Efficacy and safety of a topical diclofenac solution (pennsaid) in the treatment of primary osteoarthritis of the knee: a randomized, double-blind, vehicle-controlled clinical trial. Effect of a topical diclofenac solution for relieving symptoms of primary osteoarthritis of the knee: a randomized controlled trial. Treatment of osteoarthritis of the knee with a topical diclofenac solution: a randomised controlled, 6-week trial [ISRCTN53366886]. Equivalence study of a topical diclofenac solution (pennsaid) compared with oral diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial. Diclofenac sodium gel in patients with primary hand osteoarthritis: a randomized, double-blind, placebo-controlled trial. Safety and efficacy of topical diclofenac sodium gel for knee osteoarthritis in elderly and younger patients: pooled data from three randomized, double-blind, parallel-group, placebo-controlled, multicentre trials. Topical diclofenac patch in patients with knee osteoarthritis: a randomized, double-blind, controlled clinical trial. Intraindividual differences in pain relief and functional improvement in osteoarthritis with diclofenac or tramadol. Local NSAID gel (eltenac) in the treatment of osteoarthritis of the knee. A double blind study comparing eltenac with oral diclofenac and placebo gel.
Oral nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to relieve the symptoms of osteoarthritis (OA) but can produce harmful systemic effects and end-organ damage. A topical NSAID formulation may provide symptom relief with fewer adverse effects. A new topical diclofenac sodium solution-containing the absorption enhancer dimethyl sulfoxide-was evaluated for the relief of the symptoms of primary OA of the knee.
                A total of 326 patients met entry criteria (including abnormal radiographic findings and flare of pain) and were randomized to receive 40 drops of topical diclofenac solution or a vehicle-control solution, 4 times daily, for 12 weeks. We evaluated 3 primary outcome measures, the Western Ontario McMaster Universities LK3.1 OA Index (WOMAC) pain and physical function subscales and a patient global assessment, and 2 other measures, stiffness and pain on walking, at baseline and after final application. We assessed safety by evaluation of adverse events, vital signs, and irritation at the application site.
                Topical diclofenac solution was significantly more effective than the vehicle-control solution for all outcome measures; pain, P = .001; physical function, P = .002; patient global assessment, P = .003; stiffness, P = .005; and pain on walking, P = .004. Among patients receiving topical diclofenac, self-limiting minor skin irritation occurred in 68 (41.5%) of 164 patients, including dryness in 60 (36.6%), rash in 18 (11.0%), and paresthesia, pruritus, and vesiculobullous rash in 1 (0.6%) each. There was no significant difference between groups in NSAID-related gastrointestinal tract complaints or in dropouts due to study-related adverse effects.
                Topical diclofenac is effective in the treatment of the symptoms of primary OA of the knee, with only minor local irritation and no significant systemic adverse events. Treatment of osteoarthritis with oral NSAID therapy provides pain relief but carries a substantial risk of adverse effects. Topical NSAID therapy offers an alternative to oral treatment, with the potential for a reduced risk of side effects. The objective of this trial was to assess the safety and efficacy of a topical diclofenac solution in relieving the symptoms of primary osteoarthritis of the knee.
                We identified 248 men and women from southern Ontario with primary osteoarthritis of the knee and at least moderate pain. The patients were randomly assigned to apply 1 of 3 solutions to their painful knee for 4 weeks: a topical diclofenac solution (1.5% wt/wt diclofenac sodium in a carrier containing dimethyl sulfoxide [DMSO]); a vehicle-control solution (the carrier containing DMSO but no diclofenac); and a placebo solution (a modified carrier with a token amount of DMSO for blinding purposes but no diclofenac). The primary efficacy end point was pain relief, measured by the Western Ontario and McMaster Universities (WOMAC) LK3.0 Osteoarthritis Index pain subscale. Secondary end points were improved physical function and reduced stiffness (measured by the WOMAC subscales), reduced pain on walking and patient global assessment (PGA). Safety was evaluated with clinical and laboratory assessments.
