Madelaine M. Wohlreich

Efficacy and safety of duloxetine for treatment of fibromyalgia in patients with or without major depressive disorder: Results from a 6-month, randomized, double-blind, placebo-controlled, fixed-dose trial

&NA; The primary objectives of this study were to assess the efficacy and safety of duloxetine for reducing pain severity in fibromyalgia patients with or without current major depressive disorder. This was a 6‐month, multicenter, randomized, double‐blind, placebo‐controlled study. In total, 520 patients meeting American College of Rheumatology criteria for fibromyalgia were randomly assigned to duloxetine (20 mg/day, 60 mg/day, or 120 mg/day) or placebo, administered once daily, for 6 months (after 3 months, the duloxetine 20‐mg/day group titrated to 60 mg/day). The co‐primary outcome measures were the Brief Pain Inventory (BPI) average pain severity score and Patient Global Impressions of Improvement (PGI‐I) score. Safety was assessed via treatment‐emergent adverse events, and changes in vital sign, laboratory, and ECG measures. Compared with placebo‐treated patients, those patients treated with duloxetine 120 mg/day improved significantly more on the co‐primary outcome measures at 3 months (change in BPI score [−2.31 vs −1.39, P < 0.001] and PGI‐I [2.89 vs 3.39, P = 0.004]) and at 6 months (change in BPI [−2.26 vs −1.43, P = 0.003] and PGI‐I [2.93 vs 3.37, P = 0.012]). Compared with placebo, treatment with duloxetine 60 mg/day also significantly improved the co‐primary measures at 3 months and BPI at 6 months. Duloxetine was efficacious in patients both with and without major depressive disorder. There were no clinically significant differences between treatment groups in changes in vital signs, laboratory measures, or ECG measures. Study results demonstrated that duloxetine at doses of 60 mg/day and 120 mg/day appears to be safe and efficacious in patients with fibromyalgia.

Duloxetine versus escitalopram and placebo in the treatment of patients with major depressive disorder: onset of antidepressant action, a non-inferiority study

ABSTRACT Objective: The goal of a non-inferiority study is to test whether a new treatment has at least as much efficacy as an established treatment1. The purpose of this non-inferiority study was to compare the speed of onset of antidepressant efficacy for duloxetine (a dual serotonin and norepinephrine reuptake inhibitor) and escitalopram (a selective serotonin reuptake inhibitor). Research design and methods: This was a randomized, double-blind, placebo- and active comparator-controlled study, in which patients (≥ 18 years) meeting DSM‑IV criteria for Major Depressive Disorder (MDD) received duloxetine 60 mg once daily (QD; N = 273), escitalopram 10 mg QD (N = 274), or placebo (N = 137) for 8 weeks. The primary objective was to compare the onset of antidepressant efficacy, by testing the hypothesis that the percentage of duloxetine-treated patients achieving onset criteria at Week 2 was not inferior to that in the escitalopram group. Main outcome measures: Onset of efficacy was defined as a 20% decrease from baseline on the 17‑item Hamilton Rating Scale for Depression (HAMD17) Maier subscale that was maintained or exceeded at all subsequent visits. Results: Probabilities of meeting onset criteria at Week 2 for duloxetine- and escitalopram-treated patients were 42.6% versus 35.2%, respectively (treatment difference = 7.4%; 95% confidence interval, –1.3% to 16.2%; p = 0.097). Both drugs showed significant improvement compared with placebo ( p ≤ 0.05) on the primary efficacy measure (Maier subscale) at Week 1 and endpoint (Week 8). No differences were found between duloxetine, escitalopram, and placebo rates of remission or response at 8 weeks. Adverse events that occurred significantly more frequently among duloxetine-treated patients when compared with those receiving escitalopram were nausea, dry mouth, vomiting, yawning, and irritability. The rate of discontinuation due to adverse events did not differ significantly between treatment groups. Limitations: Given the difficulties in constructing appropriate dose comparisons, the results of this study should be interpreted specific to the doses tested and not extrapolated to the drug as a whole. This study employed a fixed-dose design; flexible-dose designs are more likely to find a difference between antidepressants and placebo. Conclusion: In this study, both duloxetine and escitalopram showed significantly greater improvement on the primary efficacy measure than placebo over the 8‑week acute treatment period, while no differences were observed between drugs or between drugs and placebo on response and remission rates at 8 weeks. Escitalopram at a starting dose of 10 mg QD was better tolerated than duloxetine at a starting dose of 60 mg QD. This study met its pre-defined primary objective of assessing if duloxetine was non-inferior to escitalopram in antidepressant onset efficacy, and the results show that duloxetine is at least as fast as (non-inferior to) escitalopram. Trial registration: ClinicalTrials.gov identifier: NCT00073411.

