Overall tolerability and analgesic activity of intra-articular sodium hyaluronate in the treatment of knee osteoarthritis

OBJECTIVE: Viscosupplementation with intra-articular hyaluronic acid (HA) is an alternative to the treatment of symptomatic knee osteoarthritis (OA) with pain relieving drugs. Sinovial, is a sterile, non-pyrogenic 0.8% solution of highly purified sodium hyaluronate for intra-articular application. The aim of the present study was to investigate the safety and tolerability profile of this preparation in patients with symptomatic knee OA over 24 weeks. RESEARCH DESIGN AND METHODS: This was a single group, open-label study, including outpatients of both sexes, aged between 18 and 85 years, with symptomatic knee OA. All patients underwent weekly intra-articular injections of HA for 5 consecutive weeks and were followed-up for 19 additional weeks. The safety and tolerability profile (primary endpoint) was assessed by adverse event (AE) reporting. The secondary endpoint was efficacy evaluated by changes in the Western Ontario and McMaster Universities (WOMAC) score vs. baseline. Patient and physician satisfaction were also recorded. RESULTS: Intra-articular HA was generally well tolerated. The most frequent AE was pain at the injection site (5.8% of the injections); no serious treatment-related AE was reported. The WOMAC score was significantly reduced within the first 2 weeks of treatment (from 4.02 +/- 1.90 to 3.55 +/- 2.04, p = 0.0011), further decreased by the end of the injection series (week 6: 2.59 +/- 1.90; p < 0.0001) and maintained during the follow-up (week 24: 2.44 +/- 1.88; p < 0.0001). The WOMAC subscores were also significantly reduced from week 4 for 'pain' and from week 6 for 'stiffness' and 'physical function'. CONCLUSIONS: In the present study, intra-articular HA was well tolerated and safe in patients with symptomatic knee OA. Based on the sustained improvements in WOMAC score and subscores, a carry-over effect lasting for at least 19 weeks after the last injection may be proposed. These results further confirm the evidence of efficacy and safety of intra-articular HA in the management of knee OA.     

Treating knee osteoarthritis with intra-articular hyaluronans

ABSTRACT

Objective: Intra-articular hyaluronan (HA) or hylan is approved for the treatment of osteoarthritis (OA) knee pain. The authors review here published evidence of efficacy and safety of intra-articular HA for the treatment of knee pain. Since the systemic safety of nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase (COX-2) inhibitors for OA knee treatment are a current concern, the authors also offer recommendations for repositioning HA in the OA treatment paradigm.

Methods: Relevant HA literature was identified by searching MEDLINE and EMBASE from their inception to April 2008 using the search words hyaluronan, hyaluronic acid, sodium hyaluronate, and hylan G-F 20, with knee and OA. Data from randomized, placebo-controlled trials were reviewed and summarized in this article. While not a systematic review, this article reviews the best available evidence for the use of HA to treat knee OA.

Results: For the most part, patients in the reviewed studies were adults over the age of 40 with mild to severe symptomatic OA of the knee. Reviewed studies demonstrated significant improvements in pain and physical function with HA or sodium hyaluronate and hylan G-F 20. HA or hylan products were most effective between 5 and 13 weeks after injection with improvements also observed at 14–26 weeks or sometimes longer, and were well tolerated with a low incidence of adverse events. HA also provides beneficial treatment effects when administered in conjunction with other therapies.

Conclusions: Intra-articular HA or hylan has proven to be an effective, safe, and tolerable treatment for symptomatic knee OA. In an effort to limit cardiovascular, gastrointestinal, and renal safety concerns with COX-2 selective and nonselective NSAIDs and maximize HA efficacy, the authors proposed using HA earlier in the treatment paradigm for knee OA and also as part of a comprehensive treatment strategy.     

玻璃酸钠治疗症状性膝骨关节炎55例临床观察

目的：观察玻璃酸钠(HA)治疗症状性膝骨关节炎(OA)的临床疗效。方法：55例症状性膝OA关节腔内注射姒，每周1次，5周为一疗程，完成治疗后每月随诊1次。记录治疗前后的关节痛或不适(包括步行痛、夜间痛等)、晨僵、步行距离、关节活动度等。结果：完成治疗后缓解率为30．9％，有效率为89．1％。重度OA治疗有效率为73．3％，较轻中度OA明显偏低。同时应用糖皮质激素者显效时间缩短。结论：姒对轻、中度OA疗效好，适宜与糖皮质激素联用，且有一定的远期疗效。     

An open-label study of a second course of hylan G-F 20 for the treatment of pain associated with knee osteoarthritis

SUMMARY

Objective: To evaluate the efficacy and tolerability of a second course of hylan G-F 20 for the treatment of osteoarthritic knee pain in patients who experienced a clinical benefit with an initial course of therapy.

