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.     

Rationale and evidence for the incorporation of heparin into the diclofenac epolamine medicated plaster

Objective: The nonsteroidal anti-inflammatory drug (NSAID) diclofenac epolamine (DHEP) formulated as a topical patch has demonstrated efficacy and safety in the localized treatment of acute pain from minor strains, sprains and contusions, and for epicondylitis and knee osteoarthritis. The glycosaminoglycan heparin enhances the activity of topical NSAIDs formulated as a medicated plaster, even in the absence of any significant release of heparin. Therefore, DHEP plus, a new formulation of the DHEP medicated plaster containing a small amount of heparin sodium as excipient, has been developed.

Methods: We reviewed the pivotal and supportive studies of the clinical development program of the new patch and evaluated the role of heparin as an enhancer in the treatment of localized pain/inflammation of musculoskeletal structures, associated with post-traumatic and/or rheumatic conditions.

Results: The data was consistent with the concept that heparin increased the clinical activity of the DHEP plus medicated plaster versus the reference DHEP medicated plaster through improved bioavailability due to enhanced movement of diclofenac from the plaster. Both DHEP formulations have the same dissolution profile, indicating that heparin does not change the physical and chemical characteristics of the plaster. Permeation testing showed that heparin is not released from the DHEP plus medicated plaster. Efficacy studies showed that the DHEP plus medicated plaster was significantly more effective in reducing pain than the reference marketed DHEP medicated plaster.

Conclusions: The benefit/risk assessment of DHEP plus 180?mg medicated plaster is favorable, with a safety profile equal to placebo and improved efficacy over the reference marketed DHEP medicated plaster.     

Efficacy of a paracetamol–pseudoephedrine combination for treatment of nasal congestion and pain-related symptoms in upper respiratory tract infection

ABSTRACT

Objective: This study compared the efficacy of 1000?mg of paracetamol combined with 60?mg of pseudoephedrine, with that of either paracetamol or pseudoephedrine alone and placebo for the treatment of symptomatic URTI.

Research design and methods: A double‐blind, parallel group study was performed on 305 patients with URTI (nasal airflow resistance [NAR] of > 0.25 Pa cm³ s and a global pain score of at least moderate intensity). NAR and pain relief/intensity scores were measured over 4?h after initial dose. Patients then dosed up to three times daily for 3 days and recorded nasal congestion and pain intensity scores.

Main outcome measures: Nasal airflow conductance (NAC) and pain relief after the initial dose were primary objectives. NAC was calculated from NAR. Pain relief was measured on a 5‐point verbal rating scale (VRS) and pain intensity and nasal congestion on a 4‐point VRS. Data were analysed using analysis of covariance. Safety was assessed by adverse events.

Results: A single dose of the combination was superior to paracetamol and placebo for NAC (?p = 0.0001) and was superior to pseudoephedrine and placebo for pain relief (?p ≤ 0.048). Multiple doses of the combination were also superior to paracetamol and placebo for decongestion (?p ≤ 0.021) and were superior to pseudoephedrine and placebo for pain reduction (?p ≤ 0.0057). All treatments were well tolerated.

Conclusions: The combination treatment provided a greater decongestant effect than either paracetamol or placebo and better pain relief than either pseudoephedrine or placebo. The additive effect of the combination was apparent for both single and multiple doses.     

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.     

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.     

Extended-release tramadol in the treatment of osteoarthritis:a multicenter,randomized, double-blind,placebo-controlled clinical trial

ABSTRACT

Objective: This study evaluated the efficacy and safety of tramadol extended-release (tramadol ER) tablets once daily in subjects with osteoarthritis pain.

Methods: This 12‐week, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial included 1020 adults with osteoarthritis of the knee or hip and baseline pain intensity ≥ 40 on a 100‐mm pain visual analog scale (0 = no pain, 100 = extreme pain). Subjects took placebo or were titrated to a target dose of tramadol ER 100, 200, 300, or 400?mg once daily.

Main outcome measures: The co-primary efficacy variables were pain and physical function subscales of the WOMAC Osteoarthritis Index and subject global assessment of disease activity.

