Adam L. Meyers

Safety and Efficacy of Duloxetine in the Treatment of Diabetic Peripheral Neuropathic Pain in Older Patients

OBJECTIVE We present a post-hoc analysis of the safety and efficacy of duloxetine, a selective serotonin/norepinephrine reuptake inhibitor, for treatment of diabetic peripheral neuropathic pain (DPNP) in older patients. METHODS Data from three double-blind, placebo-controlled trials in adult patients with DPNP were pooled and stratified by age (<65, >or=65 years). Patients were randomized to duloxetine (DLX) 60 mg once-daily, 60 mg twice-daily, or placebo for 12 weeks, followed by a 52-week extension phase (re-randomization to routine care or DLX 120 mg/day). Intent-to-treat analyses were used for safety and efficacy assessment. RESULTS In the acute phase, overall TEAE rates did not differ significantly by age. A greater percentage of older patients discontinued due to TEAEs (P<0.001), regardless of treatment group. Duloxetine improved weekly mean 24-hour average pain scores versus placebo in both age groups (P<0.01). In the extension phase, a significant therapy-by-age interaction (P<0.05) was observed in overall TEAE rate; with routine care, 86.6% of older patients had >or=1 TEAE versus 74.6% of younger patients. CONCLUSIONS Although TEAEs more frequently lead to discontinuation in older patients, duloxetine was well tolerated and efficacious for treatment of DPNP regardless of age. These data suggest duloxetine may be beneficial for treatment of DPNP in patients>or=65.

Does Pain Mediate the Pain Interference with Sleep Problem in Chronic Pain? Findings from Studies for Management of Diabetic Peripheral Neuropathic Pain with Duloxetine

Although sleep problems are common in patients with chronic pain, it is unclear whether pain mediates (causes) impaired sleep. The relationship between pain and sleep has been difficult to investigate because of the potential confounds of depression and somnolence. This report used clinical trials data for duloxetine in the management of diabetic peripheral neuropathic pain (DPNP) to investigate the direction of this association. Data were pooled from three double-blind, randomized, placebo-controlled, 12-week trials of patients with DPNP without mood disorder (n=1,139). DPNP patients reporting somnolence and those who were receiving sedating concomitant medications were removed from the analyses (n=93). Efficacy measures included weekly mean scores for average daily pain severity, night pain severity, and pain interference with sleep. Duloxetine at 60 and 120 mg per day separated from placebo for average pain and night pain improvement as early as one week after treatment began, whereas sleep interference improvement separated from placebo at the three visits it was assessed (Weeks 4, 8, and 12). Change in sleep interference was moderately to strongly correlated (P<0.001) with changes in average pain (r=0.46) and nighttime pain severity (r=0.53). These results confirm the association between the improvement in daily pain and nighttime pain, and improvement in sleep interference for a large population without depression or somnolence. Although this association cannot establish causality, these results provide some evidence for the possibility that pain may mediate the sleep problem associated with DPNP and perhaps chronic pain in general.

The effect of pain on outcomes in a trial of duloxetine treatment of major depressive disorder.

BACKGROUND Patients with major depressive disorder (MDD) frequently report one or more pain symptoms. To explore the relationship between improvement in pain symptoms and MDD treatment outcomes, we conducted a secondary analysis of an approximately 12-week, open label trial of duloxetine in MDD. The primary objective was to test the hypothesis that a greater reduction in pain was associated with a higher probability of MDD remission. METHODS Adults with DSM-IV MDD were enrolled in the study if they had a Hamilton Depression Scale (HAMD-17) total score of 15 or more and a Clinical Global Impression of Severity (CGI-S) score of 4 or more. The duloxetine dose of patients could be titrated on the basis of the degree of response within the range from 60 to 120 mg given QD, with 90 mg QD as an intermediate dose. Remission of major depressive disorder was defined as a HAMD-17 total score of < or = 7. Core emotional symptoms of depression were determined by the HAMD-17 Maier subscale. Pain was assessed using a 100 mm visual analog scale (VAS) of overall pain severity over the last week (0 = no pain, 100 = pain as severe as I can imagine). For the primary analysis, mean change in VAS overall pain score over time was compared between remitters and non-remitters at endpoint using a mixed model repeated measures approach. RESULTS Two hundred forty nine patients were included in the analysis. A greater reduction in pain was associated with a significantly higher probability of remission of MDD, after accounting for changes in the core emotional symptoms. Greater pain reduction was associated with significant improvement in MDD core emotional symptoms. A greater improvement in pain was also associated with improvements in patient and clinician-rated global assessments. CONCLUSIONS The effective treatment of pain symptoms in patients with major depressive disorder was associated with higher remission rates. The results underscore the importance of effectively treating painful symptoms associated with depression.