Research design and methods: In this prospective, open-label study, men or women (≥40 years of age) with knee osteoarthritis (OA) received three weekly injections of hylan G-F 20. Consecutive patients who requested a second course of hylan G-F 20 therapy due to OA knee pain subsequent to pain relief with a first course of therapy were enrolled between October 26, 2000 and January 18, 2001.

Main outcome measures: Pain while walking on a flat surface (Western Ontario and McMaster's Universities Osteoarthritis Index, WOMAC, question A1), WOMAC domain C (physical functioning), full WOMAC, and patient and investigator overall visual analog scales (VAS). Efficacy variables were measured at baseline and at weeks 1,2,4,8,12 and 26. An analgesic washout was required before all efficacy evaluations.

Results: Patients receiving at least one injection of hylan G-F 20 (n?=?71) were predominantly Caucasian (84.5%) and female (64.8%), with a mean age of 65.5 years and mean weight of 200.1 pounds. The mean time between the first and second courses of hylan G-F 20 was 19.6 months (median 17.6 months). With hylan G-F 20, pain while walking on a flat surface was significantly lower (p?<?0.001) than baseline at all time points up to week 26 (mean?±?SEM: ?1.40?±?0.10 at week 26). Actual scores decreased from 2.4?±?0.10 at baseline to 0.97?±?0.11 at week 26. Scores for the WOMAC domain C, full WOMAC and patient and investigator overall VAS also significantly improved (p?<?0.001) at all time points. A second course of hylan G-F 20 was generally well-tolerated, based on the low incidence of local adverse events (AEs) -only one patient (1.4%) experienced a severe event, the types of AEs, and the fact that no patients discontinued the study due to these AEs. The types of related AEs observed were not qualitatively different from those listed in the current product information and published literature.

Conclusion: A second course of hylan G-F 20 therapy is an appropriate therapy for the treatment of OA knee pain in patients who had a previous favorable clinical response. For continued relief of osteoarthritis knee pain, this study supports repeat use of hylan G-F 20 in these patients.     

Efficacy and safety of low-dose SoluMatrix meloxicam in the treatment of osteoarthritis pain: a 12-week,phase 3 study

Objective:

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as meloxicam are commonly used to treat osteoarthritis (OA) but are associated with potentially serious dose-related adverse events (AEs). SoluMatrix meloxicam has been developed with the goal of enabling effective treatment at low doses. This phase 3 study evaluated the efficacy and safety of low-dose SoluMatrix meloxicam capsules 5?mg and 10?mg administered once daily for 12 weeks in patients with OA-related pain.

Research design and methods:

This randomized, double-blind study enrolled patients ≥40 years of age with confirmed hip or knee OA (Kellgren–Lawrence grade II–III) who were chronic users of NSAIDs and/or acetaminophen for OA pain and had Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale mean scores ≥40?mm. Eligible patients experienced an OA pain flare (defined as a ≥15?mm increase in the WOMAC pain subscale score) following discontinuation of NSAIDs/acetaminophen. Patients were randomized to receive once-daily SoluMatrix meloxicam 5?mg or 10?mg, or placebo for 12 weeks.

ClinicalTrials.gov identifier: NCT01787188.

Main outcome measures:

The primary outcome measure was the mean change from baseline in WOMAC pain subscale score at week 12.

Results:

Low-dose SoluMatrix meloxicam 5?mg (?36.52 [2.49]; P?=?0.0005) and 10?mg (?34.41 [2.68]; P?=?0.0059) once-daily treatment significantly reduced the mean (standard error) WOMAC pain subscale score from baseline at week 12 compared with placebo (?25.68 [2.64]). Patients treated with SoluMatrix meloxicam 5?mg or 10?mg reported significantly greater improvements in total WOMAC score and in WOMAC stiffness and function subscale scores at 12 weeks compared with placebo. The most common AEs in the combined low-dose SoluMatrix meloxicam group were headache, diarrhea, nausea, osteoarthritis, and urinary tract infection.

Conclusions:

Low-dose SoluMatrix meloxicam may have a potential role as a new therapeutic option for the management of OA-related pain.     