Results: Mean changes in WOMAC Osteoarthritis Index pain and physical function subscales were significantly different between tramadol ER and placebo, overall (?p ≤ 0.021) and for each dose (?p ≤ 0.050). However, the protocol-specified decision rule for the 3 co-primary endpoints was not satisfied because the overall comparison of subject global assessment of disease activity was not statistically significant (?p = 0.079). All doses of tramadol ER once daily were more effective than placebo (?p ≤ 0.050) for WOMAC Osteoarthritis Index joint stiffness subscale, WOMAC Osteoarthritis Index composite score, pain intensity of the index joint, and daily pain intensity scores. Tramadol ER 200 and 300?mg were significantly more effective than placebo (?p ≤ 0.050) for subject global assessment of disease activity and pain intensity of non-index joints. Adverse events (e.g., constipation, dizziness, nausea, somnolence, headache) occurred most often with tramadol ER 400?mg.

Conclusions: Tramadol ER 100–300?mg once daily was associated with significant improvement in pain intensity and physical function, and was well tolerated, despite the use of a fixed-dose study design not reflective of usual clinical practice. Tramadol ER is a useful treatment option for patients with osteoarthritis pain.     

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.     

Chondroitin sulphate for symptomatic osteoarthritis: critical appraisal of meta-analyses

ABSTRACT

Background: Chondroitin sulphate (CS) is an important structural component of cartilage and is approved and regulated as a symptomatic slow-acting drug for osteoarthritis (OA) (SYSADOA) in Europe and some other countries. Although numerous studies have shown the clinical benefits of CS to decrease pain, improve functional disability, reduce non-steroidal anti-inflammatory drug (NSAID) or acetaminophen consumption, and good tolerability with an additional carry-over effect, there are still some concerns regarding its effectiveness in treating OA.

Purpose: To examine the data provided by meta-analyses to clarify the effectiveness of CS as a symptomatic treatment for OA.

Methods: A MEDLINE database search was conducted for appropriate meta-analyses published between 1997 and 2007. Five meta-analyses that limited their analysis to randomised controlled trials (RCTs) comparing CS with placebo or no-treatment control arms were retrieved.

Results: Four meta-analyses showed significant clinical effects of CS compared with placebo for pain and function measures and one demonstrated greater reduction of analgesic co-medication in patients assigned to the active treatment. In one meta-analysis, the 20 trials included in the study showed a high degree of heterogeneity and the conclusion that CS showed minimal symptomatic benefits was based on the analysis of only three trials. One meta-analysis showed that pain relief after CS treatment steadily increased between 4 and 12 weeks of treatment, whereas the time course of pain relief after treatment with NSAIDs decreased. Two meta-analyses reported consistently higher frequencies of side effects in the placebo group than in patients treated with CS.

Conclusion: Data provided by these meta-analyses indicate that CS has a slight to moderate efficacy in the symptomatic treatment of OA, with an excellent safety profile.     

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.     

Lidocaine medicated plaster,an additional potential treatment option for localized post-surgical neuropathic pain: efficacy and safety results of a randomized,placebo-controlled trial

Objective: To assess the efficacy and safety of lidocaine 700?mg medicated plaster (lidocaine plaster) compared to placebo in patients with moderate to severe chronic post-surgical neuropathic pain (PSNP).

Methods: Patients (n?=?363) with a diagnosis of PSNP for a minimum of 3?months to 36?months were randomized (1:1) to lidocaine plaster or placebo for a 12 week double-blind treatment period. Randomization was stratified as “plaster-only” (no concomitant medication for PSNP) or as “add-on” (stable systemic medication for PSNP). The primary efficacy endpoint was the change from baseline in 24?hour average pain intensity at Week 12, assessed by 11?point numerical rating scale (NRS). The trial was registered in ClinicalTrials.gov (NCT01752322) and EudraCT (2012-000347-28).