Duloxetine in the treatment of Major Depressive Disorder: A comparison of efficacy in patients with and without melancholic features

BackgroundThe most prominent feature of melancholic depression is a near-total loss of the capacity to derive pleasure from activities or other positive stimuli. Additional symptoms can include psychomotor disturbances, anorexia, excessive guilt, and early awakening from sleep. Melancholic patients may exhibit treatment responses and outcomes that differ from those of non-melancholic patients. Pooled data from double-blind, placebo-controlled studies were utilized to compare the efficacy of duloxetine in depressed patients with and without melancholic features.MethodsEfficacy data were pooled from 8 double-blind, placebo-controlled clinical trials of duloxetine. The presence of melancholic features (DSM-IV criteria) was determined using results from the Mini International Neuropsychiatric Interview (MINI). Patients (aged ≥ 18 years) meeting DSM-IV criteria for major depressive disorder (MDD) received duloxetine (40–120 mg/d; melancholic, N = 759; non-melancholic, N = 379) or placebo (melancholic, N = 519; non-melancholic, N = 256) for up to 9 weeks. Efficacy measures included the 17-item Hamilton Rating Scale for Depression (HAMD17) total score, HAMD17 subscales (Maier, anxiety, retardation, sleep), the Clinical Global Impression of Severity (CGI-S) and Patient Global Impression of Improvement (PGI-I) scales, and Visual Analog Scales (VAS) for pain.ResultsIn data from all 8 studies, duloxetines advantage over placebo did not differ significantly between melancholic and non-melancholic patients (treatment-by-melancholic status interactions were not statistically significant). Duloxetine demonstrated significantly greater improvement in depressive symptom severity, compared with placebo, within both melancholic and non-melancholic cohorts (p ≤ .001 for HAMD17 total score, CGI-S and PGI-I). When analyzed by gender, the magnitude of improvement in efficacy outcomes did not differ significantly between duloxetine-treated male and female melancholic patients. In the two studies that assessed duloxetine 60 mg once-daily dosing, duloxetine-treated melancholic patients had significantly greater improvement compared with placebo on HAMD17 total score, CGI-S, PGI-I, 3 of 4 subscales of the HAMD17, and VAS overall pain severity (p < .01). Estimated probabilities of response and remission were significantly greater for melancholic patients receiving duloxetine 60 mg QD compared with placebo (response 74.7% vs. 42.2%, respectively, p < .001; remission 44.4% vs. 24.7%, respectively, p = .002ConclusionsIn this analysis of pooled data, the efficacy of duloxetine in patients with melancholic features did not differ significantly from that observed in non-melancholic patients.