Efficacy and Tolerability Profile of Etoricoxib in Patients with Osteoarthritis: A Randomized,Double-blind,Placebo and Active-comparator Controlled 12-Week Efficacy Trial

Summary

Objective: To evaluate the efficacy of 12 weeks of treatment with etoricoxib, a selective COX-2 inhibitor, in patients with osteoarthritis (OA) of the knee or hip.

Methods: In the 12-week placebo- and active comparator-controlled period of a randomized, double-blind study, eligible patients were treated with etoricoxib 60?mg once daily (n?=?224), naproxen 500?mg twice daily (n?=?221), or placebo (n?=?56). Western Ontario McMaster's Osteoarthritis Index (WOMAC) pain and physical function subscales and patient's global assessment of disease status were primary end points. Key secondary and other end points were patient's and investigator's global assessment of response to therapy, WOMAC stiffness subscale, investigator's global assessment of disease status, rescue paracetamol use, proportion of patients discontinuing due to lack of efficacy, and study joint tenderness.

Results: Etoricoxib 60?mg demonstrated efficacy significantly superior to placebo (p?≤?0.005) and comparable to naproxen 500mg twice daily as assessed by the primary efficacy end points. Secondary and other end points confirmed these results. Treatment effects were evident by day 2, maximal by week 2, and sustained over the entire 12 weeks. Etoricoxib was well tolerated for 12 weeks.

Conclusions: Etoricoxib showed rapid and durable treatment effects in patients with OA of the knee or hip. Etoricoxib was generally well tolerated.     

Improvement in condition-specific and generic quality of life outcomes in patients with knee osteoarthritis following single-injection Synvisc: results from the LOBRAS study

Objective: To evaluate the effectiveness of viscosupplementation with single-injection hylan G-F20 (Synvisc-One) in knee osteoarthritis (OA), during routine clinical care, in a 52 week observational study.

Research design and methods: The LOBRAS study involved a 1 year long, multi-center, quasi-experimental, repeated measures, observational study. Consenting patients in Australia fulfilling inclusion/exclusion criteria under the care of a medical specialist in routine clinical practice were enrolled. Prior to, and for 52 weeks following, intra-articular single-injection hylan G-F20, patients were repeatedly evaluated using the WOMAC NRS4.1 Index and the SF-36 questionnaire. The WOMAC NRS4.1 was administered by mobile phone (with paper back-up), and the SF-36 was administered on paper. Patients were monitored for adverse events.

Main outcome measures: Western Ontario and McMaster (WOMAC) OA Index, and the Short Form 36 questionnaire (SF-36 v2).

Results: A total of 131 patients with knee OA were enrolled, of whom 119 provided both pre- and post-intervention WOMAC data. Statistically significant improvements (with a maximum of p ≤ .025) from baseline to Week 12, Month 6 and Week 52 were detected, by intention-to-treat (ITT) and per-protocol (PP) analyses, in WOMAC Pain, Stiffness, Function, PGA, and Total Score, SF-36 PCS, and WOMAC-derived HUI3. Adverse event (AE) monitoring detected treatment-related AEs in 5.3% of patients.

Conclusions: The effectiveness of single-injection hylan G-F20 in routine clinical care is supported by the detection of statistically significant, clinically important improvements in WOMAC Pain, Stiffness, Function, Total, and PGA outcomes, and statistically significant improvements in SF-36 PCS and WOMAC-derived HUI3 outcomes at multiple time points. Limitations of this study include lack of a control group or blinding. No predictive indicators of the response to treatment were identified. In general single-injection hylan G-F20 was well tolerated with very few patients experiencing any treatment-related adverse events. Collectively, these observations attest to the effectiveness of single-injection hylan G-F20 and complement previous observations in routine clinical care.     

Efficacy and safety of diclofenac sodium 2% topical solution for osteoarthritis of the knee: a randomized,double-blind,vehicle-controlled, 4 week study

Objective:

Nonsteroidal anti-inflammatory drugs (NSAIDs) are standard therapy for osteoarthritis (OA). Topically applied NSAIDs reduce systemic exposure compared with oral NSAIDS, and European guidelines recommend their use. The NSAID diclofenac is available in a range of topical formulations. Diclofenac 1% gel and 1.5% four times daily and 2% twice daily (BID) solutions are approved to reduce pain from OA of the knee(s). The objective of this study was to investigate the efficacy and safety of diclofenac sodium 2% topical solution BID versus vehicle control solution for treating pain associated with OA of the knee.