Results: Treatment with lidocaine or placebo plaster led to a clinically relevant reduction in average pain intensity. Pain reduction (least squares mean [LS mean] standard error [SE], [95% confidence interval, CI]) with lidocaine plaster (?1.70 [0.16], [?2.03, ?1.38]) was numerically higher than with placebo (?1.47 [0.16], [?1.78, ?1.15]) but the difference was not statistically significant (?0.23 [0.23], [?0.69, 0.22]). Pre-specified exploratory subgroup analyses showed the largest differentiation between lidocaine and placebo in patients without concomitant pain medication, and in patients with more than 1?year between surgery and enrollment. Many secondary outcomes showed a numerically larger improvement in favor of lidocaine. The most commonly reported adverse events were administration site reactions linked to topical administration.

Conclusions: A clinically relevant pain reduction was observed with lidocaine plaster in patients with PSNP. The safety and tolerability profile is consistent with current knowledge.     

Efficacy and tolerability of DHEP-heparin plaster in reducing pain in mild-to-moderate muscle contusions: a double-blind, randomized trial

Abstract Objectives: To investigate if the 180-mg diclofenac epolamine and heparin sodium 5600?IU medicated plaster (DHEP-heparin) is more effective for pain reduction in mild-to-moderate contusions than the reference diclofenac epolamine 180?mg plaster (DHEP). Research design and methods: This multicenter, multinational, prospective, double-blind versus reference comparator and versus placebo, controlled trial had balanced random assignment in three parallel treatment groups. The DHEP-heparin medicated plaster was compared to the DHEP medicated plaster and a placebo medicated plaster. A total of 331 outpatients, aged ≥18 and ≤65 years, with unilateral mild-to-moderate muscle contusion, pain on standardized movement of ≥50?mm, and superficial hematoma of ≤10?×?14?cm(2) completed the study. Plasters were applied each morning, for ≥20 hours daily for 14 consecutive days. Outcomes were assessed in three visits, over 14 days, plus patients' daily self-assessment. Clinical trial registration: 05DCz/FHp11 - Eudra CT n: 2005-003829-31 Main outcome measures: Primary efficacy endpoint was mean change from baseline in pain on movement after 3 days of treatment, compared between groups. Secondary efficacy endpoints included mean daily change from baseline in pain on movement during treatment, pain level as assessed at control visits after 7 and 14 days, time (days) to hematoma disappearance based on patients' daily evaluations, rescue medication use, and overall treatment efficacy as judged by both patients and investigators. Results: Pain progressively declined in all groups, more rapidly in DHEP-heparin recipients, compared to DHEP, and in both active treatment groups compared to placebo. Adverse events were recorded in 24 of the 355 (6.7%) exposed patients, and generally resolved without need to interrupt treatment. Conclusion: The DHEP-heparin plaster is superior to the reference DHEP plaster in reducing pain associated with mild-to-moderate muscle contusion. Both active treatments were significantly more effective than placebo, and each showed a comparably favorable, placebo-like safety profile.     

A 12-week,randomized, placebo-controlled trial assessing the safety and efficacy of oxymorphone extended release for opioid-naive patients with chronic low back pain

ABSTRACT

Objective: Determine the efficacy and tolerability of oxymorphone extended release (OPANA ER) in opioid-naive patients with moderate to severe chronic low back pain (CLBP).

Design and methods: Patients ≥ 18 years of age were titrated with oxymorphone ER (5- to 10?mg increments every 12?h, every 3–7 days) to a well-tolerated, stabilized dose. Patients were then randomized to continue their oxymorphone ER dose or receive placebo every 12?h for 12 weeks. Oxymorphone immediate release was available every 4–6?h, as needed, for the first 4 days and twice daily thereafter.

