An alternative topical treatment of osteoarthritis of the knee with cutaneous diclofenac solution

Background: Osteoarthritis (OA) is the most common chronic degenerative disease, which is characterised by the destruction of the articular cartilage and subchondral bone. The current treatment of OA is based primarily on the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics. There are disadvantages to routinely using NSAIDs in OA. Topical NSAIDs represent a potentially important advance in this regard as they may be significantly safer than oral NSAIDs. Cutaneous diclofenac solution (Pennsaid^®) was developed for the treatment of symptomatic OA of the knee and contains diclofenac sodium as an active ingredient and dimethyl sulfoxide (DMSO), a penetration enhancer. Objective: To review: i) dermal drug application; ii) the treatment of OA with systemic and topical NSAID therapies; and iii) the clinical efficiency of Pennsaid on the topical treatment of OA of the knee. Methods: A literature search was carried out on skin, topical drug delivery, treatment of OA and assessment of published clinical studies with Pennsaid. Results and discussion: The clinical studies showed that applying the topical diclofenac solution (Pennsaid) to a painful knee with primary OA could provide symptom relief equivalent to oral diclofenac with minimal systemic side effects; however, studies are needed that compare the effectiveness of Pennsaid with different topical forms of diclofenac.     

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 and its role in pain and inflammation: an evidence-based review

ABSTRACT

Objective: Topical diclofenac is widely used in the treatment of pain and inflammation. This comprehensive review assesses the safety and efficacy of topical diclo­fenac in a range of painful and inflammatory disorders.

Methods: Double-blind, randomized, placebo- or active-controlled trials (RCT) evaluating topical diclofenac in soft-tissue injuries, soft-tissue rheumatic disorders and osteoarthritis were identified through detailed literature searches. In addition, non-RCT evidence from publications evaluating the pharmacologic characteristics of topical diclofenac were also included in this review to obtain a more complete picture of the drug's profile, its efficacy and safety.

Results: Studies demonstrate that the drug prefer­entially distributes to the target tissues in sufficient concentrations to produce a therapeutic effect. A total of 19 double-blind RCTs in more than 3000 patients, supported by single-blind or open trials, consistently show that topical diclofenac significantly reduces pain and inflammation in acute and chronic conditions compared with placebo and is comparable to other topical non-steroidal anti-inflammatory drugs (NSAIDs) and some oral NSAIDs (diclofenac, ibuprofen, naproxen). Improvements have also been observed in patients’ functional capacity and mobility. Topical diclofenac is well tolerated, resulting mostly in mild, easily resolved local skin irritation, and is associated with fewer side-effects than other topical NSAIDs and a lower rate of gastrointestinal complications than oral NSAIDs (diclofenac, ibuprofen, naproxen).

Conclusion: This evidence-based review shows topical diclofenac to be an effective and well tolerated treatment in painful and inflammatory conditions, at least in the short-term. However, only published RCT studies have been included in this analysis, which may exclude some interesting data from non-RCT studies. Future trials of topical diclofenac need to be of longer duration, be better reported and consider a broader spectrum of acute and chronic pain indications.     

Ketoprofen 2.5% gel: a clinical overview

Ketoprofen (KP), a nonsteroidal anti-inflammatory drug (NSAID), possesses analgesic, antipyretic and anti-inflammatory properties. Oral KP is widely used in musculoskeletal pain and inflammation in muscles and joints, including arthritis pain, osteoarthritis, stiffness of the joints, soft tissue rheumatism, and sports injuries. In common with all NSAIDs, oral KP has been associated with systemic adverse events and in particular gastrointestinal disorders. Topical application of the active ingredient is locally effective and at the same time minimises the risk of systemic adverse events. Pharmacokinetic studies show that serum levels of the active ingredient following topical KP 2.5% gel are less than 1% of those reported after oral dosing, thereby providing good levels of pain relief without the systemic adverse events normally associated with oral NSAIDs. In comparative studies, topical KP 2.5% gel twice daily showed clinical benefits in patients with a range of musculoskeletal conditions. KP 2.5% gel is generally well tolerated but the treated skin area should not be exposed to direct sunlight, including solarium (sunbeds), during the treatment and for 2 weeks afterwards as topical photosensitization has been reported. To our knowledge, this is the first overview on the use of topical KP (tKP) 2.5% gel which includes data from both clinical trials and from 'real-life' clinical practice.     