Research design and methods:

A phase II, 4 week, randomized, double-blind, parallel-group, two-arm, vehicle-controlled study compared pain relief with diclofenac sodium 2% topical solution versus control (vehicle only) in patients aged 40 to 85 years with radiographically confirmed primary OA of the knee.

Clinical trial registration:

ClinicalTrials.gov identifier NCT01119898.

Main outcome measures:

The primary efficacy outcome was change from baseline to the final visit in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale. Secondary outcomes included additional WOMAC subscales and patient global assessment of OA. Treatment-emergent adverse events (TEAEs), skin irritation, and vital signs were assessed and collected throughout the study.

Results:

Of 260 patients randomized, 259 received ≥1 dose of study drug. Significantly greater reductions in least-squares mean (standard error) WOMAC pain scores were observed for diclofenac-treated (?4.4 [0.4]) versus vehicle-treated patients (?3.4 [0.4]) at the final visit (p?=?0.040). The most commonly reported TEAEs were administration site conditions. The vehicle-treated group experienced slightly more TEAEs than the active treatment group (38.8% vs. 31.5%). No serious adverse events were reported.

Conclusions:

Administration of diclofenac sodium 2% topical solution BID resulted in significantly greater improvement in pain reduction in patients with OA of the knee versus vehicle control and was generally well tolerated.     

Tolerability and short-term effectiveness of hylan G‐F 20 in 4253 patients with osteoarthritis of the knee in clinical practice

ABSTRACT

Objective: To determine the tolerability and short-term effectiveness of hylan G‐F 20 (Synvisc) in patients with symptomatic osteoarthritis (OA) of the knee in standard clinical practice.

Research design and methods: Over 800 orthopedic surgeons in Germany recorded adverse events (AEs) for approximately five consecutive patients each following 3 weekly intra-articular hylan G‐F 20 injections. Patients assessed their pain on a 4-point scale before and 3 weeks after the first injection. Potential risk factors for local AEs and possible predictors of short-term effectiveness of hylan G‐F 20 were explored with logistic regression.

Results: 4253 patients were treated with 12?699 injections by 840 physicians at 720 sites. Local, treatment related AEs (?n = 302) were reported in 180 patients (4.2% of patients; 2.4% of injections). The most frequently reported AEs were joint effusion (2.4% of patients), joint swelling (1.3%), arthralgia (1.2%), joint warmth (0.6%), and injection site erythema (0.3%). Most AEs were mild (21.4%) to moderate (40.3%) in nature. One patient experienced a serious AE of severe swelling and synovial fluid accumulation judged as possibly treatment related. Patients < 70 years old, patients with a longer time since diagnosis, and those previously treated with viscosupplementation were more likely to experience a local AE. Pain significantly (?p < 0.0001) decreased 3 weeks after the first injection compared with before treatment. Potential predictors of hylan G‐F 20 short-term effectiveness were being underweight, male gender, shorter time since diagnosis, and severe baseline pain.

Conclusions: In this population of 4253 patients treated with hylan G‐F 20 for OA knee pain, the overall incidence of local, treatment-related AEs was low and consistent with those reported in the current US product labeling and previously published studies. Additionally, short-term effectiveness was confirmed.     

Efficacy and tolerability of lumiracoxib 100 mg once daily in knee osteoarthritis: a 13-week, randomized, double-blind study vs. placebo and celecoxib

OBJECTIVE: To determine the efficacy and safety of lumiracoxib for knee osteoarthritis (OA). METHODS: This was a 13-week, multicentre, randomized, double-blind, double-dummy, placebo-controlled study. Males or females aged >/= 18 years with primary knee OA received lumiracoxib 100 mg od, lumiracoxib 100 mg od with a loading dose of 200 mg od for the first two weeks, celecoxib 200 mg od, or placebo. MAIN OUTCOME MEASURES: Co-primary variables, assessed at week 13, were OA pain intensity in the target knee, patient's global assessment of disease activity and the WOMAC total score. Other variables included OMERACT-OARSI responder rates and WOMAC subscale scores. Safety and tolerability were evaluated. RESULTS: All active treatments were superior to placebo for all co-primary variables. No significant differences were observed between any active treatments. Mean reductions from baseline to week 13 for lumiracoxib 100mg od, 100mg od with loading dose, celecoxib and placebo, respectively, were: OA pain intensity in the target knee: 26.8, 26.2, 26.6 and 21.4mm (all p < 0.01 vs. placebo); patient's global assessment of disease activity: 25.1, 21.9, 22.9 and 18.9 mm (all p < 0.05 vs. placebo); WOMAC total score: 15.2, 14.8, 14.7 and 11.3 (all p < 0.01 vs. placebo). Lumiracoxib was superior to placebo and similar to celecoxib for OMERACT-OARSI response and WOMAC subscale scores. Lumiracoxib was well tolerated. The incidence of adverse events was similar across groups. CONCLUSIONS: Lumiracoxib 100 mg od provided effective relief from the pain of knee OA, with efficacy similar to celecoxib 200 mg od, and was well tolerated.     

