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.     

Topical diclofenac: clinical effectiveness and current uses in osteoarthritis of the knee and soft tissue injuries

Background: Diclofenac is a commonly used non-steroidal anti-inflammatory drug (NSAID) for symptom control in osteoarthritis (OA) of the knee and soft tissue injuries. Although treatment with oral diclofenac is associated with serious adverse effects involving both the gastrointestinal and renal systems, these adverse effects are thought to be limited with topical diclofenac formulations without loss of efficacy. Objective: The aim of this review is to explore the available evidence in relation to the pharmacokinetics, efficacy and reported adverse effects of the topical diclofenac formulations available. Results/conclusions: In the majority of studies examined, topical diclofenac formulations with sodium lotion, lecithin or epolamine gel, patch or plaster were either superior or equivalent to oral diclofenac formulations or placebo. Topical diclofenac significantly reduced pain and morning stiffness and improved physical function and patient global assessment without major adverse effects reported in patients with OA of the knee; and provided significant pain relief in patients with sports and soft tissue injuries involving the ankle, knee or shoulder. In the majority of studies, the predominant adverse effect involved pruritus or rash at the site of application, or nausea. The principle outcome of these studies is that topical diclofenac is a safe and practical alternative as a method of treatment in OA of the knee or as an alternative treatment for sports and soft tissue injury.     

Gastrointestinal tolerability of NSAIDs in elderly patients: a pooled analysis of 21 randomized clinical trials with celecoxib and nonselective NSAIDs

Abstract

Background:

Gastrointestinal (GI) tolerability is an important treatment consideration for physicians when choosing a nonselective nonsteroidal anti-inflammatory drug (NSAID) for their elderly arthritis patients. The objective of this study was to compare the GI tolerability of the cyclooxygenase-2 selective NSAID celecoxib and nonselective NSAIDs in elderly patients with arthritis aged 65 years or older.     

A comparison of the therapeutic efficacy and tolerability of etoricoxib and diclofenac in patients with osteoarthritis

SUMMARY

Objective: To evaluate and compare the efficacy and tolerability of etoricoxib and diclofenac in patients with osteoarthritis of the knee or hip.

Methods: In this 6-week double-blind, active comparator controlled, parallel-group study eligible osteoarthritis patients were randomised to receive either etoricoxib 60?mg once daily (n?=?256) or diclofenac 50?mg three times daily (n?=?260). The primary study endpoint was the Western Ontario McMaster osteoarthritis index (WOMAC) pain subscale. Other endpoints included were the WOMAC stiffness and physical function subscales, and the Patient's Global Assessment of Response to Therapy (PGART) questionnaire. Early efficacy was evaluated using WOMAC first question (pain walking on a flat surface) and PGART 4?h after the morning dose of each drug on

days 1 and 2. Rescue medication (paracetamol) used was also recorded. The study was designed to show comparable efficacy between etoricoxib 60?mg once daily and diclofenac 50?mg three times daily with respect to the primary endpoint and was conducted outside the United States at 67 centres in 29 countries.

Results: Etoricoxib (60?mg once daily) was comparable in efficacy to diclofenac (150?mg daily) on all the above parameters. The one exception was in the assessment of early efficacy where etoricoxib demonstrated significantly greater benefit within 4?h of taking the first dose on the first day of therapy (p?=?0.007) as evaluated by the percentage of patients with good or excellent (PGART) responses. The treatment effects of both drugs were similar by the time day 2 was reached

and were sustained throughout the 6 weeks of therapy. Both treatments were generally well tolerated.

Conclusions: Etoricoxib is clinically effective in the therapy of osteoarthritis providing a magnitude of effect comparable to that of the maximum recommended daily dose of diclofenac. The onset of clinical benefit with etoricoxib on day one is more rapid than that of diclofenac. Both drugs were generally well tolerated.     

Tapentadol prolonged-release for moderate-to-severe chronic osteoarthritis knee pain: a double-blind,randomized, placebo- and oxycodone controlled release-controlled study

Objective: To assess efficacy and safety of tapentadol prolonged release (PR) for moderate-to-severe chronic osteoarthritis knee pain.

Methods: Patients (n?=?990) were randomized (1:1:1) to tapentadol PR, oxycodone controlled release (CR; reference compound for assay sensitivity), or placebo for a double-blind 3-week titration and 12-week maintenance period. Primary efficacy end-points were change from baseline in average pain intensity at week 12 of maintenance (US end-point) and over the entire maintenance period (non-US end-point) with “last observation carried forward” as imputation method for missing scores.

