Does pain cause the perception of fatigue in patients with chronic pain? Findings from studies for management of diabetic peripheral neuropathic pain with duloxetine.

A major issue in pain literature is whether an etiological association between pain, sleep, and vitality exists. We utilized data from clinical trials of duloxetine for management of diabetic peripheral neuropathic pain (DPNP) to investigate these associations. Data were pooled from 3 double-blind, randomized, placebo-controlled, 12-week trials of patients without mood disorder (N = 1,139). After excluding 442 patients who reported maximum vitality at baseline, experienced treatment-emergent somnolence, asthenia or fatigue, or were taking sedating concomitant medications or duloxetine 20 mg/day, 697 were included in the analysis. Efficacy measures included weekly mean scores for average daily and night pain, pain interference with sleep, and vitality. Baseline to end point mean improvements in daily and night pain, Brief Pain Inventory sleep interference, and vitality were significantly superior for duloxetine compared with placebo (P < or = 0.001). Correlations between changes in daily and night pain, and sleep interference with vitality changes were -0.34, -0.32, and -0.28, respectively (P < 0.001). The direct effect of treatment on change in vitality was statistically significant (68%, P = 0.010) when assessed in an indirect manner through change in sleep interference alone but not in daily or night pain solely. Path analyses suggested vitality improvement in patients with chronic pain may be secondary to improvement in pain by duloxetine. Results do not prove pain causes fatigue, but indicate in DPNP patients with fatigue that treatment of pain can improve perception of improvement in fatigue. Thus, improvement of pain may be important in the context of trying to improve fatigue in DPNP patients.

A comparison of initial duloxetine dosing strategies in patients with major depressive disorder.

OBJECTIVE: To compare the effects of starting doses of duloxetine taken with or without food on tolerability and efficacy in patients with major depressive disorder (MDD). METHOD: This double-blind, concurrent-dose-controlled, parallel-design trial contained a variable expected-duration placebo lead-in period and was conducted in adult outpatients with DSM-IV-TR-defined MDD at psychiatric outpatient sites between October 2004 and January 2006. In actuality, patients received placebo for 1 week and then were randomly assigned to duloxetine 30 mg once daily in the morning (q.a.m.) (N = 219), 30 mg twice daily (b.i.d.) (N = 213), or 60 mg q.a.m. (N = 215) for 1 week along with 1 of 2 instructions about food: take study drug with food or do not take within 1 hour of eating. For the remaining 5 weeks of acute treatment, all patients received 60 mg once daily. The primary objective was to compare incidence of treatment-emergent nausea at 30 mg q.a.m. versus 60 mg q.a.m. using item 112 (nausea) of the Association for Methodology and Documentation in Psychiatry adverse event scale (AMDP-5). Secondary outcome measures included mean change on AMDP-5 item 112, discontinuations due to adverse events, mean changes in AMDP-5 items and subscales, spontaneously reported treatment-emergent adverse events, and vital signs. Efficacy was evaluated by the 17-item Hamilton Rating Scale for Depression (HAM-D-17). RESULTS: The primary analysis, which combined data from both food groups, showed no significant difference in the incidence of nausea between starting doses of 30 mg q.a.m. and 60 mg q.a.m. (23% vs. 29%, respectively; p = .207). However, mean changes on the AMDP-5 nausea item revealed a significant main effect of food (p = .010) and a significant interaction between food and starting dose (p = .033). The food-by-dose interaction indicated that the benefit from taking drug with food was greatest in patients started at 60 mg q.a.m., and the benefit of starting at 30 mg q.a.m. was greatest in patients taking drug without food. In patients who took study drug without food, there was a significant difference across initial-dose groups for discontinuation due to adverse events (30 mg q.a.m. = 3.6%, 30 mg b.i.d. = 14.0%, 60 mg q.a.m. = 10.2%; 30 mg q.a.m. vs. 30 mg b.i.d., p = .008; 30 mg q.a.m. vs. 60 mg q.a.m., p = .066); however, in patients who took study drug with food, discontinuations due to adverse events did not significantly differ (30 mg q.a.m. = 5.4%, 30 mg b.i.d. = 7.5%, 60 mg q.a.m. = 7.4%; all p values > .50). Patients who started at 30 mg b.i.d. or 60 mg q.a.m. without food did not differ regarding mean changes (i.e., increases) in the common adverse events score after 1 week of treatment but had significantly greater mean changes than patients who started at 30 mg q.a.m. without food (0.87, 0.82, and 0, respectively; p < .05 vs. 30 mg b.i.d. and 60 mg q.a.m.). No significant differences were found between initial-dose groups in vital signs. CONCLUSIONS: These data imply that starting dulox-etine at 30 mg q.a.m. for 1 week with or without food or starting duloxetine at the therapeutic dose of 60 mg q.a.m. with food can improve the initial tolerability of the medication. Adding this information to existing knowledge of duloxetine will enable the clinician to tailor therapy most appropriately for the individual patient. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT 00191061.