A pragmatic 12-week, randomized trial of duloxetine versus generic selective serotonin-reuptake inhibitors in the treatment of adult outpatients in a moderate-to-severe depressive episode

Some evidence suggests that medications that modulate both serotonin and norepinephrine may be more effective than selective serotonin-reuptake inhibitors (SSRIs) in severe major depressive disorder (MDD). This prospective pragmatic trial tests this hypothesis. Patients with severe MDD were randomly assigned to either duloxetine (a serotonin and norepinephrine-reuptake inhibitor) or physicians’ choice of four generic SSRIs. Nonblinded, flexibly dosed treatment was used to mimic clinical practice. To address potential investigator bias, the patient-reported Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) was used as the primary efficacy outcome measure. A total of 750 outpatients (19.2%, African descent; 14.8%, Hispanic) were randomized. The primary outcome, remission at week 12 by QIDS-SR, was numerically greater for duloxetine compared with SSRIs (36 vs. 32%), but this difference was not statistically significant. Mean changes in secondary outcomes were significantly superior in favor of duloxetine for the Hamilton Depression Scale-17 item, the Brief Pain Inventory, and the Sheehan Disability Scale. Remission superiority on the QIDS-SR was not achieved. Significantly greater benefit for duloxetine compared with SSRIs was demonstrated on measures of pain and functioning. Study demographics suggest a more generalizable racial and ethnic population than is typical in randomized clinical trials.

The relationship between functional outcomes and the treatment of anxious and painful somatic symptoms in patients with generalized anxiety disorder

ABSTRACT Objective: To examine the relationship between global functional impairment and the treatment of anxious symptoms and painful somatic symptoms (PSS) in patients with generalized anxiety disorder (GAD). Research design and methods: Data from two double-blind, placebo-controlled trials in adult outpatients meeting DSM-IV criteria for GAD were pooled. In the first trial (9-week, fixed-dose treatment period), patients were randomized to duloxetine 60 mg QD (n = 168), duloxetine 120 mg QD (n = 170), or placebo (n = 175). In the second trial (10-week, flexible-dose treatment period), patients were randomized to 60–120 mg QD of duloxetine (n = 168) or placebo (n = 159). Path analysis was used to assess the relative contributions of changes in psychic and somatic anxiety and PSS on improved functional outcomes. Clinical trial registration information: Study 1: NCT00122824; Study 2: study completed before registration required. Main outcome measures: Sheehan Disability Scale (SDS), Hamilton Anxiety Rating Scale (HAMA), and Visual Analog Scale for overall pain (VAS). Results: There was a moderate correlation (0.45, p < 0.05) at endpoint between changes in global functional impairment and changes in psychic anxiety (controlling for somatic anxiety and PSS); whereas the correlation between changes in global functional impairment and changes in somatic anxiety (controlling for psychic anxiety and PSS) was weak (0.09, p < 0.05). The correlation between changes in global functional impairment and changes in PSS (controlling for psychic and somatic anxiety) was weak (0.27, p < 0.05). Path analysis revealed that 37% of the total improvement in functional impairment (Sheehan Disability Scale total score) due to duloxetine treatment was independent of improvement in the Hamilton Anxiety Rating Scale (HAMA) psychic and somatic anxiety subscale scores or Visual Analog Scale for overall pain (VAS) score. Improvement in psychic anxiety accounted for 47% of the total treatment effect on improvement of functional impairment, whereas 7% and 9% of the improvement in functional impairment was accounted for by improvements in somatic anxiety and overall pain, respectively. Limitations: This was a post-hoc exploratory analysis. Patients with co-morbid Major Depressive Disorder (MDD) or significant depressive symptoms were excluded from these GAD studies. Conclusions: In patients with GAD, there was a moderate correlation between improvement in psychic anxiety symptoms and improvement in global functional impairment, whereas the correlation between improvements in somatic anxiety or PSS and improvement in global functional impairment was low. Most of the treatment effect of duloxetine in improvement of functional impairment was mediated through improvement in psychic anxiety, with smaller contributions through improvement in somatic anxiety and PSS. Some of the improvement in functional impairment for duloxetine-treated patients was independent of improvement through any of these domains.

Acute Insulin Response and β-Cell Compensation in Normal Subjects Treated With Olanzapine or Risperidone for 2 Weeks Response to Jindal

We recently reported that short-term treatment with olanzapine or risperidone did not impair acute insulin response or β-cell compensation in healthy subjects (1). Dr. Jindal (2) has cited some possible inconsistencies between our study and other reports, which we would like to address. First, Dr. Jindal notes that our conclusions contrast with those of Ader et al. (3) and points to differences in antipsychotic doses as one possible reason. However, the final olanzapine dose in our study (10 mg/day) is consistent with the package inserts target dose for patients with schizophrenia and also appears to be consistent with common prescribing practices for the treatment of schizophrenia at the time our …