                In the intent-to-treat group the mean change (and 95% confidence interval [CI]) in pain score from baseline to final assessment was significantly greater for the patients who applied the topical diclofenac solution (-3.9 [- 4.8 to -2.9]) than for those who applied the vehicle-control solution (-2.5 [- 3.3 to -1.7]; p = 0.023) or the placebo solution (-2.5 [-3.3 to -1.7]; p = 0.016). For the secondary variables the topical diclofenac solution also revealed superiority to the vehicle-control and placebo solutions, leading to mean changes (and 95% CIs) of -11.6 (-14.7 to -8.4; p = 0.002 and 0.014, respectively) in physical function, -1.5 (-1.9 to -1.1; p = 0.015 and 0.002, respectively) in stiffness and -0.8 (-1.1 to -0.6; p = 0.003 and 0.015, respectively) in pain on walking. The PGA scores were significantly better for the patients who applied the topical diclofenac solution than for those who applied the other 2 solutions (p = 0.039 and 0.025, respectively). The topical diclofenac solution caused some skin irritation, mostly minor local skin dryness, in 30 (36%) of the 84 patients, but this led to discontinuation of treatment in only 5 (6%) of the cases. The incidence of gastrointestinal events did not differ between the treatment groups. No serious gastrointestinal or renal adverse events were reported or detected by means of laboratory testing.
                This topical diclofenac solution can provide safe, site-specific treatment for osteoarthritic pain, with only minor local skin irritation and minimal systemic side effects. Topical NSAIDs have been proven to relieve the symptoms of osteoarthritis (OA) in short-term studies (2 weeks). To justify its chronic use, efficacy of a topical NSAID over a longer term of study should be demonstrated. The efficacy and safety of a topical diclofenac solution over a 6-week treatment course in symptomatic primary OA of the knee was investigated.
                216 men and women, age 40-85 years, with radiologically confirmed primary OA of the knee and a flare of pain at baseline following discontinuation of prior therapy were enrolled into this double-blind study. Participants applied either a topical diclofenac solution (Pennsaid) or vehicle control solution (carrier with no diclofenac); 40 drops 4 times daily directly to the painful knee(s), without massage, for 6 weeks. Pre-planned primary efficacy outcome measures included the core continuous variables pain relief and improved physical function measured by the Western Ontario and McMaster Universities (WOMAC) LK3.1 OA Index, and improved patient global assessment (PGA). Secondary efficacy measure was reduced stiffness. Safety assessments included adverse events and vital signs.
                The topical diclofenac group had a significantly greater mean change in score (final minus baseline) compared to the vehicle control group for pain (-5.2 vs. -3.3, p = 0.003), physical function (-13.4 vs. -6.9, p = 0.001), PGA (-1.3 vs. -0.7, p = 0.0001) and stiffness (-1.8 vs. -0.9, p = 0.002). The mean difference between treatment arms (95% confidence interval [CI]) was 1.9 (0.7 to 3.2), 6.5 (2.5 to 10.5), 0.6 (0.2 to 0.9), and 0.9 (0.3 to 1.4), respectively. Safety analyses showed that topical diclofenac caused skin irritation, mostly minor local skin dryness, in 42/107 (39%), leading to discontinuation of treatment in 5/107 (5%) participants.
                This topical diclofenac solution demonstrated relief at 6 weeks of the symptoms of primary osteoarthritis of the knee. . To compare the safety and efficacy of a topical diclofenac solution versus oral diclofenac in relieving the symptoms of primary osteoarthritis (OA) of the knee, in a randomized, double-blind, double-dummy equivalence trial.
                A total of 622 men and women with radiological evidence of primary knee OA and mild to severe symptoms were randomly assigned to treatment with a topical diclofenac solution plus placebo oral capsules, or placebo topical solution plus oral diclofenac (50 mg) capsules. Patients applied 50 drops of study solution and took 1 study capsule 3 times daily for 12 weeks. Efficacy variables were pain and physical function, measured by the Western Ontario and McMaster Universities (WOMAC) VA 3.1 OA Index, and patient global assessment (PGA). Equivalence in the per-protocol group was based on previously defined ranges of clinically significant difference. Safety was assessed by evaluation of adverse events, vital signs, and laboratory data.
                The difference in mean (95% CI) change scores (final minus baseline) between treatments was 13.3 mm (-8.6 to 35.2) for pain (total scale 500 mm), 71.0 mm (-2.4 to 144.5) for physical function (total scale 1700 mm), and 4.3 mm (-1.2 to 9.8) for PGA (total scale 100 mm). The CI for each efficacy variable fell within the predefined equivalence ranges (pain, +/- 75 mm; physical function, +/- 255 mm; PGA, +/- 20 mm), indicating that no clinically relevant difference was found between the 2 treatment arms. Safety analyses of patients applying topical diclofenac solution revealed some minor skin irritation at the application site--mostly skin dryness in 83/311 (27%) patients--but a significantly reduced incidence, relative to oral diclofenac, of total and severe gastrointestinal (GI) adverse events, including dyspepsia, abdominal pain, diarrhea, and nausea. The number of patients developing abnormal liver function tests (including clinically significant elevation), hemoglobin, and creatinine clearance was significantly higher in the oral diclofenac group.
