<b>OBJECTIVE: </b>To evaluate the efficacy and safety of the cyclooxygenase-inhibiting nitric-oxide donator, naproxcinod, compared with naproxen and placebo in patients with osteoarthritis (OA) of the knee.<b>METHOD: </b>918 eligible patients were randomly assigned to double-blind treatment with either naproxcinod 375 mg, naproxcinod 750 mg, naproxen 500 mg or placebo, twice daily for 13 weeks. The primary objective was to show superiority of naproxcinod compared to placebo. Main efficacy criteria were assessment of pain and physical function using the Western Ontario and MacMaster Universities Osteoarthritis Index (WOMAC) and patients' overall rating of disease status (Likert scale). The main secondary objectives were to show that naproxcinod was non-inferior to naproxen 500 mg and to evaluate overall safety.<b>RESULTS: </b>Both doses of naproxcinod were statistically and clinically superior to placebo in relieving signs and symptoms of OA of the knee after 13 weeks of treatment, as demonstrated by all three co-primary endpoints (P< or =0.0003). The evaluation of the other secondary efficacy measures was consistent with the primary endpoint results. Naproxcinod 750 mg was non-inferior to equimolar doses of naproxen 500 mg in the Intent-to-Treat (ITT) population. 24.5% of patients discontinued prematurely, with a higher incidence in the placebo group (18.6%) than the active groups (4.3-7.1%) discontinuing due to lack of efficacy. Both doses of naproxcinod were well-tolerated, with most adverse events being mild or moderate. Compared to placebo, naproxcinod 750 mg and 375 mg showed a similar blood pressure (BP) profile in contrast to naproxen which increased BP.<b>CONCLUSIONS: </b>These results demonstrated the clinical efficacy and safety of naproxcinod in the management of the signs and symptoms of OA. Naproxcinod was well-tolerated, with BP effects similar to placebo and different from naproxen. Clinical Trials.gov identifier: NCT00542555.
To evaluate the efficacy and safety of duloxetine in the treatment of chronic pain due to osteoarthritis of the knee. This was a 13-week, randomized, double-blind, placebo-controlled trial in patients meeting American College of Rheumatology clinical and radiographic criteria for osteoarthritis of the knee. At baseline, patients were required to have a ≥ 4 weekly mean of the 24-hour average pain ratings. Patients were randomized to either duloxetine 60 mg once daily (QD) or placebo. At week 7, the duloxetine dosage was increased, in a blinded fashion, to 120-mg QD in patients reporting < 30% pain reduction. The primary efficacy measure was Brief Pain Inventory (BPI) 24-hour average pain. Secondary efficacy measures included Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC); Clinical Global Impressions of Severity (CGI-S). Safety and tolerability was also assessed. Of the total ( n = 256) patients, 111 (86.7%) in placebo group and 93 (72.7%) in duloxetine group completed the study. Patients treated with duloxetine had significantly ( P ≤ 0.001) greater improvement at all time points on BPI average pain and had significantly greater improvement on BPI pain severity ratings ( P ≤ 0.05), WOMAC total ( P = 0.044) and physical functioning scores ( P = 0.016), and CGI-S ( P = 0.009) at the study endpoint. Frequency of treatment-emergent nausea, constipation, and hyperhidrosis were significantly higher in the duloxetine group ( P ≤ 0.05). Significantly more duloxetine-treated patients discontinued the trial because of adverse events ( P = 0.002). Treatment with duloxetine 60 mg to 120 mg QD was associated with significant pain reduction and improved function in patients with pain due to osteoarthritis of the knee.
OBJECTIVE: Comparison of naproxcinod (375 and 750 mg), placebo (up to 13 weeks), and naproxen 500 mg (all bid) for treatment of osteoarthritis (OA) signs and symptoms. METHODS: A 53-week, randomized, double-blind, parallel-group study. One thousand twenty patients with primary knee OA were randomized to naproxcinod 750 mg, naproxcinod 375 mg, naproxen 500 mg, or placebo (all bid). Coprimary efficacy endpoints were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC™) pain and function subscales and patient overall rating of disease status. An analysis of covariance model tested superiority for both naproxcinod doses over placebo at week 13, and noninferiority of naproxcinod 750 mg bid versus naproxen at weeks 13 and 26. RESULTS: Least-square mean changes from baseline were greater for both naproxcinod doses compared with placebo at week 13 for WOMAC pain (−31.3 [standard error 1.67], −28.1 [1.64], and −20.4 [1.62] mm with naproxcinod 750 mg bid [P < 0.0001], 375 mg bid [P = 0.0008], and placebo, respectively), WOMAC function (−27.8 [1.60], −23.8 [1.58], and −14.9 [1.56] mm, respectively, P < 0.0001), and patient overall rating of disease status (1.00 [0.061], 0.81 [0.060], and 0.49 [0.059], respectively, P < 0.0001). Naproxcinod 750 mg bid was noninferior to naproxen at weeks 13 and 26. Naproxcinod was well tolerated, with no notable differences in orthostatic blood pressure response between treatments. CONCLUSION: Naproxcinod 750 mg bid and 375 mg bid demonstrated superior efficacy over placebo for treatment of OA and were well tolerated over 1 year. Naproxcinod 750 mg bid was noninferior to naproxen 500 mg bid.
