Deborah N. D'Souza

A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder

&NA; This was a 12‐week, randomized, double‐blind, placebo‐controlled trial to assess the efficacy and safety of duloxetine, a selective serotonin and norepinephrine reuptake inhibitor, in 354 female patients with primary fibromyalgia, with or without current major depressive disorder. Patients (90% Caucasian; mean age, 49.6 years; 26% with current major depressive disorder) received duloxetine 60 mg once daily (QD) (N=118), duloxetine 60 mg twice daily (BID) (N=116), or placebo (N=120). The primary outcome was the Brief Pain Inventory average pain severity score. Response to treatment was defined as ≥30% reduction in this score. Compared with placebo, both duloxetine‐treated groups improved significantly more (P<0.001) on the Brief Pain Inventory average pain severity score. A significantly higher percentage of duloxetine‐treated patients had a decrease of ≥30% in this score (duloxetine 60 mg QD (55%; P<0.001); duloxetine 60 mg BID (54%; P=0.002); placebo (33%)). The treatment effect of duloxetine on pain reduction was independent of the effect on mood and the presence of major depressive disorder. Compared with patients on placebo, patients treated with duloxetine 60 mg QD or duloxetine 60 mg BID had significantly greater improvement in remaining Brief Pain Inventory pain severity and interference scores, Fibromyalgia Impact Questionnaire, Clinical Global Impression of Severity, Patient Global Impression of Improvement, and several quality‐of‐life measures. Both doses of duloxetine were safely administered and well tolerated. In conclusion, both duloxetine 60 mg QD and duloxetine 60 mg BID were effective and safe in the treatment of fibromyalgia in female patients with or without major depressive disorder.

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.

Duloxetine: meta-analyses of suicidal behaviors and ideation in clinical trials for major depressive disorder.

Background: Uncertainty regarding relationships of antidepressant treatment and suicidality encouraged systematic review of data on suicidal behaviors and ideation from Phase II and III clinical trials of duloxetine for major depressive disorder (MDD). Methods: We evaluated all completed duloxetine trials in MDD with data lock by February 2, 2004. We compared incidence of suicide-related events with duloxetine versus placebo in controlled trials, using Mantel-Haenszel incidence difference (MHID) and exposure time-adjusted rate difference (MHRD) methods, and analyzed changes in Hamilton Depression Scale (HAMD) Item-3 (suicidality) scores. Results: There were no significant differences in the incidence of suicide-related events with duloxetine versus placebo in 12 placebo-controlled trials (duloxetine, 1812; placebo, 1814 patients). The MHID for suicide-related behaviors was −0.03% (95% confidence interval [CI], −0.48 to 0.42) and MHRD −0.002 (95% CI, −0.02 to 0.02). Changes in HAMD Item-3 suicidality scores showed more improvement with duloxetine (MHID, 9.56%; 95% CI, 4.50 to 14.6; P < 0.001) and less worsening of suicidal ideation with duloxetine (MHID, −4.25%; 95% CI, −6.55 to −1.95; P < 0.001). Other Item-3 findings showed no consistent pattern; a slightly higher proportion of duloxetine-treated patients with a change from 0 (absent) to 3 was balanced against a higher proportion of placebo-treated patients changing from 0 to 2. Conclusions: We found no evidence of an increased risk of suicidal behaviors or ideation during treatment with duloxetine compared with placebo in MDD patients. HAMD Item-3 suicidality scores had more improvement and less worsening of suicidal ideation with duloxetine than placebo.

Burden of illness and treatment patterns for patients with fibromyalgia.

OBJECTIVE   This study was designed to describe burden of illness and treatment patterns, and to examine the patient, physician, and care factors associated with the treatment choices of individuals receiving new prescriptions for fibromyalgia (FM). DESIGN   This is a baseline assessment of the Real-World Examination of Fibromyalgia: Longitudinal Evaluation of Costs and Treatments (REFLECTIONS), a prospective observational study. Baseline data (including a physician survey, a patient visit form, and computer-assisted telephone interviews) were collected from July 2008 through May 2010 in 58 care settings in the United States, including Puerto Rico. RESULTS   Patients (N = 1,700) were mostly female (94.6%) and white (82.9%). Mean age was 50.4 years and mean duration of illness was 5.6 years. Mean Fibromyalgia Impact Questionnaire total score was 54.4 (range 0-80), and Brief Pain Inventory average pain severity level was 5.5 (range 0-10). Patients reported high annual health care use and numerous work limitations related to FM. Patients were taking 182 unique types of medications prescribed for FM, including duloxetine (26.8%), nonsteroidal anti-inflammatory drugs (26.6%), pregabalin (24.5%), opioids (24.2%), tramadol (15.3%), benzodiazepines (15.2%), cyclobenzaprine (12.9%), milnacipran (8.9%), and others. Most patients took more than one medication concurrently (77.8%). Type of current medications used was most strongly associated with medication history and physician specialty. CONCLUSIONS   Burden of illness was high for patients with FM, and treatment patterns were highly variable. Importantly, the treatments with the most evidence to support their use were not always the most frequently chosen.

Hepatic effects of duloxetine-I: non-clinical and clinical trial data.