                Application of this topical diclofenac solution to the knee of patients with OA produced relief of symptoms equivalent to oral diclofenac, with minor local skin irritation, but significantly reduced incidence of diclofenac-related GI complaints and abnormal laboratory values. To measure the efficacy and safety of diclofenac sodium gel in patients with primary hand osteoarthritis (OA).
                In a randomized, double-blind, placebo-controlled trial, men and women aged > or = 40 years diagnosed with primary OA in the dominant hand were randomly assigned to self-apply topical 1% diclofenac sodium gel (Voltaren Gel) (n = 198) or vehicle (n = 187) to both hands 4 times daily for 8 weeks. Primary outcome measures included OA pain intensity (100-mm visual analog scale), total Australian/Canadian Osteoarthritis Hand Index (AUSCAN) score, and global rating of disease activity at 4 and 6 weeks. Secondary outcomes included onset of efficacy in Weeks 1 and 2, durability of efficacy at 8 weeks, measures of disease activity in the dominant hand, pain intensity in the non-dominant hand, AUSCAN subindices, end of study rating of efficacy, and Osteoarthritis Research Society International response criteria.
                Diclofenac sodium gel decreased pain intensity scores by 42%-45%, total AUSCAN scores by 35%-40%, and global rating of disease by 36%-40%. Significant differences favoring diclofenac sodium gel over vehicle were observed at Week 4 for pain intensity and AUSCAN, with a trend for global rating of disease activity. At Week 6, diclofenac sodium gel treatment significantly improved each primary outcome measure compared with vehicle. Secondary outcomes generally supported the primary outcomes. The most common treatment-related adverse event (AE) was application-site paresthesia. Most AE were mild. No cardiac events, gastrointestinal bleeding, or ulcers were reported.
                Topical diclofenac sodium gel was generally well tolerated and effective in primary hand OA. (NCT ID: NCT00171665). NSAIDs used for the treatment of osteoarthritis (OA) have dose-related risks for gastrointestinal, cardiovascular and renal adverse events (AEs), particularly in elderly patients. Topical NSAIDs reduce systemic NSAID exposure and may mitigate these risks.
                To evaluate the safety and efficacy of topical diclofenac sodium 1% gel (DSG) versus vehicle in patients aged 25-64 or ≥65 years who have been diagnosed with knee OA.
                Pooled data from three 12-week, randomized, double-blind, parallel-group, multicentre trials.
                US primary care, internal medicine, orthopaedic and rheumatology practices.
                Aged ≥25 years with mild to moderate (Kellgren-Lawrence grade 1-3) knee OA.
                After a 1-week analgesic washout, patients applied 4 g of DSG or vehicle four times daily to one knee. Rescue paracetamol (acetaminophen) up to 4 g/day was allowed.
                Key efficacy outcomes common to the three trials were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain (0-20) and physical function (0-68) subscales, global rating of disease (GRD; 100-mm visual analogue scale [VAS]) and pain on movement (POM; 100-mm VAS). ANOVA was used to compare efficacy outcome differences (DSG vs vehicle) by age (25-64 or ≥65 years). A flare design was used that defined a subset of patients who experienced increased pain during the washout period (modified efficacy subpopulation [MES]).
                The MES included both patients aged 25-64 (n = 602) and ≥65 (n = 374) years. Patients in each age group applied >90% of scheduled doses. Among patients aged 25-64 years, the improvement from baseline to week 12 (least squares mean [standard error]) was greater for DSG versus vehicle for WOMAC pain (-5.8 [0.3] vs -4.7 [0.3], p = 0.007), WOMAC physical function (-17.9 [0.9] vs -14.2 [0.9], p = 0.002), GRD (-29.5 [1.6] vs -23.8 [1.6], p = 0.01) and POM (-37.3 [1.8] vs -29.0 [1.8], p < 0.001). Among patients aged ≥65 years, the improvements from baseline for most efficacy outcome scores were significantly greater with DSG versus vehicle: WOMAC pain (-5.3 [0.3] vs -4.1 [0.4], p = 0.02), WOMAC physical function (-15.5 [1.1] vs -11.0 [1.1], p = 0.004) and POM (-33.7 [2.2] vs -26.4 [2.2], p = 0.02). The efficacy of DSG did not differ significantly between patients aged 25-64 years and ≥65 years: WOMAC pain (p = 0.85), WOMAC physical function (p = 0.70), GRD (p = 0.86) and POM (p = 0.81). The incidence of any AE was greater with DSG than with vehicle among patients aged 25-64 years (56.6% vs 50.8%) and ≥65 years (55.8% vs 43.9%). Treatment-related application site dermatitis was more common with DSG compared with vehicle in both younger (4.0% vs 0.7%, respectively) and older (5.8% vs 0.4%, respectively) patients and was the main reason for the difference in treatment-related AEs between the DSG and vehicle groups. Gastrointestinal AEs were infrequent among patients treated with DSG and similar to incidence rates with vehicle in both age groups.