Results: Both primary end-points were not significantly different for tapentadol PR nor for oxycodone CR vs placebo at week 12 (least squares [LS] mean difference?=?–0.3 [95% CI?=?–0.61–0.09]; p?=?0.152 and 0.2 [95% CI?=?–0.16–0.54]; p?=?0.279, respectively) and over the maintenance period (LS mean difference?=?–0.2 [95% CI?=?–0.55–0.07]; p?=?0.135 and 0.1 [95% CI?=?–0.18–0.44]; p?=?0.421, respectively). Considerably more patients receiving tapentadol PR than oxycodone CR completed the trial (58.3% vs 36.6%). This is consistent with better results with tapentadol PR on the overall health status (PGIC) compared to oxycodone CR. Indeed, respectively, 56% and 42.5% rated at least “much improved” at the end of treatment. Incidences of gastrointestinal adverse events were higher for both active treatments compared to placebo. Tapentadol PR was associated with a better gastrointestinal tolerability profile with incidences of constipation (17.9% vs 35%) and of the composite of nausea and/or vomiting (23.8% vs 46.8%) significantly lower vs oxycodone CR (p?Conclusions: The study did not demonstrate assay sensitivity. The finding that both primary end-points for tapentadol PR were not met can, thus, not be interpreted. Tapentadol PR was better tolerated than oxycodone CR, largely due to fewer gastrointestinal side-effects.     

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).     

Upper gastrointestinal and overall tolerability of alendronate once weekly in patients with osteoporosis: results of a randomized,double-blind,placebo-controlled study

SUMMARY

Objective: To compare the upper gastrointestinal (GI) and overall tolerability profiles of alendronate 70?mg once weekly with placebo.

Research design and methods: This 12-week international, multi-center, randomized, double-blind, placebo-controlled trial included 449 postmenopausal women and men with osteoporosis at 44 sites in 19 countries in Europe, the Americas, Africa, and Asia-Pacific. Subjects were randomized to alendronate 70?mg once weekly or matching placebo in a 1:1 ratio.

Main outcome measures: The safety and tolerability of weekly alendronate and placebo were captured as clinical and laboratory adverse events. The primary endpoint was upper GI tolerability based on the incidence of upper GI tract adverse events. Secondary endpoints included the percentage of subjects who discontinued therapy due to a drug-related upper GI adverse event. Change from baseline in bone turnover as measured by the urinary N-telopeptide-collagen crosslinks corrected for creatinine (NTx/Cr) was assessed at 12 weeks as an indicator of efficacy.

Results: The percentages of subjects reporting an upper GI tract adverse event in the alendronate 70?mg once weekly group (9.8%) and the placebo group (9.4%) were similar. The risk difference between the two treatment groups (alendronate minus placebo) was 0.4% [95% confidence interval (CI), –5.1%, 5.9%]. Percentages of subjects who discontinued due to a drug-related upper GI adverse event were also similar (alendronate 2.7%; placebo 2.2%; risk difference 0.4%, 95% CI, –2.4, 3.3). The overall tolerability profile of alendronate 70?mg once weekly, as measured by the percentage of subjects reporting any adverse event, was similar to that of placebo (risk difference 2.1%, 95% CI –6.9,11.0). There was a significant 43.3% (95% CI, –47.9%, –38.3%) decrease from baseline in urinary NTx/Cr in the alendronate group compared with an 8.0% (95% CI, 1.4%, 15.0%) increase in the placebo group at Week 12

Conclusion: Alendronate 70?mg administered once weekly to women and men with osteoporosis has an upper GI and overall tolerability profile similar to that of placebo.     

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.     

Clinical trial on the efficacy and safety of different diclofenac formulations: Multiple-unit formulations compared to enteric coated tablets in patients with activated osteoarthritis

—This double-blind, randomised, multicentre study investigated the efficacy and safety of two different dosages of a diclofenac sodium dual release capsule (150 mg or 75 mg once daily) in comparison to a standard treatment with enteric coated tablets (50 mg t.i.d.) and placebo in patients with activated osteoarthritis. Pain relief as the main efficacy variable was measured through 24 hours by means of a Visual Analogue Scale at baseline and on five assessment days during the 12 weeks of treatment. Efficacy was observed in all treatment groups with a statistically significant difference between the verum groups and placebo. The overall safety and tolerability of the active treatments was good. For the 75 mg group, a lower incidence of liver and biliary system-related side effects was reported. Considering efficacy, safety, and compliance aspects, the once daily administration of diclofenac sodium 75 mg dual release capsule is the appropriate dosage regimen for mid- and long-term treatment of osteoarthritis.     