Switching patients from daily citalopram, paroxetine, or sertraline to once-weekly fluoxetine in the maintenance of response for depression.

BACKGROUND: Major depressive disorder is frequently a chronic, recurrent condition necessitating maintenance treatment. For some patients, compliance with daily pharmacotherapy is difficult over time. As an alternative approach, a once-weekly administered formulation of fluoxetine has recently been made available. This raises the important question of whether once-weekly enteric-coated fluoxetine, 90 mg, is effective for maintenance of response in patients whose depressive symptoms have responded to daily dosing with selective serotonin reuptake inhibitors (SSRIs) such as citalopram, paroxetine, or sertraline. METHOD: Patients had met DSM-IV criteria for major depressive disorder prior to beginning treatment for their current episode, had received 6 to 52 weeks of treatment with citalopram (20-40 mg/day [N = 83]), paroxetine (20 mg/day [N = 77]), or sertraline (50-100 mg/day [N = 86]), and had responded to that treatment (Clinical Global Impressions-Severity of Illness [CGI-S] score < or = 2, modified 17-item Hamilton Rating Scale for Depression [HAM-D-17] score < or = 10). Patients meeting these criteria (N = 246) continued treatment with their current SSRI for 1 week, then were switched to open-label enteric-coated fluoxetine, 90 mg, taken once weekly for 12 weeks. Safety measures were comparisons of spontaneously reported and solicited treatment-emergent adverse events. Efficacy measures were percentages of patients who discontinued the study for relapse and lack of efficacy and comparison of change from baseline to endpoint in scores on the modified HAM-D-17, subscales of the HAM-D-28, and the CGI-S. Quality of life measures were assessed with the MOS 36-Item Short-Form Health Survey (SF-36). We hypothesized that the once-weekly administration of fluoxetine could be safely and effectively initiated among subjects who had been stabilized on daily SSRI treatment. RESULTS: Seventy-nine percent of patients successfully completed a switch to enteric-coated fluoxetine, 90 mg, with 9.3% discontinuing due to relapse or lack of efficacy. Enteric-coated fluoxetine at a once-weekly dose of 90 mg was well tolerated in all groups. No significant increases were found in the HAM-D-17 total, HAM-D-28 subscores, or CGI-S score. Patients showed improvement from baseline to endpoint in most of the SF-36 health concepts. CONCLUSION: Enteric-coated fluoxetine taken once weekly appears to be well tolerated and efficacious in patients who responded to acute therapy with other SSRIs and were subsequently switched to fluoxetine once weekly for continuation/maintenance therapy.

Acute efficacy of fluoxetine versus sertraline and paroxetine in major depressive disorder including effects of baseline insomnia.

This study assessed whether fluoxetine, sertraline, and paroxetine differ in efficacy and tolerability in depressed patients and the impact of baseline insomnia on outcomes. Patients (N = 284) with DSM-IV major depressive disorder were randomly assigned in a double-blind fashion to fluoxetine, paroxetine, or sertraline for 10 to 16 weeks of treatment. Using the Hamilton Rating Scale for Depression (HAM-D) sleep disturbance factor score, patients were categorized into low (<4) or high (>or=4) baseline insomnia subgroups. Changes in depression and insomnia were assessed. Safety assessments included treatment-emergent adverse events (AEs), reasons for discontinuation, and AEs leading to discontinuation. In addition, AEs were evaluated within insomnia subgroups to determine emergence of activation or sedation. Depression improvement, assessed with the HAM-D-17 total score, was similar among treatments in all patients (p = 0.365) and the high (p = 0.853) and low insomnia (p = 0.415) subgroups. Insomnia improvement, assessed with the HAM-D sleep disturbance factor score, was similar among treatments in all patients (p = 0.868) and in the high (p = 0.852) and low insomnia (p = 0.982) subgroups. Analyses revealed no significant differences between treatments in the percentages of patients with substantial worsening, any worsening, worsening at endpoint, or improvement at endpoint in the HAM-D sleep disturbance factor in either insomnia subgroup. Treatments were well tolerated in most patients. No significant differences between treatments in the incidence of AEs suggestive of activation or sedation were seen in the insomnia subgroups. These data show no significant differences in acute treatment efficacy and tolerability across fluoxetine, sertraline, and paroxetine in major depressive disorder patients. Improvement in overall depression and in associated insomnia was achieved by most patients regardless of baseline insomnia.