Weekly luteal-phase dosing with enteric-coated fluoxetine 90 mg in premenstrual dysphoric disorder: a randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND Because the symptoms of premenstrual dysphoric disorder (PMDD) are limited to the luteal phase of the menstrual cycle, the potential benefit of luteal-phase dosing has been hypothesized. OBJECTIVE This multicenter, randomized, double-blind, placebo-controlled, parallel-group trial evaluated the efficacy and tolerability of enteric-coated fluoxetine 90 mg given once or twice during the luteal phase for the treatment of PMDD. METHODS Study drug was given 14 and 7 days before expected menses during the luteal phase of 3 menstrual cycles. After a screening period and single-blind placebo lead-in period, eligible women were randomized to I of 3 treatment groups: enteric-coated fluoxetine 90 mg on both days (LPWDx2); placebo 14 days before menses and enteric-coated fluoxetine 90 mg 7 days before menses (LPWDx1); or placebo on both days (PLC). The primary efficacy measure was change from baseline in mean luteal-phase scores on the Daily Record of Severity of Problems (DRSP). Secondary efficacy measures included scores on the Rating Scale for Premenstrual Tension Syndrome, Clinician-Rated (PMTS-C); the Clinical Global Impression (CGI)-Severity scale; and the Patient Global Impression (PGI)-Improvement scale. Quality of life was assessed using the Sheehan Disability Scale. RESULTS Two hundred fifty-seven women were randomized to treatment. At the end of the study, the LPWDx2 group had statistically significant improvements in DRSP total, DRSP mood subtotal, DRSP social functioning subtotal, PMTS-C, CGI-Severity, PGI-Improvement, and Sheehan Disability Scale work and family life scores compared with LPWDx1 and PLC (each measure, P < 0.05). There was also a statistically significant improvement in the score on the social life section of the Sheehan Disability Scale with LPWDx2 compared with PLC (P = 0.037). Across all treatment groups, 5 patients discontinued due to nonserious adverse events. Rates of discontinuation for any reason did not differ between the 3 treatment groups. CONCLUSION The findings of this study support the efficacy and tolerability of enteric-coated fluoxetine 90 mg given twice during the luteal phase of the menstrual cycle for the treatment of PMDD.

Efficacy of duloxetine in patients with fibromyalgia: Pooled analysis of 4 placebo-controlled clinical trials

OBJECTIVE To investigate the efficacy of duloxetine in the treatment of pain and improvement in functional impairment and quality of life in patients with fibromyalgia from a pooled analysis of 4 placebo-controlled, double-blind, randomized trials. METHOD Patients were eligible for inclusion in the studies if they were at least 18 years of age, met criteria for fibromyalgia as defined by the American College of Rheumatology, and had specified minimum pain severity scores. Across all studies, 797 patients received duloxetine 60-120 mg/d and 535 patients received placebo. Pain was assessed by the Brief Pain Inventory (BPI) 24-hour average pain severity score; other efficacy measures included the Clinical Global Impressions-Severity of Illness scale (CGI-S), Patient Global Impressions-Improvement scale (PGI-I), 17-item Hamilton Depression Rating Scale (HDRS-17), Fibromyalgia Impact Questionnaire (FIQ) total score, BPI pain interference items, Sheehan Disability Scale (SDS), and Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) mental and physical components. Changes from baseline to endpoint (last observation carried forward) for most of the above efficacy measures were analyzed using an analysis-of-covariance model. RESULTS After 12 weeks of treatment, pain was significantly reduced in patients treated with duloxetine (P < .001) compared with placebo. In addition, duloxetine was superior to placebo in improving CGI-S (P < .001); PGI-I (P < .001); FIQ total (P < .001); HDRS-17 total (P = .003); SDS global functioning (P < .001), work/school (P = .018), and family life (P < .001); SF-36 mental (P < .001) and physical (P = .026) component; and BPI pain interference (P < .001) scores. Treatment-by-subgroup interactions were not significant for sex (P = .320), age (P = .362), or race (P = .180). CONCLUSIONS This pooled analysis provides evidence that 12 weeks of treatment with duloxetine 60-120 mg/d effectively improves fibromyalgia symptoms and may offer benefits beyond pain relief.

Flexible Dosed Duloxetine in the Treatment of Fibromyalgia: A Randomized, Double-blind, Placebo-controlled Trial