Biodistribution of diclofenac following repeated topical applications of two diclofenac sodium formulations to minipigs

This study evaluated diclofenac concentrations in plasma, selected hind limb tissues and synovial fluid after repeated topical applications of two diclofenac formulations. Group 1 Gottingen minipigs (n = 18) were administered diclofenac sodium 2.0% topical solution twice daily on days 1–6 and once on day 7. Group 2 minipigs (n = 18) were administered diclofenac sodium 1.5% topical solution four times daily on days 1–6 and twice on day 7. Approximately 20 mg of diclofenac was applied daily to a 10 × 15 cm dosing site centered over the patella of the right knee. Plasma and tissue samples were collected throughout and analysed for diclofenac concentrations using liquid chromatography with tandem mass spectrometry. On day 1, diclofenac sodium 2.0% topical solution produced higher plasma concentrations compared with the 1.5% formulation; however, after 24 h and throughout the remainder of the dosing period, plasma concentrations appeared similar, except at the 72 h time point. Twenty‐four hours after the final application, skin treated with diclofenac sodium 2.0% topical solution retained a significantly (p < 0.02) greater amount of diclofenac than the 1.5% formulation. Generally, both formulations produced similar diclofenac concentrations in synovial fluid, underlying muscle, tendon and bone 24 h after the last application. The 2.0% diclofenac formulation applied twice daily delivered similar amounts of diclofenac as the 1.5% formulation administered four times daily. The skin retained a significant portion of the applied dose to serve as a depot for continuous diffusion of diclofenac into underlying tissues and systemic circulation. Copyright © 2013 John Wiley & Sons, Ltd.     

双氯芬酸钠贴片治疗骨性关节炎的有效性及安全性研究

目的 研究双氯芬酸钠贴片治疗骨性关节炎的有效性及安全性。方法 采用随机、单盲、阳性药物平行对照方法，试验组给予双氯芬酸钠贴片，对照组给予双氯芬酸钠乳胶剂。记录治疗前后患者和医师对药物疗效的评价，监测不良事件的发生。结果 试验组和对照组患者对疼痛评价和总体评价的评分治疗后较治疗前下降，医师对关节压痛指数和总体评价的评分治疗后较治疗前下降，治疗后患者疼痛症状减轻。治疗过程中未见皮肤有水肿、发红、皮疹、瘙痒等及全身不适反应。血常规、肝功能、肾功能各项指标治疗前后差异无统计学意义。结论 双氯芬酸钠贴片是治疗骨性关节炎的安全有效、使用方便的外用镇痛抗炎药。     

Time to significant pain reduction following DETP application vs placebo for acute soft tissue injuries

Abstract

Objective:

Nonsteroidal anti-inflammatory drugs (NSAIDs) provide fast and effective acute pain relief, but systemic administration has increased risk for some adverse reactions. The diclofenac epolamine 1.3% topical patch (DETP) is a topical NSAID with demonstrated safety and efficacy in treatment of acute pain from minor soft tissue injuries. Significant pain reduction has been observed in clinical trials within several hours following DETP application, suggesting rapid pain relief; however, this has not been extensively studied for topical NSAIDs in general. This retrospective post-hoc analysis examined time to onset of significant pain reduction after DETP application compared to a placebo patch for patients with mild-to-moderate acute ankle sprain, evaluating the primary efficacy endpoint from two nearly identical studies.     

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).     

