Daniel K. Kajdasz

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 for the Management of Diabetic Peripheral Neuropathic Pain: Evidence-Based Findings from Post Hoc Analysis of Three Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Studies

OBJECTIVE This post hoc analysis was aimed to summarize the efficacy and tolerability of duloxetine as represented by number needed to treat (NNT) and number needed to harm (NNH) to provide a clinically useful assessment of the position of duloxetine among current agents used to treat diabetic peripheral neuropathic pain (DPNP). METHODS Data were pooled from three 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies in which patients received 60 mg duloxetine either QD or BID or placebo. NNT was calculated based on rates of response (defined as >or=30% and >or=50% reductions from baseline in the weekly mean of the 24-hour average pain severity scores); NNH was calculated based on rates of discontinuation due to adverse events (AEs). RESULTS Patients receiving duloxetine 60 mg QD and 60 mg BID had NNTs (95% CI) of 5.2 (3.8-8.3) and 4.9 (3.6-7.6), respectively, based on last observation carried forward; NNTs of 5.3 (3.8-8.3) for 60 mg QD and 5.7 (4.1-9.7) for 60 mg BID were obtained based on baseline observations carried forward. The NNHs (95% CI) based on discontinuation due to AEs were 17.5 (10.2-58.8) in the duloxetine 60-mg QD group and 8.8 (6.3-14.7) in the 60-mg BID group. CONCLUSION These post hoc results suggest that duloxetine was effective and well tolerated for the management of DPNP and further support the importance of duloxetine as a treatment option for clinicians and patients to assist with the management of DPNP.

An evaluation of the cardiovascular safety profile of duloxetine: findings from 42 placebo-controlled studies.

AbstractBackground and objective: In recent years, new classes of medication, such as the serotonin-noradrenaline reuptake inhibitors (SNRIs), have been developed for use in the treatment of major depressive disorder (MDD). For many years, treatment options were largely limited to the use of monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). However, there have been published reports of orthostatic hypotension, arrhythmias and corrected QT (QTc) interval changes in patients treated with TCAs. As new medications become available, it is important to understand how their cardiovascular safety profile compares with that of more established agents to aid clinicians and patients in choosing the best treatment options. This study was designed to evaluate the cardiovascular safety profile of the SNRI duloxetine through evaluation of cardiovascular-related parameters and adverse events (AEs). Methods: The cardiovascular safety of duloxetine was assessed using all placebocontrolled duloxetine clinical trial data as of December 2005. This consisted of data from 42 placebo-controlled clinical trials of 8504 patients who were treated with duloxetine. Additional information from a high-dose clinical pharmacology study and postmarketing safety surveillance are also presented. Of the placebocontrolled trials included in this analysis, clinical indications under investigation included MDD (15 studies), diabetic peripheral neuropathic pain (3 studies), fibromyalgia (2 studies), generalised anxiety disorder (3 studies) and lower urinary tract disorders (19 studies, all related to incontinence). Cardiovascular safety was evaluated based on vital signs, ECGs and the incidence of treatment-emergent AEs potentially related to cardiovascular safety. These safety parameters were analysed across all indications. To identify both serious and non-serious cardiovascular-related AEs, as well as AEs reported as the reason for discontinuation, a comprehensive list of terms derived from the Medical Dictionary for Regulatory Activities (version 8.0) was generated and used to search the duloxetine databases for cardiovascular-related events. Results: Calculation of change from baseline to maximum in ECG parameters showed significant differences between treatment groups for all parameters, with decreases from baseline in RR, QRS and QT intervals for patients receiving duloxetine and increases from baseline for patients treated with placebo. These shifts were related to small heart rate changes, but the mean differences were not considered clinically relevant. Categorical analyses of shifts from normal to abnormal (or abnormal to normal) for heart rate and QT corrected for heart rate using Fridericia’s formula (QTcF) values showed that most patients did not shift from their baseline category. Patients with MDD who were treated for up to 1 year with duloxetine had blood pressure changes early in treatment that then stabilised. Even in patients with elevated blood pressure at baseline in these clinical trials, no increased risk of sustained blood pressure elevation with duloxetine treatment was found. Conclusion: Overall, the findings presented here support our conclusions that use of duloxetine does not appear to be associated with significant cardiovascular risks in patients with conditions for which the drug has been approved or studied.