Objective. To investigate the efficacy of flexible dose duloxetine 60–120 mg/day on changes in fibromyalgia (FM) symptoms assessed by the Patient Global Impression of Improvement (PGI-I) scale. Methods. Outpatients ≥ 18 years of age who met American College of Rheumatology criteria for FM, and had ≥ 4 score on the Brief Pain Inventory (BPI) average pain item, were randomized to duloxetine (n = 263) or placebo (n = 267) for 24 week double-blind treatment (primary endpoint at Week 12). Key secondary measures included BPI average pain severity, patient-rated scales assessing mood, anxiety, pain, sleep, and stiffness, Clinical Global Impression of Severity (CGI-S), Multidimensional Fatigue Inventory, Cognitive and Physical Functioning Questionnaire, Beck Depression Inventory (BDI), Beck Anxiety Inventory, and Medical Outcome Study Short-Form Health Survey (SF-36). Results. At Week 12, duloxetine-treated patients reported significantly greater global improvement with mean PGI-I scores of 2.8 compared to 3.4 in the placebo group (p < 0.001). Significantly more duloxetine- versus placebo-treated patients (57% vs 32%; p < 0.001) reported feeling “much” or “very much better” (PGI-I score ≤ 2). There was significantly greater improvement with duloxetine versus placebo treatment in BPI average pain severity, mood (including BDI total), anxiety (patient-rated only), stiffness, CGI-S, fatigue, all SF-36 domains (except role-physical and physical component summary), and being less bothered by pain or sleep difficulties. Treatment-emergent adverse events occurring significantly more frequently with duloxetine included: nausea, headache, constipation, dry mouth, dizziness, diarrhea, and hyperhidrosis. Conclusion. Treatment with duloxetine 60, 90, and 120 mg/day was associated with feeling much better, pain reduction, being less bothered by sleep difficulties, and improvement in mood, stiffness, fatigue and functioning. (Clinical trial registry NCT00673452).

Duloxetine for the Treatment of Major Depressive Disorder in Older Patients

OBJECTIVE The efficacy and safety of duloxetine, a dual reuptake inhibitor of serotonin (5-HT) and norepinephrine (NE), were evaluated in the treatment of major depressive disorder (MDD) and associated pain symptoms in patients age 55 and older. METHODS Efficacy data were obtained from patients age > or =55 who participated in two identical, multicenter, double-blind studies in which patients with MDD were randomized to receive placebo (N=43) or duloxetine (60 mg/day; N=47) for 9 weeks. The primary efficacy measure was the mean change in Ham-D-17 total score. Pain symptoms were assessed with visual-analog scales. Safety data for patients age > or =55 were pooled from six randomized, 8- or 9-week, double-blind studies of duloxetine in which patients with MDD were randomized to receive placebo (N=90) or duloxetine (40 mg/day-120 mg/day; N=119). RESULTS The combined results of these two investigations found that duloxetine was significantly superior to placebo for mean change in Ham-D-17 total score. The estimated probability of remission for duloxetine-treated patients (44.1%) was also significantly higher than that for placebo (16.1%). Reductions in overall pain, back pain, and pain while awake were also significantly greater for duloxetine than placebo. The rate of discontinuation due to adverse events was significantly higher for duloxetine-treated patients (21.0%) than placebo (6.7%). Abnormal elevations in vital signs at endpoint were not significantly different from placebo. CONCLUSIONS In these two investigations, duloxetine 60 mg/day was an efficacious treatment for MDD and also alleviated pain symptoms in depression patients age 55 and older.

Long-Term Safety, Tolerability, and Efficacy of Duloxetine in the Treatment of Fibromyalgia

OBJECTIVES To assess the long-term safety, tolerability, and efficacy of duloxetine in patients with fibromyalgia. METHODS We report results from the 6-month extension phases of 2 randomized, double-blind, placebo-controlled clinical trials having 6-month placebo-controlled phases. In Study 1, all patients received duloxetine 120 mg/d after 28 weeks on placebo or duloxetine 60 or 120 mg/d. In Study 2, patients taking placebo were titrated to duloxetine 60 mg/d after 27 weeks on treatment, while duloxetine-treated patients remained on their dosages of 60 or 120 mg/d. Safety and tolerability were assessed via discontinuation rates, treatment-emergent adverse events (TEAEs), and changes in vital signs and laboratory measures. The primary efficacy measure was the Brief Pain Inventory average pain severity score. RESULTS The percentage of patients entering and completing the extension phase was 56% (156/278) for Study 1 and 69% (140/204) for Study 2. Groups titrating from placebo to duloxetine showed the highest discontinuation rates due to an adverse event (Study 1, 25%; Study 2, 19%) and TEAE rates (Study 1, 82%; Study 2, 77%). The most common TEAEs were nausea and dry mouth. No significant within-group changes in blood pressure occurred in any group. Significant within-group mean increases in pulse (bpm) were observed in the placebo/duloxetine 120 mg group in Study 1 (3.7 [SD = 11.2], P <or= 0.01) and the placebo/duloxetine 60 mg group in Study 2 (4.8 [SD = 10.2], P <or= 0.001). Most treatment groups showed small mean change improvements in the Brief Pain Inventory average pain severity score. CONCLUSIONS These findings support a positive risk/benefit profile for duloxetine in the long-term treatment of fibromyalgia.

