The risk of bleeding with duloxetine treatment in patients who use nonsteroidal anti-inflammatory drugs (NSAIDs): analysis of placebo-controlled trials and post-marketing adverse event reports.

PURPOSE: To assess the safety of duloxetine with regards to bleeding-related events in patients who concomitantly did, versus did not, use nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin. METHODS: Safety data from all placebo-controlled trials of duloxetine conducted between December 1993 and December 2010, and post-marketing reports from duloxetine-treated patients in the US Food and Drug Administration Adverse Event Reporting System (FAERS), were searched for bleeding-related treatment-emergent adverse events (TEAEs). The percentage of patients with bleeding-related TEAEs was summarized and compared between treatment groups in all the placebo-controlled studies. Differences between NSAID user and non-user subgroups from clinical trial data were analyzed by a logistic regression model that included therapy, NSAID use, and therapy-by-NSAID subgroup interaction. In addition, to determine if higher duloxetine doses are associated with an increased incidence of bleeding-related TEAEs, and whether the use of concomitant NSAIDs might influence the dose effect if one exists, placebo-controlled clinical trials with duloxetine fixed doses of 60 mg, 120 mg, and placebo were analyzed. Also, the incidence of bleeding-related TEAEs reported for duloxetine alone was compared with the incidence in patients treated with duloxetine and concomitant NSAIDs. Finally, the number of bleeding-related cases reported for duloxetine in the FAERS database was compared with the numbers reported for all other drugs. RESULTS: Across duloxetine clinical trials, there was a significantly greater incidence of bleeding-related TEAEs in duloxetine- versus placebo-treated patients overall and also in those patients who did not take concomitant NSAIDS, but no significant difference was seen among those patients who did take concomitant NSAIDS. There was no significant difference in the incidence of bleeding-related TEAEs in the subset of patients treated with duloxetine 120 mg once daily versus those treated with 60 mg once daily regardless of concomitant NSAID use. The combination of duloxetine and NSAIDs was associated with a statistically significantly higher incidence of bleeding-related TEAEs compared with duloxetine alone. A similarly higher incidence of bleeding-related TEAEs was seen in patients treated with placebo and concomitant NSAIDs compared with placebo alone. Bleeding-related TEAEs reported in the FAERS database were disproportionally more frequent for duloxetine taken with NSAIDs compared with the full FAERS background, but there was no difference in the reporting of bleeding-related TEAEs when the cases reported for duloxetine taken with NSAIDs were compared against the cases reported for NSAIDs alone. CONCLUSION: Concomitant use of NSAIDs was associated with a higher incidence of bleeding-related TEAEs in clinical trials regardless of whether patients were taking duloxetine or placebo; bleeding-related TEAEs did not appear to increase along with duloxetine dose regardless of NSAID use. In spontaneously reported post-marketing data, the combination of duloxetine and NSAID use was not associated with an increased reporting of bleeding-related events when compared to NSAID use alone.

Review of Efficacy and Safety of Duloxetine 40 to 60 mg Once Daily in Patients with Diabetic Peripheral Neuropathic Pain.

We summarize efficacy and safety findings from 4 double-blind, placebo-controlled, 12-week studies and 1 open-label, uncontrolled, 34-week maintenance-of-effect (MOE) study that examine duloxetine 40 and 60 mg once daily (QD) in patients with diabetic peripheral neuropathic pain (DPNP). In all placebo-controlled studies, duloxetine showed significantly (P ≤ .01) greater reduction in pain severity (weekly mean of 24-hour average pain severity ratings, primary outcome measure) compared with placebo. In all placebo-controlled studies, duloxetine showed significantly (P ≤ .05) greater improvement on brief pain inventory-Interference ratings. Patient global impression of improvement ratings were superior to placebo (P ≤ .01) for duloxetine patients in all placebo-controlled studies. Response rates (based on 30% pain reduction) ranged from 57% to 68% for duloxetine and from 35% to 47% for placebo and were statistically significantly different (P ≤ .01) between treatment groups in 3 out of 4 studies. The open-label study showed maintenance of analgesic effect of duloxetine in DPNP. In the duloxetine groups, 4.3% to 14.9% of patients discontinued because of adverse events (placebo groups: 2.6% to 7.4%). Most commonly reported treatment-emergent adverse events were nausea, somnolence, and headache. Duloxetine 40 and 60 mg QD was efficacious and well tolerated in the management of DPNP.

Duloxetine added to oral nonsteroidal anti-inflammatory drugs for treatment of knee pain due to osteoarthritis: results of a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To determine the efficacy, tolerability, and safety of duloxetine when added to oral nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with osteoarthritis (OA) of the knee with pain of moderate or greater severity. RESEARCH DESIGN AND METHODS: This was a 10-week randomized, double-blind, flexible-dose (duloxetine 60/120 mg/day), placebo-controlled trial that enrolled adult outpatients who had persistent moderate pain (≥4 on a 0-10 numerical rating scale) due to OA of the knee, despite, per protocol, having received optimized oral NSAID therapy (specific drug, dose, and frequency at investigator discretion). CLINICAL TRIALS REGISTRATION: ClinicalTrial.gov identifier: NCT01018680. MAIN OUTCOME MEASURE: Patients entered daily pain ratings in a telephone-based diary. The primary efficacy outcome was the weekly mean of the daily average pain rating at week 8. Safety outcomes were assessed during the entire 10-week study. RESULTS: A total of 524 patients randomly received duloxetine 60/120 mg/day (N = 264) or placebo (N = 260). In total, 74% of the patients completed the study. Mean age was 61 years (SD 9.2), 57% were female, and 81% were white. Duloxetine-treated patients had significantly greater pain reduction at week 8 (p < 0.001) than placebo-treated patients. In addition, relative to placebo at week 8, duloxetine-treated patients had significant improvements in physical function as measured by the Western Ontario and McMaster Universities Osteoarthritis Index (p < 0.001), and Patient Global Impression of Improvement (p < 0.001). Compared to placebo, significantly more nausea, dry mouth, constipation, fatigue and decreased appetite were reported by patients taking duloxetine (each p < 0.05). Discontinuation due to adverse events occurred more commonly in the duloxetine group than the placebo group (p = 0.03). CONCLUSION: Duloxetine added to oral NSAID therapy provided additional significant pain reduction, improved function, and patient-rated impression of improvement. Adverse events were consistent with those seen in previous duloxetine trials. The short duration of the study may not reflect the longer term efficacy and safety of NSAID/duloxetine cotherapy.

Pain mechanisms in osteoarthritis: understanding the role of central pain and current approaches to its treatment.

In this literature review, the mechanisms underlying pain associated with osteoarthritis (OA) are discussed, along with evidence for the efficacy of medications thought to act centrally to relieve OA pain. We survey the cascade of events from inflammation to activation of nociceptive and neuropathic pathways, to the development and maintenance of central and peripheral sensitization. Preclinical and clinical evidence for the sensitization hypothesis is discussed, along with recently identified genetic variations that may increase sensitivity to pain in patients with OA. Evidence is presented for the efficacy of centrally acting analgesics for OA pain (opioids, antiepileptics, tricyclic antidepressants, and serotonin/norepinephrine receptor inhibitors).