Profile of adverse events with duloxetine treatment: a pooled analysis of placebo-controlled studies.

BACKGROUND: The serotonin and noradrenaline (norepinephrine) reuptake inhibitor duloxetine has been approved in the US and elsewhere for a number of indications, including psychiatric illnesses and chronic pain conditions. Because the patient populations are diverse within these approved indications, and duloxetine is not yet approved for treatment of other conditions, we wanted to determine if adverse event profiles would differ among patients being treated for these various conditions. OBJECTIVE: To provide detailed information on the adverse events associated with duloxetine and to identify differences in the adverse event profile between treatment indications and patient demographic subgroups. METHODS: Data were analysed from all placebo-controlled trials of duloxetine completed as of December 2008. The 52 studies included 17,822 patients (duloxetine n = 10,326; placebo n = 7496) with major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathic pain, fibromyalgia, osteoarthritis knee pain (OAKP), chronic lower back pain and lower urinary tract disorders. The main outcome measures were rates of treatment-emergent adverse events (TEAEs) and adverse events reported as the reason for discontinuation. RESULTS: The overall TEAE rate was 57.2% for placebo-treated patients and 72.4% for duloxetine-treated patients (p < or = 0.001). Patients with OAKP had the lowest TEAE rate (placebo 36.7% vs duloxetine 50.2%, p < or = 0.01), while patients with fibromyalgia had the highest rate (placebo 80.0% vs duloxetine 89.0%, p < or = 0.001). The most common TEAE for all indications was nausea (placebo 7.2% vs duloxetine 23.4%, p < or = 0.001), which was predominantly mild to moderate in severity. No statistically significant treatment-by-subgroup interactions for age were found between placebo and duloxetine treatment for the most common TEAEs. The rates of duloxetine-associated dry mouth and fatigue were greater in women than in men (13.1% vs 10.4%, interaction p = 0.004; and 9.4% vs 7.6%, interaction p = 0.03, respectively). Duloxetine-associated dry mouth incidence was higher in Caucasians than non-Caucasians (13.2%, 11.0%, interaction p = 0.04). CONCLUSIONS: Duloxetine treatment is associated with significantly higher rates of common TEAEs versus placebo, regardless of indication or demographic subgroup. Differences across indications are likely to be attributable to the underlying condition rather than duloxetine, as suggested by the similar trends observed in placebo- and duloxetine-treated patients.

The placebo response in pain and depression: in search of a common pathway.

The placebo effect has been extensively studied in many disease states, some of the most notable being pain and depression. Utilizing a Medline search, studies were identified that reported on areas of the brain shown to be involved in either placebo analgesia or mood response. This paper presents a distillation of this research, in an effort to identify a common "placebo pathway" between mood and pain. Placebo-related responses to both analgesia and relief from depression were reported to be associated with an increase in activity in the frontal cortex and a decrease in activity in the thalamus.

Duloxetine, a centrally acting analgesic, in the treatment of patients with osteoarthritis knee pain: a 13-week, randomized, placebo-controlled trial.

Pain is a common cause of disability in osteoarthritis. Duloxetine, a serotonin and norepinephrine reuptake inhibitor (SNRI), has demonstrated analgesic effects in diabetic peripheral neuropathy and fibromyalgia. Considering its central mechanism of action, duloxetine may be effective in other pain states with evidence of central sensitization. Herein, we report the results of a 13-week, randomized, double-blind, placebo-controlled trial of duloxetine (60-120 mg/day) versus placebo in the treatment of knee pain in 231 patients meeting clinical and radiographic criteria for osteoarthritis of the knee. Duloxetine was superior to placebo on the primary efficacy measure (weekly mean 24-h pain scores) beginning at Week 1 and continuing through the treatment period (P < or = .05). There was also a significant improvement in the WOMAC physical functioning subscale and several other secondary outcomes. Adverse-event rates did not differ significantly between treatment groups (49.5% for duloxetine 60-120 mg/day, and 40.8% for placebo).

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.

Clinical evidence for serotonin and norepinephrine reuptake inhibition of duloxetine.