Results: Sixty-three percent of patients (205/325) were titrated to a stabilized dose of oxymorphone ER, most (203/205) within 1 month. During titration, 18% discontinued from adverse events (AEs) and 1% from lack of efficacy. For patients completing titration, average pain intensity decreased from 69.4?mm at screening to 22.7?mm (?p < 0.0001). After random­ization, 68% of oxymorphone ER and 47% of placebo patients completed 12 weeks of double-blind treatment. Approximately 8% of patients in each group discontinued because of AEs. Placebo patients discontinued significantly sooner from lack of efficacy than those receiving oxymorphone ER (?p < 0.0001). Pain intensity increased significantly more in the placebo group (least squares [LS] mean change 26.9 ± 2.4 [median 28.0]) than in the oxymorphone ER group (LS mean change 10.0 ± 2.4 [median 2.0]; p < 0.0001). Oxymorphone ER was generally well tolerated without unexpected AEs. Although limitations of a randomized withdrawal study include the potential for unblinding and opioid withdrawal in placebo patients, opioid withdrawal was limited to two patients in the placebo group and one in the oxymorphone ER group.

Conclusions: Stabilized doses of oxymorphone ER were generally safe and effective over a 12?week double-blind treatment period in opioid-naive patients with CLBP.     

The efficacy of rofecoxib 50 mg and hydrocodone/acetamino­phen 7.5/750 mg in patients with post-arthroscopic pain

ABSTRACT

Objective: To compare the efficacy and tolerability of rofecoxib, hydrocodone/acetaminophen 7.5?mg/750?mg (H/A) and placebo in treating pain after arthroscopy of the knee.

Methods: A randomized, double-blind, placebo-controlled, single dose study enrolling patients experiencing moderate or severe pain after knee arthroscopy. Patients with moderate-to-severe postoperative pain received either rofecoxib 50?mg (n = 151), H/A (n = 145), or placebo (n = 147). Pain was measured over 24?h. The primary endpoint was total pain relief at 6?h for rofecoxib 50?mg compared with placebo.

Results: H/A (?p = 0.003), but not rofecoxib (?p = 0.256) was significantly more effective than placebo for total pain relief at 6?h (TOPAR6). Although analgesic onset and peak were significantly better for H/A than for both rofecoxib (?p < 0.01, p < 0.05, respectively) and placebo (?p < 0.05, p < 0.001, respectively), rofecoxib patients used significantly less rescue analgesia (?p < 0.001) over 24?h. Rofecoxib also provided better Brief Pain Inventory Severity (?p = 0.008) and Interference Domain (?p = 0.045) scores at 24?h compared to placebo and had lower 24?h Pain Severity scores than H/A (?p < 0.05). Treatments were generally well tolerated, with no significant difference in the frequency of patient-reported adverse events between groups.

Conclusions: Rofecoxib 50?mg did not provide significantly different pain relief than placebo at 6?h, and the primary endpoint TOPAR was not attained, although it did show several efficacy benefits at 24?h, including a significant opioid-sparing effect. All treatments were well tolerated, with no significant differences observed. The limited efficacy of rofecoxib in this study contrasts to the results of previous surgical studies evaluating rofecoxib, and may be partially explained by the postoperative dosing in this arthroscopic surgical model.     

Topical lidocaine patch 5% may target a novel underlying pain mechanism in osteoarthritis

SUMMARY

Recent literature and animal research has provided insight to potentially new analgesic targets for managing osteoarthritis (OA) pain. Primary afferent neurons located in affected joints express excessive amounts of abnormally functioning sodium (Na) channels on their surface in response to the inflammatory process. These Na channels may play an integral role in production of pain and hyperalgesia. Hence, the authors set out to conduct a 2-week, open-label, multicenter proof-of-concept study to evaluate the effectiveness and safety of lidocaine patch 5% monotherapy in adults with OA pain of the knee (?n = 20). Patients with OA of one or both knees who were experiencing inadequate pain relief (defined as an average daily pain intensity of > 4 on a 0 to 10 pain scale) with their current analgesic regimen (i.e. APAP, NSAIDs, COX-2 inhibitors, tramadol) were enrolled and had all analgesic medications discontinued. Treatment with the lidocaine patch 5% resulted in significant improvements in the Western Ontario and McMaster Universities OA Index (WOMAC) pain, stiffness, physical function subscales and composite index (48.4, 41.1, 47.0, and 46.8% improvements respectively, p < 0.01). In addition, significant improvement was noted for pain intensity, pain relief, and pain interference with quality of life as measured by the Brief Pain Inventory (?p < 0.05). The lidocaine patch 5% was generally well tolerated and no patients discontinued due to treatment-related adverse events. Given the open-label design, lack of a control group, and small sample size, the findings from our pilot study need to be confirmed by larger randomized controlled trials. Topical lidocaine patch 5% may provide clinicians with a novel, non-systemic therapy for OA pain with a unique mechanism of action.     