Intra-articular administration of hylan G-F 20 in patients with symptomatic hip osteoarthritis: tolerability and effectiveness in a large cohort study in clinical practice

ABSTRACT

Objective: This prospective, observational, open study aimed to assess the efficacy and safety of hylan G-F 20 in a large cohort of patients with symptomatic hip osteoarthritis (OA), and identify predictors of clinical response.

Research design and methods: Patients presenting with symptomatic hip OA received one 2?mL intra-articular (IA) injection of hylan G-F 20 under ultrasound guidance. Patients were followed-up every 3 months for a total of 12 months and were offered an optional, additional injection at each follow-up visit if symptomatically justified. At each visit, pain scores (100?mm visual analogue scale [VAS]), Lequesne index scores, NSAID intake, and physician and patient global assessments scores were recorded. Adverse events (AEs) were recorded throughout the study.

Main outcome measures; results: 250 patients completed the 12 month follow-up and received a total of 734 injections. Statistically significant reductions in VAS pain scores, Lequesne index scores and NSAID usage were reported at all time-points (?p < 0.05). No systemic, serious or severe side effects were observed. Fifty-two local AEs were reported (7.08% per injection) all of which were mild and transient. One predictor of clinical response was identified, with patients?<?75 years of age reporting better outcomes.

Conclusions: This study supports the safety, tolerability and effectiveness of hylan G-F 20 in the treatment of symptomatic hip OA. Hylan G-F 20 may also offer economic benefits due to a reduction in NSAID usage and the resultant reduction in management costs of NSAID related side-effects. These data reflect those obtained in previous studies of hylan G-F 20 in patients with knee OA.     

Assessment of the efficacy of joint lavage versus joint lavage plus corticoids in patients with osteoarthritis of the knee

SUMMARY

Purpose: Joint lavage (JL), involves the passage of cold sterile 0.9% saline through the knee joint in order to have the fluid reach the inside of the joint capsule. This technique was evaluated as a local treatment for osteoarthritis (OA) of the knee alone (JL) and in combination with intra-articular infiltration with glucocorticoids (JLC).

Patients and methods: An overall 299 knees belonging to 205 patients (22% males, 78% females) with a mean age of 67 ± 8?years and osteoarthritis of the knee of radiological grade II or III on the Kellgren scale were randomised in the ratio of 1:4 into two therapeutic groups, namely: JL (n = 62) and JLC (n = 237). All patients received joint lavage on day 0; in those of the JLC group, joint lavage was followed by infiltration of 40?mg of triamcinolone acetonide. The efficacy of both treatments was assessed by recording the corresponding values for the following variables: pain strength as measured by a visual analogy scale (VAS), effusion, crepitation, restricted motion, spontaneous pain, pain on pressure, pain on passive motion and pain on active motion; all of these were recorded at the onset of the study, and after 1 and 3?months.

Results: There were no significant differences in the values of the variables at the different follow-up times. Also, pain severity was similar in both treatment groups. Thus, VAS for pain was 7.3 ± 0.3 for the JL group and 7.1 ± 0.2 for the JLC group at the onset, and decreased to 3.0 ± 0.3 in the former and 2.8 ± 0.2 in the latter after 1?month; the decrease was statistically significant in both cases. After 3?months, the JL and JLC groups had a VAS of 3.5 ± 0.3 and 3.8 ± 0.2, respectively.

Conclusions: The results of this work suggest the absence of significant differences between the two treatments, such that both joint lavage alone and with infiltration with corticoids can be concluded as similarly effective for the symptomatic management of osteoarthritis of the knee.     