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

Abstract 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: Trial registration: ClinicalTrials.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.

Duloxetine versus escitalopram and placebo: an 8-month, double-blind trial in patients with major depressive disorder*

ABSTRACT Background: Duloxetine and escitalopram were compared in an 8-month, randomized, double-blind, placebo-controlled trial in adult outpatients meeting DSM‑IV criteria for major depressive disorder (MDD). The results regarding the primary objective of the study (onset of antidepressant action) have been previously published. The current paper focuses on the longer-term (8-month) comparisons of efficacy and safety between duloxetine and escitalopram. Research design and methods: Upon completion of the 8-week, fixed-dose, placebo-controlled, acute-treatment phase (duloxetine 60 mg/day (n = 273), escitalopram 10 mg/day (n = 274), placebo (n = 137)), patients remaining in the duloxetine (n = 188) and escitalopram (n = 208) groups were eligible for double-blind dose increases (duloxetine to 120 mg/day, escitalopram to 20 mg/day), and placebo non-responders were eligible for double-blind rescue to active drug. Main outcome measures: Efficacy was primarily assessed using the HAMD17. Safety/tolerability assessments included spontaneously reported adverse events (AEs), overall rates and reasons for discontinuation, laboratory analyses, and vital signs. Results: Both drugs demonstrated similar remission rates over the course of the study, with the probability of remission reaching 70% (duloxetine) and 75% (escitalopram) at 8 months ( p = 0.44). Similar improvement was observed for both duloxetine and escitalopram on efficacy measures with the exception of the sleep subscale of the HAMD17, wherein escitalopram had a statistically significant advantage over duloxetine in improving sleep. Over the entire 8-month study, discontinuation rates differed significantly for duloxetine (62%) compared with escitalopram (55%; p = 0.02). Rates of discontinuation due to AEs did not differ significantly between duloxetine (12.8%), escitalopram (12.0%), and placebo (10.2%) ( p > 0.05 all pairwise comparisons). AEs associated with duloxetine tended to emerge early in treatment (e.g., nausea, dry mouth), whereas AEs associated with escitalopram tended to emerge later in treatment (e.g., diarrhea, weight increase). The incidence of sustained hypertension was similar between drugs (1.5 vs. 1.1% patients for duloxetine and escitalopram, respectively). Statistically significant drug differences were identified in the mean changes from baseline to study endpoint for pulse (+3.05 beats per minute (bpm), duloxetine; –0.89 bpm, escitalopram; p < 0.001) and systolic blood pressure (+3.73 mmHg, duloxetine; +0.31 mmHg, escitalopram; p < 0.05), but not diastolic blood pressure (+0.81 mmHg, duloxetine; –0.24 mmHg, escitalopram; p = 0.27). At 8 months, mean change in weight was significantly higher for escitalopram compared with duloxetine (+0.61 kg, duloxetine; +1.83 kg, escitalopram; p < 0.05), however, the incidence of treatment-emergent abnormal weight gain (≥ 7% increase in weight from baseline) was similar between drugs and was significantly greater for both duloxetine and escitalopram compared with placebo. Limitations: Because so few patients on placebo (n = 15), in comparison to duloxetine (n = 104) or escitalopram (n = 123), completed the entire 8-month study, the power to detect a difference between the active treatments and placebo after 8 weeks was significantly decreased and very likely insufficient. Conclusion: Throughout the 8-month study, similar improvement was observed for both duloxetine and escitalopram on most efficacy measures with the exception of the sleep subscale of the HAMD17. Drug differences were identified in safety/tolerability measures.