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.     

活血止痛胶囊联合依托考昔治疗膝关节骨性关节炎的疗效观察

目的探讨活血止痛胶囊联合依托考昔治疗膝关节骨性关节炎的临床疗效。方法选取选取2016年2月—2017年2月天津中医药大学第一附属医院骨伤科膝关节骨性关节炎患者60例,随机分为对照组和治疗组,每组各30例。对照组患者饭后口服依托考昔片,1片/次,1次/d。治疗组在对照组治疗基础上口服活血止痛胶囊,6粒/次,2次/d。两组均连续治疗4周。观察两组的临床疗效,比较两组治疗前后VAS评分、WOMAC评分、Lysholm评分、Lequesne指数、患肢红外热成像温度的变化情况。结果治疗后,对照组和治疗组的总有效率分别为86.67%、96.67%,两组比较差异具有统计学意义(P0.05)。治疗后,两组VAS评分、WOMAC评分和Lequesne指数均较治疗前显著降低,Lysholm评分较治疗前显著升高,同组治疗前后比较差异具有统计学意义(P0.05);治疗后,治疗组VAS评分、WOMAC评分和Lequesne指数低于对照组,Lysholm评分高于对照组,两组比较差异有统计学意义(P0.05)。治疗后,两组患膝红外热成像温度均较治疗前显著降低,同组治疗前后比较差异具有统计学意义(P0.05);治疗后治疗组患膝红外热成像温度低于对照组,两组比较差异有统计学意义(P0.05)。结论活血止痛胶囊联合依托考昔治疗膝关节骨性关节炎具有较好的临床疗效,能减轻患者膝关节疼痛和改善膝关节功能,降低患膝红外热成像温度,具有一定的临床推广应用价值。     

Randomized study of tramadol/acetaminophen versus placebo in painful diabetic peripheral neuropathy

ABSTRACT

Objective: To examine the efficacy and safety of tramadol/acetaminophen (APAP) for the management of painful diabetic peripheral neuropathy (DPN).

Methods: Adults with painful DPN involving the lower extremities received 37.5?mg tramadol/325?mg APAP or placebo, up to 1–2 tablets four times daily, for 66 days. Subjects rated average daily pain and sleep interference from 0 (‘none’) to 10 (‘pain as bad as you can imagine’ or ‘complete interference’) every night. Baseline values were recorded for 7 days before starting study medication. The primary endpoint was change in mean of average daily pain scores from baseline to final week. Secondary efficacy outcomes included pain intensity, sleep interference, quality of life, mood, and global impression of change. Potential study limitations included permission to use serotonin reuptake inhibitors concomitantly (except venlafaxine or duloxetine) and the lack of a tramadol-alone or APAP-alone control group.

Results: A total of 160 subjects received tramadol/APAP and 153 received placebo. Tramadol/APAP reduced average daily pain significantly compared to placebo from baseline to the final week (–2.71 vs. –1.83, p = 0.001). Tramadol/APAP was associated with significantly greater improvement than placebo (?p ≤ 0.05) for all measures of pain intensity, sleep interference, and global impression, as well as several measures of quality of life and mood. The only adverse event reported by > 10% of subjects in either the tramadol/APAP or placebo group was nausea (11.9% and 3.3%, respectively). Adverse events resulted in early study discontinuation for 8.1% and 6.5% of subjects in the tramadol/APAP and placebo groups, respectively.

Conclusion: Tramadol/APAP was more effective than placebo and was well tolerated in the management of painful DPN.     

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 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.     

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.