Multicenter study of hyaluronic acid obtained by biotechnology to evaluate clinical efficacy and safety in knee osteoarthritis

Viscosuppplementation with intra-articular hyaluronic acid (hyaluronan [HA]) is a relatively new option for improving pain and articular function in patients with symptomatic knee osteoarthritis. An open multi-center study was performed in 365 patients with definite and symptomatic knee osteoarthritis from seven Latin American countries. Five doses of HA were administered once a week. The parameters studied were pain (six items), stiffness (two items) and functional capacity (17 items). The parameters were evaluated 1 week after the corresponding injection. Statistical differences were found when basal determinations of the three parameters were compared with the results of the first and fourth administration (p < 0.05). Intra-articular HA administration was well tolerated. Treatment-related nonserious adverse events were registered in 2.5% of administrations. Based on the results obtained, HA is a useful and well-tolerated symptomatic treatment for knee osteoarthritis with a rapid onset of action.     

Efficacy and safety of rofecoxib 12.5 mg and celecoxib 200 mg in two similarly designed osteoarthritis studies

ABSTRACT

Objective:?To compare the lower osteoarthritis (OA) dose of rofecoxib to the recommended dose of celecoxib in two identically designed studies.

Methods:?Patients with knee OA were randomized (2:2:1 ratio: rofecoxib 12.5?mg once daily (qd), celecoxib 200?mg qd, or placebo, respectively). The primary endpoint was patient global assessment of response to therapy (PGART) averaged over 6 weeks on a five-point scale. Rofecoxib would be declared at least as effective as celecoxib if the lower bound of the 95% confidence interval (95% CI) for difference in means was no lower than –0.5. Additional endpoints included Pain and Physical Function subscales of the Western Ontario and McMaster (WOMAC) OA Index. Adverse experiences (AEs) were recorded and combined from the two studies for analysis.

Results:?Study 1 enrolled 395 patients (rofecoxib, n = 160; celecoxib, n = 157; placebo, n = 78). Study 2 enrolled 413 patients (rofecoxib, n = 159; celecoxib, n = 169; placebo, n = 85). Rofecoxib 12.5?mg was at least as effective as celecoxib 200?mg by PGART (Study 1 difference –0.09 [95% CI: –0.32, 0.14] and Study 2 difference 0.02 [95% CI: –0.20, 0.24]), and both were significantly (?p < 0.001) more effective than placebo. Comparable efficacy was also seen for WOMAC Pain and Physical Function subscales with the active treatments. There was a significantly higher (?p < 0.05) incidence of serious AEs with celecoxib than rofecoxib or placebo, none of which was drug-related. There were no significant differences in the pre-specified measurements of safety including drug-related AEs or discontinuations due to AEs, and the medications demonstrated similar safety as assessed by spontaneous reporting.

Conclusions:?Rofecoxib 12.5?mg and celecoxib 200?mg provided comparable efficacy over 6 weeks, and both were significantly more efficacious than placebo. The medications demonstrated similar safety compared to one another and placebo. The primary limitations of these studies were that they were only 6 weeks long and were powered for efficacy. Therefore, conclusions about long-term safety cannot be inferred.     

Comparative efficacy and tolerability of two sustained-release formulations of diclofenac: results of a double-blind,randomised study in patients with osteoarthritis and a reappraisal of diclofenac's use in this patient population

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 of 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.     

Effect of the NSAID nimesulide on the radical scavenger glutathione S‑transferase in patients with osteoarthritis of the knee

ABSTRACT

Objective: Osteoarthritis (OA) of the knee is a secondary inflammatory, painful disease of the knee joint with increasing destruction of the articular cartilage. In the inflammatory process the formation of free radicals (reactive oxygen species, ROS) plays a major role in progression of disease and in the subsequent destruction of joint cartilage. The aim of this pilot study was to examine the antioxidative potency of the non-steroidal anti-inflammatory drug (NSAID) nimesulide on glutathione S?transferase (GST), an enzymatic free radical scavenger. In addition, the effects on matrix metalloproteinase MMP?3 and its antagonist tissue inhibitor of matrix-metalloproteinase 3 (TIMP-1) were determined.

Research design and methods: This was an open-pilot study on 20 patients (aged 41–71 years old) suffering from painful OA of the knee, treated for 3 weeks with nimesulide 100?mg b.i.d. Twenty-three healthy subjects (aged 23–57 years), not age matched, served as a comparison group. GST, MMP?3 and TIMP?1 were measured by enzyme-immunoassays. Clinical symptoms and joint function were measured using the WOMAC Index.