                DSG was effective and generally well tolerated in adults regardless of age. These data support the topical application of DSG for relief of OA knee pain in elderly and younger patients. Clinicaltrials.gov registration numbers NCT00171626, NCT00171678, NCT00426621. To assess the efficacy and safety of a diclofenac hydroxyethylpyrrolidine (DHEP) patch in the treatment of symptomatic osteoarthritis (OA) of the knee joint.
                A double-blind, randomised, placebo-controlled trial was carried out on 103 outpatients for 2 weeks. The main efficacy parameters were spontaneous pain and Lequesne's Index. Secondary endpoints were walking time over a standard distance, global assessment of efficacy and tolerability, and paracetamol consumption.
                The active treatment group showed a significant improvement in pain, Lequesne's Index, and the physician's and patient's global assessment of efficacy. For these parameters the difference between groups was statistically significant in favour of the DHEP patch. Adverse reactions were seen in a small number of probands and were similar in both groups.
                The results of this trial suggest that the DHEP patch appears to be an effective and safe treatment for patients suffering from symptomatic knee OA. To investigate how individual patients with painful osteoarthritis (OA) respond to the non-steroidal anti-inflammatory drug (NSAID) diclofenac and the centrally acting analgesic tramadol when individual on-demand dose titration is allowed. In addition, we studied whether the differences in the mode of action of the different analgesics were important for functional outcome in OA patients.
                This was performed as a double-blind, crossover, randomised study in 60 patients with OA of the hip (19 patients) or knee (41 patients) without clinical joint inflammation. Patients received either tramadol (50 to 100mg up to three times daily, on demand) for 4 weeks, followed by diclofenac (25 to 50mg up to three times daily, on demand) for 4 weeks, or vice versa. The multidimensional 'Western Ontario and McMaster Universities Osteoarthritis Index' (WOMAC) questionnaire (pain, stiffness and functional impairment) was used to assess the effect of the drugs on pain and functional capability.
                54 patients completed both study periods. The mean (+/- SD) daily dose of tramadol consumed was 164.8mg (+/- 54.1mg) and that of diclofenac was 86.9mg (+/- 21.4mg). Both treatments modestly improved median pain intensity, paralleled by an improvement in functional parameters, and there were no statistically significant differences between the groups. However, individual treatment effects varied greatly, and within individual patients there were considerable variations in analgesic effectiveness between the two treatments. Consistently, pain relief correlated linearly with functional improvement. More patients reported adverse events with tramadol than with diclofenac (20 vs 3%, p = 0.0056), but there was no difference in adverse event-related withdrawals (p = 0.69).
                OA patients' response to analgesic treatment was highly individual and the response to one drug was not predictive of that to another drug. A significant proportion of patients were not treated satisfactorily with diclofenac or tramadol alone. The results obtained from a descriptive analysis of group effects (means, medians) were inappropriate for drawing conclusions on individual treatment benefits. Improvement of functional capability apparently was a consequence of pain relief. Effective pain relief should therefore be the main therapeutic goal in patients with OA where inflammation is less prominent. In a randomized, double blind, multicentre study with 4 weeks follow-up of 290 patients with osteoarthritis of the knee joint, a topical NSAID (eltenac) was compared with oral diclofenac and placebo. The main outcome, Lequesne's Index and pain by VAS showed no statistically significant differences between neither of the active treatments and placebo for the total study population. However, in patients with more severe symptoms, both active groups showed statistically significant differences to placebo. No severe adverse drug reactions were seen but the number of GI reactions were three times higher in the diclofenac group compared to the topical treatment. Local skin reactions were twice as frequent in the eltenac than in the placebo group. Taking into account the nature of the treatment for a chronic disease like OA, our results indicate that eltenac gel could be a safe alternative to oral NSAIDs.
Topical NSAIDs can provide good levels of pain relief; topical diclofenac solution is equivalent to that of oral NSAIDs in knee and hand osteoarthritis, but there is no evidence for other chronic painful conditions. Formulation can influence efficacy. The incidence of local adverse events is increased with topical NSAIDs, but gastrointestinal adverse events are reduced compared with oral NSAIDs.