Aceclofenac–paracetamol(n=101) pvalue

Morning stiffness (%) 31/70 (44) 43/75 (57) 0.116

Nocturnal pain (%) 39/61 (64) 44/59 (75) 0.207

Swelling/inflammation (%) 32/51 (63) 36/52 (69) 0.487

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Figure6.Patient’soverallefficacyassessmentattheendofthestudy.

from baseline for various laboratory parameters were evaluated at day 10 (end of therapy) for all the patients. There were no clinically significant trends evident across the treatment groups. No serious laboratory abnormality was reported in any patient in this study.

4. Discussion

As recommended by the American College of Rheumatology, the addition of other analgesics is a rational approach in patients achieving inadequate relief of OA flare-up pain with NSAIDs or COX-2-selective inhibitors alone [25]. To our knowledge, ours is the first study to evaluate the benefits of adding paracetamol to aceclofenac in the treatment of patients with OA flare-up. Results of our study clearly indi-cate that a significant and marked early reduction in pain was experienced by OA flare-up patients treated with aceclofenac–paracetamol combination during the first 4 days of the study.

Evaluation of pain intensity at different time points in the present study allowed for the characterization of the analgesic effect of aceclofenac–paracetamol treatment for OA flare-up pain. A clear time response pattern for both treatments was evident, consistent with their known pharmacokinetic and clinical profiles. Differences in pain intensity between both the drugs began to emerge from 30 min after the first dose. The treatment effect was statistically significant in favor of combination from 30 min onwards compared with aceclofenac alone. This confirms the benefit of adding paracetamol to aceclofenac for relieving pain due to OA flare-up. The sum of pain intensity difference for the 4-h time period confirmed that patients on aceclofenac–paracetamol achieved marked overall reductions in pain intensity over the 4-h period. Peak pain intensity was also significantly lower for the combination treatment compared with monotherapy (p = 0.014).

Many studies evaluating pain flare-up have been conducted in patients with cancer [26-28] in whom it has been suggested that the presence of pain flare-up may contribute to the development of more severe chronic pain [28]. A study done on the evaluation of flare intensity in OA patients [29] reported that, once the flare intensity is controlled there is dramatic pain reduction for those patients with the most intense flares. In the present study, there were nine patients in total (aceclofenac–paracetamol group: 5 patients, aceclofenac group: 4 patients) reported the worst possible pain at baseline.

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Figure 7. Investigators’ overall efficacy assessment at theendofstudy.

incidence of adverse events with aceclofenac–paracetamol was similar to that reported in literature for aceclofenac and paracetamol administered induvidually.

The laboratory evaluations were done at baseline (screening visit) and at the end of therapy (day 10). Mean changes

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All five patients (100%) from combination therapy and two out of four patients (50%) from monotherapy showed marked reduction in pain at the end of therapy. The worst pain remained unresolved in remaining two patients from monotherapy till the end of study.

Also, adequate control and prevention of pain flare-up may require higher doses of maintenance medication; possi-bly leading to an increased incidence of adverse effects [26]. Although not significant, there were more patients on com-bination therapy in whom the OA flare-up signs and symp-toms, such as morning stiffness (57.33% vs 44%), nocturnal pain (74.57% vs 63.9%) and swelling (69.23% vs 62.7%), were resolved at the end of the therapy. The statistically significant improvements from baseline were seen for the WOMAC overall score as well as for pain, stiffness and physical function subscores, which indicates that there are specific benefits of aceclofenac–paracetamol on symptoms and physical disability associated with OA flare-up patients. WOMAC has been shown to be a reliable, valid outcome measurement for the effects of analgesic therapy in patients with OA, especially for the pain and physical function sub-scales, whereas supporting evidence for the stiffness subscale is sparse [30]. Moreover, previous studies using WOMAC measurements suggest that the magnitude of the changes

Table4.Adverseeventsreportedinbothtreatmentgroups.

Adverseevents Aceclofenac(n=98)

Aceclofenac–paracetamol(n=101)

Nausea 3 5

Gastritis 2 3

Vomiting 1 1

Dizziness 1 1

Dyspepsia 1 0

Itching & swelling 0 1

Generalized puffiness

1 0

seen in the current study is likely to be clinically relevant [31].

The adverse events reported in this study are of a type that are generally expected with NSAIDs. The adverse events reported were similar to those documented in the literature for aceclofenac and paracetamol [32]. No serious adverse event was reported with aceclofenac–paracetamol, and it was well tolerated. We observed that the addition of paracetamol to aceclofenac is well tolerated and safe for the treatment of patients with OA flare-up.

4.1 LimitationsThe study design was open-label owing to the different shape and size of two tablets. Larger, multicentric, random-ized, double blind, comparative studies are required to con-firm further the efficacy of combination therapy in the wider population.

5. Conclusion

The findings of this open-label, comparative study in Indian patients demonstrates that aceclofenac–paracetamol combination is effective and well tolerated in relieving OA flare-up pain. The combination showed rapid pain relief compared with monotherapy which is desirable by such patients, and hence this combination can play an important role in the management of acute, painful OA flare-up.

Acknowledgements

The authors thank Smita Talekar, for her technical assistance from the inception of the study, and Mitesh Sharma, bio-statistician for statistical analysis and data management for the study.

Declarationofinterest

This study was sponsored by Ipca Laboratories Ltd. Anil Pareek and Nitin Chandurkar are employees of Ipca Laboratories Ltd.

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AffiliationAnil Pareek†1, Nitin Chandurkar1, VD Sharma2, Mohan Desai3, Seema Kini4 & Girish Bartakke5

†Author for correspondence1Medical Affairs and Clinical Research, Ipca Laboratories Ltd, 142 AB, Kandivli Industrial Estate, Kandivli (West), 400067, Mumbai, India Tel: +91 22 66474747; Fax: +91 22 2868 6954; E-mail: [email protected] George Medical University & GM & Associated Hospitals, Department of Orthopedic Surgery, Lucknow 226003, India3Associate Professor & Unit Head, Seth GS Medical College & KEM Hospital, Department of Orthopedics, E Borges Marg, Parel, 400012, Mumbai, India4TN Medical College and BYL Nair Charitable Hospital, Department of Rheumatology, Dr. A. L. Nair Road, 400008, Mumbai, India5BJ Medical College and Sassoon Hospital, Department of Orthopedics, 411001, Pune, India