Favourable dermal penetration of diclofenac after administration to the skin using a novel spray gel formulation

AIMS: The study was designed to evaluate the relative bioavailability of diclofenac in plasma, subcutaneous adipose and skeletal muscle tissue after repeated topical administration using MIKA Diclofenac Spray Gel (4%), a novel formulation, and after oral dosing using VOLTAREN 50 mg enteric coated tablets. METHODS: Diclofenac (48 mg) was administered topically three times daily for 3 days onto a defined area of the thigh of 12 healthy males. After a 14-day wash out period, subjects were orally treated with 50 mg diclofenac three times daily for 3 days. In vivo microdialysis in subcutaneous and muscle tissues was performed immediately after the final doses from both treatments on day 4, and 48 h later. Plasma samples were taken simultaneously. RESULTS: The relative bioavailability of diclofenac in subcutaneous adipose and skeletal muscle tissue was substantially higher after topical compared with oral dosing (324% and 209%, respectively) whereas relative plasma bioavailability was 50-fold lower. Plasma C(max) values were approximately 250-fold lower after topical compared with oral drug administration (i.e. median values = 4.89 ng mL(-1); 95% CI: 3.37-7.68 and 1240 ng mL(-1); 95% CI: 787-1389 ng mL(-1)). Both treatments were well tolerated. CONCLUSIONS: Owing to its favourable penetration characteristics and low systemic availability, MIKA Diclofenac Spray Gel 4% is a rational alternative to oral diclofenac formulations for the treatment of inflammatory soft tissue conditions.     

Review of the pharmaceutical properties and clinical effects of the topical NSAID formulation,diclofenac epolamine

ABSTRACT

Background: Topical formulations of non-steroidal anti-inflammatory drugs (NSAIDs), in particular diclofenac (DI), have become popular for treating various acute and chronic painful inflammatory conditions.

Objective: To perform a literature review of (1) the use of topical NSAIDs; (2) the pharmaceutical, pharmacokinetic and pharmacodynamic properties of a medicated plaster (patch) containing diclofenac epolamine (DI-EP, Flector Tissugel, Flector patch^*) compared with other formulations of topical NSAIDs; and (3) evaluation of the clinical findings from studies with this novel DI-EP patch.

Outcomes: (1) Pharmacokinetic studies involved determination of DI from DI-EP and separately epolamine (EP) and the epoxide metabolite (N-oxide-EP) in laboratory animals and humans; the latter being the major metabolite in humans. About 2% of DI is absorbed by the skin in humans and is excreted in the urine. Maximum plasma concentrations of 17.4?ng/mL DI are reached at 5.4 hours (approximate steady state conditions); the plasma elimination half-time (t_½) being 26.4 hours. Low systemic levels of DI and EP are produced from DI-EP. Pronounced accumulation of DI occurs in the muscle layers and in synovial fluids of arthritic patients; (2) No significant toxicity occurs from EP nor N-oxide-EP, while that of oral DI-EP was similar to that from DI; and (3) In acute musculoskeletal conditions (sprains, tendonitis and sports injuries) and osteoarthritis DI-EP patches control pain and signs of joint or physical injury compared with placebo controls by 3–5 days with almost complete pain relief at 14 days. DI-EP was shown to have equivalent therapeutic effect to another DI diethylammonium gel formulation (Voltaren Emulgel^?).

There were no reports of serious adverse events in the gastro-intestinal (GI) tract, kidneys or liver from DI-EP. Mild GI symptoms and skin reactions occur in 2 and10% of patients, respectively.

Conclusions: The patch delivery of DI in DI-EP affords controlled delivery of the active drug in contrast to that from application of gels or ointments of NSAIDs.     

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.     

双氯芬酸钠缓释片临床观察

双氯芬酸钠缓释片用于治疗类风湿关节炎、骨关节炎、慢性腰腿痛及软组织损伤共106例,采用该药普通片为对照组共64例.结果缓释片治疗有效率类风湿关节炎为89.2%、骨关节炎为83.3%,慢性腰腿痛为79.3%,软组织损伤为87.5%,与对照组基本一致,但缓释片的不良反应较普通片小.     