A Phase III, Double-blind, Placebo-controlled, Multicenter Study on the Efficacy of Recombinant Human Antithrombin in Heparin-resistant Patients Scheduled to Undergo Cardiac Surgery Necessitating Cardiopulmonary Bypass

Background:The study evaluated the efficacy of recombinant human antithrombin (rhAT) for restoring heparin responsiveness in heparin resistant patients undergoing cardiac surgery. Methods:This was a multicenter, randomized, double-blind, placebo-controlled study in heparin-resistant patients undergoing cardiac surgery with cardiopulmonary bypass. Heparin resistance was diagnosed when the activated clotting time was less than 480 s after 400 U/kg heparin. Fifty-four heparin-resistant patients were randomized. One cohort received 75 U/kg rhAT, and the other received normal saline. If the activated clotting time remained less than 480 s, this was considered treatment failure, and 2 units fresh frozen plasma was transfused. Patients were monitored for adverse events. Results:Only 19% of patients in the rhAT group received fresh frozen plasma, compared with 81% of patients in the placebo group (P < 0.001). During their hospitalization, 48% of patients in the rhAT group received fresh frozen plasma, compared with 85% of patients in the placebo group (P = 0.009). Patients in the placebo group required higher heparin doses (P < 0.005) for anticoagulation. There was no increase in serious adverse events associated with rhAT. There was increased blood loss 12 h postoperatively (P = 0.05) with a trend toward increased 24-h bleeding in the rhAT group (P = 0.06). There was no difference between the groups in blood and platelet transfusions. Conclusion:Treatment with 75 U/kg rhAT is effective in restoring heparin responsiveness and promoting therapeutic anticoagulation in the majority of heparin-resistant patients. Treating heparin-resistant patients with rhAT may decrease the requirement for heparin and fresh frozen plasma.

A 1-year Safety and Efficacy Study of Duloxetine in Patients With Fibromyalgia

ObjectivesEvaluate the efficacy and safety of duloxetine at doses up to 120 mg once daily in patients with fibromyalgia. MethodsThis was a phase 3, 60-week study, which included an 8-week open-label period followed by a 52-week, randomized, double-blind period. Patients received duloxetine 30 mg daily for 1 week and duloxetine 60 mg daily for 7 weeks and were then randomized to receive either 60 or 120 mg daily (1:2 ratio). ResultsEnrolled patients (N=350, 95.7% female) exhibited moderate disease symptoms at study entry (Brief Pain Inventory average pain=6.7, Clinical Global Impression of Severity=4.1, and Patients Global Impression of Severity=4.1). Significant pain reduction in patients was observed during the open-label study phase. This pain reduction continued during the 52-week double-blind study phase, as demonstrated by additional mean decreases in the Brief Pain Inventory average pain score within both duloxetine groups. The most common (≥15%) treatment-emergent adverse events (overall phase) were nausea, headache, insomnia, dizziness, constipation, and dry mouth. Seventy-four (21.1%) patients reported adverse events as a reason for discontinuation [most common (>1%) were insomnia, vomiting, diarrhea, dizziness, and nausea]. The mean change (SD) in sitting systolic blood pressure (mm Hg) was −0.1 (14.4), in sitting diastolic blood pressure was −0.2 (9.6), in sitting pulse rate was 1.9 (10.4) bpm, and in weight was 0.7 (4.3) kg. DiscussionThe profile of duloxetine for the long-term treatment of fibromyalgia was consistent with that seen in other indications for which the drug is currently marketed.

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.

Estimation of minimum clinically important difference for pain in fibromyalgia

To estimate the minimum clinically important difference (MCID) for several pain measures obtained from the Brief Pain Inventory (BPI) for patients with fibromyalgia.

The relationship between antidepressant and analgesic responses: findings from six placebo-controlled trials assessing the efficacy of duloxetine in patients with major depressive disorder

Objective: Debate continues regarding whether onset of analgesia is faster than antidepressant effect in antidepressants with both properties. Duloxetine hydrochloride (from here on referred to as duloxetine) is effective in both major depressive disorder and diabetic peripheral neuropathic pain. This post-hoc analysis of six placebo-controlled duloxetine trials in patients with major depressive disorder was designed to compare onset of antidepressant activity to pain relief. Research design and methods: Duloxetine was administered at 40–120 mg/day versus placebo for up to 9 weeks in outpatient clinic settings. The primary depression measure was the HAMD17 and pain severity was measured using visual analog scale (VAS) measuring overall pain, headache, back and shoulder pain, and pain while awake. The time course of improvement was profiled using repeated measures modeling and Kaplan–Meier product limit estimation. Results: In all but one case, significant reductions in HAMD17 and VAS scores were seen within 2 weeks of treatment. Median time to VAS response was consistently shorter across all VAS measures than that to HAMD17 response in both placebo- and duloxetine-treated patients with at least modest levels of pain at study entry. Regression analyses consistently demonstrated little association between analgesic and antidepressant responses. Limitations of these findings include that the studies used in these analyses did not require the patients to enroll with any specific level of pain. Moreover, the type of pain exhibiting at presentation was not routinely identified; therefore, the impact of different pain types on these findings is unknown. Conclusions: Duloxetines analgesic effect is independent of the drugs antidepressant effect. Additionally, faster onset of the analgesic effect appears to be a population-specific phenomenon that is unmodified in the presence of active agents.