Results: During the 3-week treatment period with nimesulide 100?mg b.i.d., both scavenger GST and the TIMP?1/MMP?3 ratio significantly increased. This change was accompanied by significant clinical improvement in terms of pain reduction, stiffness and joint function. Two adverse events occurred possibly related to nimesulide treatment: one case of moderate eyelid swelling, and one case of moderate diarrhea with no abnormality in the endoscopic examination.

Conclusions: These results confirm the antioxidative properties of the study drug, indicating that nimesulide, beside its known anti-inflammatory properties, also shows an evident antioxidative activity that adds further supportive evidence to its key role in the treatment of OA patients (thanks to the absence of degenerative effects on cartilage).     

Short-term treatment with topical diclofenac epolamine plaster in patients with symptomatic knee osteoarthritis: pooled analysis of two randomised clinical studies

ABSTRACT

Background: Data from two randomised, double-blind, placebo-controlled studies were considered in order to investigate the efficacy and safety of a bio-adhesive plaster for topical administration containing diclofenac epolamine (DHEP) in patients with symptomatic knee osteoarthritis (OA).

Methods: Patients with radiologically confirmed symptomatic knee OA were included. The 14‐day treatment consisted of two daily applications of either DHEP or placebo plaster. The algofunctional Lequesne index and pain intensity, measured by means of the Huskisson's visual analogue scale (VAS), were considered as main efficacy parameters. The main analysis of the pooled data was by intention-to-treat.

Results: Of the 258 patients included, 235 completed the study. At the end of the study, the mean decrease in the Lequesne index was 35% in the DHEP group and 15% in the placebo group (?p < 0.0001). The mean decrease in pain intensity was 59.5% in the DHEP group and 29.9% in the placebo group. No interaction resulted between treatment and study effects (?p ≥ 0.2 whatever the test). The non-parametric Hodges–Lehmann estimator of the treatment effect resulted in a reduction of 21.9% for the Lequesne index and of 30.0% in pain intensity.

The number needed to treat (NNT) for at least a 50% reduction of pain was 3.0 and the effect size for pain was 0.75.

Conclusions: Topical application of DHEP plaster was shown to be an efficacious and safe short-term treatment for symptomatic knee OA, reducing pain and increasing physical function and may be similar in efficacy to oral non-steroidal anti-inflammatory drugs (as indicated by relative benefit data and NNT value).     

An open-label study of a second course of hylan G-F 20 for the treatment of pain associated with knee osteoarthritis

OBJECTIVE: To evaluate the efficacy and tolerability of a second course of hylan G-F 20 for the treatment of osteoarthritic knee pain in patients who experienced a clinical benefit with an initial course of therapy. RESEARCH DESIGN AND METHODS: In this prospective, open-label study, men or women (>/=40 years of age) with knee osteoarthritis (OA) received three weekly injections of hylan G-F 20. Consecutive patients who requested a second course of hylan G-F 20 therapy due to OA knee pain subsequent to pain relief with a first course of therapy were enrolled between October 26, 2000 and January 18, 2001. MAIN OUTCOME MEASURES: Pain while walking on a flat surface (Western Ontario and McMaster's Universities Osteoarthritis Index, WOMAC, question A1), WOMAC domain C (physical functioning), full WOMAC, and patient and investigator overall visual analog scales (VAS). Efficacy variables were measured at baseline and at weeks 1, 2, 4, 8, 12 and 26. An analgesic washout was required before all efficacy evaluations. RESULTS: Patients receiving at least one injection of hylan G-F 20 (n = 71) were predominantly Caucasian (84.5%) and female (64.8%), with a mean age of 65.5 years and mean weight of 200.1 pounds. The mean time between the first and second courses of hylan G-F 20 was 19.6 months (median 17.6 months). With hylan G-F 20, pain while walking on a flat surface was significantly lower (p < 0.001) than baseline at all time points up to week 26 (mean +/- SEM: -1.40 +/- 0.10 at week 26). Actual scores decreased from 2.4 +/- 0.10 at baseline to 0.97 +/- 0.11 at week 26. Scores for the WOMAC domain C, full WOMAC and patient and investigator overall VAS also significantly improved (p < 0.001) at all time points. A second course of hylan G-F 20 was generally well-tolerated, based on the low incidence of local adverse events (AEs) - only one patient (1.4%) experienced a severe event, the types of AEs, and the fact that no patients discontinued the study due to these AEs. The types of related AEs observed were not qualitatively different from those listed in the current product information and published literature. CONCLUSION: A second course of hylan G-F 20 therapy is an appropriate therapy for the treatment of OA knee pain in patients who had a previous favorable clinical response. For continued relief of osteoarthritis knee pain, this study supports repeat use of hylan G-F 20 in these patients.     