Most antidepressants in clinical use are believed to function by enhancing neurotransmission of serotonin [5-hydroxytryptamine (5-HT)] and/or norepinephrine (NE) via inhibition of neurotransmitter reuptake. Agents that affect reuptake of both 5-HT and NE (serotonin-norepinephrine reuptake inhibitors) have been postulated to offer greater efficacy for the treatment of major depressive disorder (MDD). These dual-acting agents also display a broader spectrum of action, including efficacy for MDD and associated painful physical symptoms, diabetic peripheral neuropathic pain, generalized anxiety disorder, and fibromyalgia syndrome. Substantial preclinical evidence shows that duloxetine, an approved drug for the treatment of MDD, generalized anxiety disorder, and the management of diabetic peripheral neuropathic pain, inhibits reuptake of both 5-HT and NE. This paper reviews clinical and neurochemical evidence of duloxetine's effects on 5-HT and NE reuptake inhibition. The clinical evidence supporting duloxetine's effects on NE reuptake inhibition includes indirect measures such as altered excretion of NE metabolites, cardiovascular effects, and treatment-emergent adverse event profiles similar to those for other drugs believed to act through the inhibition of NE reuptake. In summary, the data presented in this report provide clinical evidence of a mechanism for duloxetine involving both 5-HT and NE reuptake inhibition in humans and are consistent with preclinical evidence for 5-HT/NE reuptake inhibition.

Efficacy of duloxetine and selective serotonin reuptake inhibitors: comparisons as assessed by remission rates in patients with major depressive disorder.

It has been proposed that serotonin and norepinephrine reuptake inhibitors (SNRIs) may result in higher remission rates of major depressive disorder than therapy with selective serotonin reuptake inhibitors (SSRIs). To test this hypothesis, a meta-analysis of individual patient data (N = 1833) was performed for the complete set of 6 phase II/III studies that compared duloxetine (fixed doses; range, 40-120 mg/d) with 2 SSRIs (paroxetine or fluoxetine; 20 mg/d) in outpatients with major depressive disorder. Remission was defined as an end point score of less than or equal to 7 on the 17-item Hamilton Rating Scale for Depression (HAMD17); alternate outcome criteria were also examined, as were remission rates among the 1044 patients with moderate-to-severe depression (HAMD17 total score greater than or equal to 19). The HAMD17 remission rates were 40.3% (351/871), 38.3% (162/423), and 28.4% (144/507) for duloxetine, the 2 SSRIs, and placebo, respectively. Both active treatments were superior to placebo; the difference between duloxetine and SSRIs was not statistically significant. Similar findings were observed for alternate outcomes. Duloxetine therapy was significantly more effective than therapy with the 2 SSRIs for patients with more severe depression, with remission rates of 35.9% (183/510) versus 28.6% (70/245) (P = 0.046). A secondary analysis of dose-response relationships indicated that this advantage was not attributable to the studies using higher doses of duloxetine. Thus, whereas duloxetine and the 2 SSRIs were comparably efficacious overall, therapy with the serotonin and norepinephrine reuptake inhibitor resulted in a significantly higher remission rate among patients with moderate-to-severe depression.

A retrospective pooled analysis of duloxetine safety in 23,983 subjects.

OBJECTIVE: The safety and tolerability of duloxetine for major depressive disorder (MDD), generalized anxiety disorder (GAD), diabetic peripheral neuropathic pain (DPNP), fibromyalgia, and lower urinary tract disorders (LUTD) (including female stress urinary incontinence [SUI] and other LUTDs) has been established in individual clinical studies. The objective of this manuscript is to characterize the overall safety profile of duloxetine, regardless of indication, based on data from the duloxetine exposures integrated safety database. RESEARCH DESIGN AND METHODS: The duloxetine exposures integrated safety database was examined using pooled data from 23,983 patients randomized to receive duloxetine in 64 studies for MDD, GAD, DPNP, fibromyalgia, or LUTDs. Evaluated aspects of drug safety included treatment-emergent adverse events (TEAEs), adverse events leading to discontinuation, serious adverse events (SAEs), clinical laboratory tests, vital signs, and electrocardiograms. RESULTS: Common TEAEs included nausea, headache, dry mouth, insomnia, constipation, dizziness, fatigue, somnolence, diarrhea, and hyperhidrosis. Most TEAEs emerged early; the majority were mild to moderate in severity, and did not worsen. Overall, discontinuation rates due to AEs were 20.0%. SAEs occurred at a rate of 3.5% and no single event was predominant. Mean pulse increased by < 2 beats per minute. Mean increases in systolic and diastolic blood pressure were < 1 mmHg. Mean alanine transaminase and aspartate transaminase values increased by < 2 U/L. CONCLUSIONS: The safety profile for the molecule from the overall duloxetine exposures integrated safety database suggests that benign and common pharmacologic side effects occur with duloxetine treatment. Because these pooled analyses do not allow for statistical comparison to placebo or active comparator, and include data from five different studied indications, these data do not suggest causality for AEs, nor are they necessarily generalizable to each disease stated studied.