The efficacy profile of vilazodone, a novel antidepressant for the treatment of major depressive disorder.

Abstract Objective: Vilazodone is a novel serotonin reuptake inhibitor and serotonin 1A receptor partial agonist approved for the treatment of major depressive disorder (MDD). This evaluation presents side-by-side efficacy data from two randomized, double-blind, placebo-controlled, short-term 8-week trials (referred to as randomized controlled trial [RCT]-1 [N = 410] and RCT-2 [N = 481]); efficacy data for demographic and clinical subgroups (derived from pooled RCT data); and effectiveness data from a 52-week, open-label, long-term study (N = 616). The objective is to summarize the efficacy profile of vilazodone at its approved dose of 40 mg/day. Methods: The main assessment in individual pivotal trials and pooled subgroup analyses was the change from baseline to end of treatment (EOT, 8 weeks) in the Montgomery–Åsberg Depression Rating Scale (MADRS) total score. Mixed-effects repeated-measures analyses were conducted in the placebo-controlled trials. Effectiveness analyses in the long-term study included mean MADRS score change over time. Results: Vilazodone-treated patients in both short-term studies showed greater improvement from baseline to EOT in mean MADRS scores than placebo-treated patients (least-squares mean [LSM] treatment difference: −3.2 [p = 0.001], RCT-1; −2.5 [p = 0.009], RCT-2). Clinical Global Impressions–Improvement mean scores at EOT reflected greater improvement with vilazodone compared with placebo in both studies (LSM treatment difference: −0.4 [p = 0.001], RCT-1; −0.3 [p = 0.004], RCT-2). MADRS response rates were significantly greater among patients receiving vilazodone versus those receiving placebo (RCT-1: 40.4% versus 28.1%, respectively [p = 0.007]; RCT-2: 43.7% versus 30.3%, respectively [p = 0.002]). The greater efficacy of vilazodone versus placebo was consistent for the majority of demographic and MDD characteristic subgroups. In the long-term study, the mean MADRS score improved from 29.9 (baseline) to 11.4 (week 8), 8.2 (week 24), and 7.1 (week 52). Conclusion: Vilazodone 40 mg/day resulted in clinically meaningful, statistically significant improvement in MDD symptoms in two placebo-controlled, 8-week studies. Findings are supported by subgroup analysis and open-label, long-term effectiveness data. Trial registration: Trial registration: ClinicalTrials.gov identifier: NCT00285376. Trial registration: ClinicalTrials.gov identifier: NCT00683592. Trial registration: ClinicalTrials.gov identifier: NCT00644358.

Comparisons of the efficacy and safety of duloxetine for the treatment of fibromyalgia in patients with versus without major depressive disorder.

ObjectivesTo investigate whether comorbid major depressive disorder (MDD) influenced the efficacy and safety of duloxetine in treating fibromyalgia (FM). MethodsThis was a post-hoc analysis using pooled data from 4 double-blind, placebo-controlled studies of patients with American College of Rheumatology-defined primary FM with or without MDD. Patients were randomized to duloxetine [60 or 120 mg/d (N=797)] or placebo (N=535) for approximately 3 months. Efficacy measures included the Brief Pain Inventory average pain score, 17-item Hamilton Depression Rating Scale, Fibromyalgia Impact Questionnaire, and Patients/Clinicians Global Impressions of Improvement/Severity scales. ResultsAt baseline, 26% of patients met diagnostic criteria for MDD. At endpoint (3 mo or last observation), duloxetine showed significantly (P<0.05) greater improvement versus placebo on the Brief Pain Inventory, Fibromyalgia Impact Questionnaire, Patients Global Impressions of Improvement scale, and Clinicians Global Impressions of Severity scale in patients with and without comorbid MDD. The effect of duloxetine on these efficacy measures was consistent across FM patients with or without MDD (P>0.1 for treatment-by-strata interaction). On the 17-item Hamilton Depression Rating Scale, duloxetine showed significantly (P<0.05) greater improvement versus placebo in patients with comorbid MDD. The safety profile of duloxetine versus placebo with respect to serious adverse events and discontinuation owing to adverse events was similar for FM patients with versus without MDD (P>0.1 treatment-by-strata interaction). DiscussionDuloxetine was effective in reducing pain and other symptoms in FM patients with and without MDD and demonstrated a similar safety profile for both groups.