The rate of decline of joint space width in patients with osteoarthritis of the knee: a systematic review and meta-analysis of randomized placebo-controlled trials of chondroitin sulfate

ABSTRACT

Background: Chondroitin sulfate has been shown to relieve pain and improve functional limitation in patients with osteoarthritis (OA) of the knee in numerous clinical trials and meta-analyses. Its role as a potential structure-modifying drug for knee OA, however, remains controversial.

Objective: To perform a meta-analysis of randomized double-blind placebo-controlled clinical trials to assess the efficacy of chondroitin sulfate as a structure-modifying drug for knee OA.

Research design and methods: A Medline search was conducted from 1996 through 2007 and five articles that reported results from three trials were identified; one additional trial was identified through review of presentations at annual rheumatology meetings. There was no evidence of heterogeneity across the trials and results were pooled using a fixed effects meta-analysis.

Results: Pooled results demonstrated a small significant effect of chondroitin sulfate on the reduction in rate of decline in minimum joint space width of 0.07?mm/year (95% CI 0.03, 0.10) that corresponded to an effect size of 0.26 (95% CI 0.14, 0.38) (p?<?0.0001). This result was robust in sensitivity analyses.

Limitations: The individual studies included in the meta-analysis varied in the number of patients enrolled and the techniques used to acquire knee radiographs and to measure joint space width.

Conclusion: These results demonstrate that chondroitin sulfate is effective for reducing the rate of decline in minimum joint space width in patients with OA of the knee. Chondroitin sulfate may have a role as a structure-modifying agent in the management of patients with knee OA.     

关节腔内注射透明质酸治疗膝骨关节炎康复效果的Meta分析

目的 评价关节腔内注射透明质酸对膝骨关节炎功能康复和生活质量效果,为临床应用提供指导依据.方法 计算机检索中文数据库(CNKI、CBM、维普和万方)和英文数据库(PubMed、Web of Science、Cochrane Library、SCIE、ScienceDirect、BP)中关于关节腔内注射透明质酸治疗膝骨关节炎的随机对照试验,检索年限均为2007年2月至2017年2月.由2名研究者按照纳入排除标准进行文献筛选、资料提取、质量评价,采用RevMan 5.3软件进行Meta分析,以WOMAC 6周疼痛指数、僵硬、日常生活能力为结局指标的漏斗图提示存在发表偏倚.结果 共纳入9篇文章,共有1404例患者,透明质酸组702例,盐水组702例.Meta分析的结果显示:透明质酸组与盐水组在WOMAC疼痛指数[6周:MD=-0.02,95％CI:(-0.62～0.59),P=0.95;12周:MD=-0.43,95％ CI:(-1.17～0.31),P=0.25;24周:MD=3.15,95％CI:(-2.42～8.73),P=0.27]、WOMAC僵硬指数[6周:MD =0.05,95％ CI:(-0.21 ～0.30),P=0.70;12周:MD=-0.11,95％ CI:(-0.73 ～0.51),P=0.73;24周:MD =0.87,95％ CI:(-0.16～1.90),P=0.10]、WOMAC日常生活自理指数[6周:MD=0.30,95％CI:(-0.82～1.41),P =0.60;12周:MD =0.41,95％ CI:(-2.20～3.02),P=0.76]、50 m步行试验[6周:MD=1.16,95％CI:(-2.11～4.44),P =0.49;12周:MD=1.30,95％ CI:(-1.85 ～4.45),P=0.42]、VAS[6周:MD=-0.09,95％ CI:(-0.62～0.44),P =0.74;12周:MD=0.39,95％CI:(-0.43～ 1.21),P=0.35]中比较均差异无统计学意义,WOMAC改善日常生活自理能力优于盐水组[24周:MD =6.85,95％ CI:(6.39～7.31),P＜0.0001],有统计学意义.结论 关节腔内注射透明质酸对提高长期日常生活质量作用明显;然而缓解膝骨关节炎的疼痛、僵硬程度和提高中短期生活质量效果不明显,这可能与样本量大小以及随访时间的设置有一定联系,该结论尚需增大样本量和设置相同随访时间进行研究论证.