消瘀散治疗急性软组织损伤的临床疗效

目的：观察消瘀散对急性软组织损伤的治疗效果。方法：将急性软组织损伤患者分为两组：治疗组35例，采用消瘀散治疗，每日1贴；对照组组32例，采用双氯芬酸二乙胺盐（扶他林）乳胶剂治疗，每日外涂3～4次。治疗周期均为7d。然后对两组患者的疼痛、压痛、肿胀、功能障碍、肌痉挛、皮肤灼热等各项症状分别进行观察和比较。结果：消瘀散和双氯芬酸二乙胺盐乳胶对急性软组织损伤均有较好的治疗效果。两组之间综合疗效的差别无统计学意义，治疗组对肌痉挛和肿胀的疗效优于对照组，对照组对皮肤灼热的疗效优于治疗组。结论：消瘀散对急性软组织损伤具有较好的治疗效果。     

Viscosupplementation with hyaluronans for osteoarthritis of the knee: clinical efficacy and economic implications

Treatment with intra-articular viscosupplementation with hyaluronan (hyaluronic acid) and its derivatives is an important component of the management of osteoarthritis (OA) of the knee. Several intra-articular hyaluronan formulations are now available that vary in their physical properties, duration of effect and treatment schedules. Although aspects regarding their mechanism of action are not completely understood, numerous clinical trials, systematic reviews and meta-analyses have confirmed the efficacy of intra-articular hyaluronan therapies for relieving OA-related pain and improving joint function. Data indicate that intra-articular hyaluronan preparations provide OA pain relief that is comparable to or greater than that observed with conventional treatment, NSAID medications, intra-articular corticosteroids, arthroscopic lavage, physical therapy and exercise. Other studies indicate that multiple courses of hyaluronan are effective. Intra-articular hyaluronan formulations are well tolerated and are associated with a low incidence of adverse effects, usually localised to the injected joint. Local adverse events associated with intra-articular hyaluronan products are typically mild to moderate in severity, benign and transient, although their aetiology is unknown. The cost effectiveness of intra-articular hyaluronan has been demonstrated, but only in a limited number of studies. Cost savings with intra-articular hyaluronan can also be realised with reduction of NSAID medication use and the possibility of delaying total knee replacement, which can reduce the need for costly revision procedures. Because different intra-articular hyaluronan formulations require different numbers of injections and office visits, are associated with variable treatment costs, and provide varying degrees of efficacy, not all intra-articular hyaluronan formulations may be equally cost effective over time.     

Diclofenac epolamine medicated plaster in the treatment of minor soft tissue injuries: a multicenter randomized controlled trial

Abstract

Objective:

To investigate the efficacy and safety of a topical plaster containing diclofenac epolamine (DHEP) 1.3% in the treatment of patients with acute minor soft tissue injuries in China.     

A new topical formulation enhances relative diclofenac bioavailability in healthy male subjects

AIMS

To evaluate the relative plasma and tissue availability of diclofenac after repeated topical administration of a novel diclofenac acid-based delivery system under development (DCF100C).

METHODS

This was a single-centre, open-label, three-period, crossover clinical trial of five discrete diclofenac formulations. Test preparations comprised two concentrations (1.0% and 2.5%) of DCF100C, with and without menthol and eucalyptus oil (total daily doses of 5 mg and 12.5 mg). Voltaren® Emulgel® gel (1.0%) was the commercially available comparator (total daily dose of 40 mg). Topical application was performed onto the thigh of 20 male healthy subjects for 3 days. Applying a Youden square design, each drug was evaluated in 12 subjects, with each subject receiving three test preparations. Blood sampling and in vivo microdialysis in subcutaneous adipose and skeletal muscle tissues were performed for 10 h after additional final doses on the morning of day 4.