Efficacy and safety of aceclofenac in the treatment of osteoarthritis: a randomized double-blind comparative clinical trial versus diclofenac - an Indian experience

OBJECTIVE: Osteoarthritis is one of the most common forms of arthritis seen in primary care. Non-steroidal anti-inflammatory drugs (NSAIDs) play an important role in the management of osteoarthritis. However, gastrointestinal (GI) side effects limit their use. Cyclooxygenase-2 (COX-2) selective inhibitors exhibit better GI tolerability than conventional NSAIDs, but their cardiovascular safety is controversial. An NSAID with high efficacy, high GI tolerability and devoid of adverse cardiovascular effects is therefore a profile preferred by physicians. Aceclofenac is an anti-inflammatory and analgesic drug with preferential COX-2 inhibition. The objective of this study was to assess the efficacy and safety of aceclofenac in the treatment of osteoarthritis in an Indian population. RESEARCH DESIGN AND METHODS: The trial was controlled, comparative, randomized, and double-blind. The study included 247 patients (82 males and 165 females, 40-82 years), suffering from osteoarthritis. Patients were randomized to receive either aceclofenac (100 mg twice daily) or diclofenac (75 mg twice daily). MAIN OUTCOME MEASURES: Clinical assessment was done at screening, randomization, and at 2 weeks, 4 weeks and 8 weeks of treatment by calculating Western Ontario MacMaster (WOMAC) scores, time taken to walk 100 feet, visual analogue scores for pain, investigator's assessment on a Likert scale and joint tenderness. Tolerability assessment was based on adverse events. Patient compliance was also assessed. RESULTS: Aceclofenac was found to be statistically superior to diclofenac in efficacy parameters of WOMAC scores, investigator's assessment and joint tenderness. Aceclofenac was found to be statistically superior to diclofenac in terms of epigastric discomfort, dyspepsia and abdominal pain. Compliance was also better with aceclofenac. The overall response of patients' osteoarthritis to aceclofenac was found to be statistically superior to diclofenac by both physician and patient. CONCLUSIONS: Aceclofenac is an effective and well-tolerated drug in osteoarthritis in the Indian setting.     

膝骨性关节炎患者平衡功能障碍及其影响因素分析

目的 探讨膝骨性关节炎（KOA）患者平衡功能及其相关影响因素。方法 选取2014年12月至2017年9月合肥市第二人民医院骨科收治的单膝受累30例KOA患者为观察对象,采用平衡测试仪对患者进行平衡功能检测,比较健、患侧测试完成耗时及平均轨迹误差,收集患者体质量指数、K-L分级、疼痛指数、美国膝关节协会评分（KSS）等指标,利用多元回归分析上述指标对患者平衡功能的影响。结果 患者健、患侧平衡指标比较,患侧平均轨迹误差值（46.63±25.30）%大于健侧值（40.77±23.85）%,差异有统计学意义（t=-2.299,P<0.05）;多元回归分析示：KSS临床评分对睁眼时前-后平均运动速度（t=-2.593,P<0.05）及重心摆动轨迹长度（t=-2.178,P<0.05）的影响具有统计学意义,对两者变异的解释比例分别为19%、15%,而疼痛指数对闭眼轨迹长度/睁眼轨迹长度比（Romberg值长度比）的影响具有统计学意义（t=-2.641,P<0.05）,解释比例为20%。结论 KOA患者存在平衡功能障碍;膝关节疼痛指数及KSS临床评分对于评估KOA患者平衡功能障碍具有重要意义。     

Efficacy and safety of oral strontium ranelate for the treatment of knee osteoarthritis: rationale and design of randomised,double-blind,placebo-controlled trial

Abstract

Objective:

The osteoporosis drug strontium ranelate dissociates bone remodelling processes. It also inhibits subchondral bone resorption and stimulates cartilage matrix formation in vitro. Exploratory studies in the osteoporosis trials report that strontium ranelate reduces biomarkers of cartilage degradation, and attenuates the progression and clinical symptoms of spinal osteoarthritis, suggesting symptom- and structure-modifying activity in osteoarthritis. We describe the rationale and design of a randomised trial evaluating the efficacy and safety of strontium ranelate in knee osteoarthritis.     