<b>OBJECTIVE: </b>To determine response with duloxetine versus placebo in patients with osteoarthritis (OA) of the knee using the Outcome Measures in Rheumatoid Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) responder index and other clinically relevant outcomes including minimal clinically important improvement (MCII) and patient acceptable symptom state (PASS) for pain and function.<b>METHODS: </b>Data were pooled from two 13-week, randomized, double-blind, placebo-controlled trials comparing duloxetine 60 to 120 mg/day with placebo in patients with symptomatic OA of the knee. Treatment response was determined according to the OMERACT-OARSI responder index, ≥ 30% pain reduction, ≥ 50% pain reduction, and MCII and PASS for pain and function. (ClinicalTrials.gov identifiers NCT00433290 and NCT00408421)<b>RESULTS: </b>Duloxetine-treated patients were 33% more likely to experience an OMERACT-OARSI response than placebo-treated patients [p < 0.001, number needed to treat (NNT) = 6]. A significantly greater percentage of duloxetine-treated patients, compared with placebo-treated patients, reported ≥ 30% improvement in pain from baseline to endpoint (p < 0.001, NNT = 5) and ≥ 50% improvement in pain relative to baseline (p < 0.001, NNT = 7). The duloxetine-treated patients were also more likely to fulfill MCII criteria for pain (p < 0.001, NNT = 6) and function (p < 0.001, NNT = 7), and to achieve PASS for pain (p < 0.001, NNT = 6) and function (p = 0.009, NNT = 9). More duloxetine-treated patients compared with placebo-treated patients experienced ≥ 1 treatment-emergent adverse event (p = 0.003, number needed to harm = 8).<b>CONCLUSION: </b>Significantly more patients receiving duloxetine than placebo achieved an OMERACT-OARSI response, improvements in pain and function exceeding the level accepted as MCII, and reached PASS. Results support the clinical relevance of outcomes of prior duloxetine studies in symptomatic OA of the knee.
BACKGROUND: Knowing when to change pain- medication strategy is not well researched and remains a gap in treating chronic pain. OBJECTIVE: Our aim was to determine how long to treat osteoarthritis (OA) knee pain and chronic low back pain (CLBP) with duloxetine before considering a change in medication strategy. METHODS: We employed a post hoc analysis of changes in pain-severity data from placebo- controlled studies of duloxetine treatment in nondepressed patients with OA knee pain and CLBP. The studies were selected for inclusion in the analyses based on similarity of study design. Pain severity was recorded daily in patient diaries using an ordinal 11-point numerical rating scale (0 = no pain to 10 = most severe pain). The weekly means of the daily 24-hour average pain severity ratings from these diaries were pooled within disease states. Moderate response was defined as at least a 30% reduction from baseline in pain severity, and minimal improvement was defined as <10% reduction from baseline. The probability of achieving at least moderate pain reduction during 3 months treatment with duloxetine was estimated by Kaplan-Meier methods in patients with no or minimal improvement after 2, 4, and 6 weeks of treatment, as well as in all patients who had not yet achieved a moderate response (< 30% reduction in pain severity). RESULTS: There were 239 OA patients and 541 CLBP patients who were randomly assigned to treatment with duloxetine 60/120 mg/d. OA and CLBP patients with minimal improvement at 2 weeks of treatment had < 40% probability of achieving a moderate response, and at 4 weeks of treatment their chances were reduced to < 30% in OA patients and 25% in CLBP patients. In patients showing < 30% improvement at week 2 of treatment, OA patients had a 62% probability of achieving a moderate response, and CLBP patients had a 52% probability for a moderate response, and at 4 weeks of treatment, their chances were reduced to < 50% in OA patients and 40% in CLBP patients. CONCLUSIONS: Patients taking duloxetine for OA or CLBP who have < 10% reduction in pain after 4 weeks of treatment have limited possibility for eventually achieving even moderate pain reduction by the end of 12 weeks.