RESULTS

All four DCF100C formulations demonstrated a three- to fivefold, dose-dependent increase in systemic diclofenac availability compared with Voltaren® Emulgel® and were approximately 30–40 times more effective at facilitating diclofenac penetration through the skin, taking different dose levels into account. Tissue concentrations were low and highly variable. The 2.5% DCF100C formulation without sensory excipients reached the highest tissue concentrations. AUC(0,10 h) was 2.71 times greater than for Voltaren® Emulgel® (90% CI 99.27, 737.46%). Mild erythema at the application site was the most frequent adverse event associated with DCF100C. There were no local symptoms after treatment with the reference formulation.

CONCLUSION

DCF100C formulations were safe and facilitated greater diclofenac penetration through the skin compared with the commercial comparator. DCF100C represents a promising alternative to oral and topical diclofenac treatments that warrants further development.     

Comparative pharmacokinetics and bioavailability study of percutaneous absorption of diclofenac from two topical formulations containing drug as a solution gel or as an emulsion gel.

In a 3-way cross-over study on 12 healthy adult volunteers, the percutaneous absorption of diclofenac (CAS 15307-79-6) was studied for two topical formulations containing 1% diclofenac. The relative bioavailability from the test formulation (a solution gel) in terms of Cmax and AUC, calculated from the amount of drug reaching the systemic circulation, was found to be twice the amount after application of reference product (an emulsion gel). The maximum concentration of the drug, from both topical formulations reaching the blood after cutaneous absorption was less than 10% of that obtained after the parenteral administration, which indirectly is indicative that adverse effects normally related to high drug blood concentrations, such as reached after oral administration, are unlikely to be experienced.     

Oxybutynin chloride topical gel: a new formulation of an established antimuscarinic therapy for overactive bladder

Background: Oxybutynin, a cholinergic-muscarinic receptor antagonist, is established as a safe and effective pharmacological treatment for patients with overactive bladder syndrome (OAB). Oxybutynin is available in multiple immediate- and extended-release oral and two transdermal formulations. Oxybutynin chloride topical gel (OTG) (Gelnique^®, Watson Pharmaceuticals, Corona, CA, USA) was approved in January 2009 by the US FDA. OTG was designed to provide consistent plasma oxybutynin levels with daily application, favorably altering the circulating N-desethyloxybutynin metabolite:oxybutynin ratio, and to utilize a biocompatible delivery system, thus minimizing both the anticholinergic adverse effects of oral formulations and the application-site skin reactions associated with other available forms of transdermal delivery. Objective/methods: This review summarizes the pharmacological properties and the clinical efficacy and safety profile of OTG based on the published literature and unpublished data provided by the manufacturer upon request. Results/conclusion: OTG represents an efficacious, safe, and convenient alternative to other oxybutynin formulations and other oral anticholinergic medications for the treatment of OAB. Future studies and broad clinical experience should confirm the promising early experience observed with this formulation.     

Extent and time course of pain intensity upon treatment with a topical diclofenac sodium patch versus placebo in acute traumatic injury based on a validated end point: post hoc analysis of a randomized placebo-controlled trial

Objective: To investigate the extent and time course of pain intensity upon treatment with a topical diclofenac patch compared with placebo in acute traumatic sport injury based on a validated and established end point. Methods: Post hoc analysis of a randomized, placebo-controlled, double-blind, multicentre, 1-week study in 120 patients with traumatic blunt soft tissue injury. Visual analogue scale (VAS) scores (in millimetres) for pain on movement were analysed. The mean absolute VAS changes in pain intensity from baseline over the study course were calculated for the diclofenac patch formulation (active) and placebo; mean differences between active and placebo were assessed twice daily during the first 3 days after enrolment and then once daily up to day 7. Results: The diclofenac patch was consistently superior to placebo in relieving pain. The mean differences compared with placebo were greatest on day 2 (23.6 – 30.6 mm, p <?0.0001) and day 3 (24.5 – 24.6 mm, p <?0.0001). Diminishing differences were observed over the study course. Conclusion: The investigated diclofenac sodium patch provides clinically relevant pain relief in patients with acute traumatic injuries. Maximum effects versus placebo are detected at 2 – 3 days post-injury. This analysis may serve as useful information for the planning of clinical trials in acute traumatic injury.