Perioperative blood loss and gastrointestinal tolerability of etoricoxib and diclofenac in total hip arthroplasty (ETO-DIC study): a single-center,prospective double-blinded randomized controlled trial

Objective:

Non-selective NSAIDs can cause serious gastrointestinal side-effects. Selective COX-2 blockers are a reasonable alternative for pain treatment. They do not seem to affect platelet function and consequently cause a lower perioperative blood loss than non-selective NSAIDs. This study compared etoricoxib and diclofenac during a perioperative (9 days) period after THA to investigate total blood loss and gastrointestinal tolerability. The hypothesis was that etoricoxib is superior to diclofenac.

Methods:

A total of 100 patients (50 in each group) were included in this trial. Etoricoxib (90?mg) was administered once and diclofenac sodium (75?mg) twice daily for 9 days. Total blood loss during and after primary cementless THA was detected. The rate of adverse events (AEs) and serious adverse events (SAEs) was analyzed to detect gastrointestinal tolerability.

Results:

The mean total blood loss (calculated) was 1548?±?SD 468?ml in the etoricoxib (ETO) group and 1649 (SD 547) ml in the diclofenac (DIC) group. The mean duration of THA was 81?min (SD 29) in the DIC and 75?min (SD 30) in the ETO group. Hence, the mean calculated total blood loss was 101?ml higher in the DIC group. This difference was not statistically significant (p?=?0.334). Fifty-six patients (28 in each group) received a cell saver retransfusion, but only one patient (ETO group) needed an additional red blood cell transfusion. The hidden blood loss was 1067?ml (SD 603) in the DIC group and 999?ml (SD 378) in the ETO group. The gastrointestinal tolerability (number of adverse and serious adverse events) was not significantly different between groups.

Conclusion:

There was no statistically significant difference in perioperative blood loss after primary THA under etoricoxib (90?mg) compared to diclofenac (75?mg). Furthermore, no gastrointestinal superiority of etoricoxib could be detected during a short period of 9 days.     

氨基葡萄糖联合推拿法治疗膝骨关节炎30例报告

目的观察氨基葡萄糖联合推拿法治疗膝骨关节炎(Knee Osteoarthritis)的疗效。方法对2004年7月至2006年12月收治的30例膝骨关节炎患者行口服氨基葡萄糖加推拿治疗,为期30d,并与对照组对照。对照组予布洛芬 维生素B治疗,共治疗30d。结果治疗组疗效优于对照组(P<0.01)。结论氨基葡萄糖配合手法是治疗膝骨关节炎的有效方法之一。     

醋氯芬酸缓释片治疗骨关节炎有效性和安全性评价

目的比较醋氯芬酸缓释片和阳性对照药醋氯芬酸片治疗骨关节炎（Osteoarthritis,OA）疗效和安全性。方法采用随机、双盲双模拟、平行对照方法,选择疾病活动期患者40例,试验组19例,对照组21例,实验药醋氯芬酸缓释片200mg,每天一次;对照药醋氯芬酸片100mg,每天二次。4周为一疗程。结果治疗4周后,醋氯芬酸缓释片总有效率为84．21％;醋氯芬酸总有效率为85．27％;两组间疗效比较差异无显著性（P〉0．05）。4周疗程后,两药均能显著改善骨关节炎患者的症状和体征（P〈0．05）。不良反应发生率试验组为10．53％,对照组为15．79％,两组间不良反应发生率统计学分析无明显差异（P〉0．05）。不良反应均以轻度消化道症状为主,无需特殊处理。结论醋氯芬酸缓释片治疗骨关节炎的疗效和安全性与醋氯芬酸片类似,但用药方便。     

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

ABSTRACT

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.     

恩再适对膝关节骨关节炎患者血TNF-α的影响

目的 观察恩再适对膝关节骨关节炎(KOA)患者血肿瘤坏死因子-α(TNF-α)的影响.方法 96例KOA患者随机均分为对照组及实验组,对照组超激光局部照射10 min,1日2次;口服洛素洛芬钠60 mg,每日3次.实验组将恩再适7.2 U加入0.9％氯化钠注射液250 ml中静滴,每日1次.两组患者均连续治疗两周.结果 治疗结束后两组患者均取得了较好的疗效,但1个月后,实验组疗效优于对照组.两组患者血TNF-α治疗结束后明显下降(P＜0.01),且实验组低于对照组(P＜0.01);1个月后,对照组升高但仍低于治疗前(P＜0.01),实验组变化不明显.结论 恩再适可有效降低KOA患者血TNF-α水平.