OBJECTIVE Review nonclinical and clinical trial data for hepatic effects of duloxetine. METHODS Review studies of toxicology, metabolism, mitochondrial effects, and clinical trials. RESULTS Nonclinical studies revealed no treatment-related transaminase elevations and no effects of duloxetine on mitochondrial beta-oxidation in rat hepatocytes. In patients with a normal baseline alanine transaminase (ALT), duloxetine was associated with elevated transaminases >3X ULN in about 1% of patients. ALT and aspartate transaminase values peaked at 8 weeks, alkaline phosphatase steadily increased to maximum value at Week 52 and mean total bilirubin values were not increased. Hepatic-related treatment-emergent adverse events were uncommon. Seven of 23,000 duloxetine- and 2/6000 placebo-treated patients met criteria for modified Hys rule (significant elevation of both ALT and total bilirubin) but were complicated by contributing factors such as excessive alcohol consumption (n=3), gall stones, common bile duct calculus, hepatitis C, and liver adenocarcinoma (n=1 each). CONCLUSIONS Duloxetine has an effect on the liver, manifested by transient, self-limiting transaminase elevations. Rare events characterized as hepatocellular injury, cholestatic injury, or mixed type of hepatic injury have been reported. The pattern of liver effects was different from that in laboratory animals.

Hepatic Effects of Duloxetine-II: Spontaneous Reports and Epidemiology of Hepatic Events

OBJECTIVE Review spontaneous reports and epidemiology of hepatic events associated with duloxetine. METHODS Spontaneous reports of adverse events potentially associated with hepatic injury were identified. Classification schemes were Clinical Significance and Etiologic Category relative to likelihood of being related to duloxetine. RESULTS Duloxetine has been taken by an estimated 5,083,000 patients, representing approximately 1,551,000 person-years (PY) of worldwide exposure. In the Etiologic categorization of the 406 cases containing event terms potentially related to the liver that have been reported to the manufacturer, 26 were deemed Probable and 127 Possible. Because of scantly-reported information, 182 cases were considered Indeterminate. For Severe Hepatic Injury, the observed spontaneous reporting rate was 0.7/100,000 persons exposed. Of the 406 cases, 225 experienced enzyme elevations to values <500 U/L, most with concentrations well below this level. The calculated cumulative spontaneous reporting rate of all duloxetine hepatic-related events combined was 0.00799%, in the context of other drug-induced hepatic injury rates reported in the literature of 0.7 to 40.6 per 100,000 PY of observation. CONCLUSIONS There were few cases of true hepatic injury possibly or probably related to duloxetine. The calculated cumulative reporting rate is consistent with very rarely reported per the Council for International Organizations of Medical Sciences.

Duloxetine in the long-term management of diabetic peripheral neuropathic pain: An open-label, 52-week extension of a randomized controlled clinical trial

BACKGROUND Duloxetine hydrochloride, a selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor, is relatively balanced in its affinity for both 5-HT and NE reuptake inhibition and is the first US Food and Drug Administration-approved prescription drug for the management of diabetic peripheral neuropathic pain (DPNP). OBJECTIVES The aim of this study was to determine whether management of DPNP with duloxetine interferes with the treatment of diabetes. It also examined the tolerability of long-term exposure to duloxetine with regard to the progression of diabetic complications, and assessed the impact of DPNP management with duloxetine versus routine care. METHODS This was a 52-week, multicenter, re-randomized, open-label extension of a parallel, double-blind, randomized, placebo-controlled, acute (12-week) study. Patients who completed the duloxetine or placebo acute treatment period were randomly reassigned in a 2:1 ratio to treatment with duloxetine 60 mg BID or routine care for an additional 52 weeks. The study included male and female outpatients aged ≥18 years with a diagnosis of DPNP caused by type 1 or type 2 diabetes. Over the course of the 52-week study, visits were scheduled on the following weeks (of the extension phase of the study): 1 (via phone only), 2, 4, 8, 12, 20, 28, 40, and 52. Tolerability was assessed by review and analyses of discontinuation rates, adverse events (AEs), laboratory data, vital signs, electrocardiographic results, concomitant medications, and diabetic complications. Treatment-emergent AEs (TEAEs) were defined as AEs that appeared during therapy (were not present at baseline) or were exacerbated during treatment. Data on AEs and concomitant medications were collected at every visit. Data on blood pressure, heart rate, and significant hypoglycemic events were collected at every visit starting from week 2. Fasting clinical chemistry and electrolyte group laboratory assessments were done at every visit, starting from week 4. Electrocardiographic data was collected at weeks 4 and 52, and glycosylated hemoglobin and lipid profile data were collected at weeks 20 and 52. Hematology and urinalysis laboratory assessments and diabetic complication assessments were done at week 52. All safety data was assessed in cases of early discontinuation. Treatment differences on quality of life (QOL) were compared using the Short Form-36 Health Status Survey (SF-36) and the EQ-5D instrument of the European Health-Related Quality of Life Measures. This was assessed at the last visit or at early discontinuation. RESULTS The open-label extension-phase study included 337 patients (duloxetine, n = 222; routine care, n = 115). For the duloxetine group, mean age was 60.2 years, 61.3% were male, and 78.4% were white. For the routine-care group, mean age was 58.9 years, 60.0% were male, and 74.8% were white. Mean weight was 95.3 kg for both groups. None of the TEAEs occurred significantly more often in the duloxetine-treated group than in the routine-care-treated group. No TEAEs were reported by >10% of patients in the duloxetine group. The TEAEs reported by >10% of patients in the routine-care group included dizziness (11.3%), somnolence (13.0%), headache (10.4%), and vomiting (10.4%). No significant differences were found between treatment groups in the occurrence of serious AEs or in the number of patients discontinuing because of AEs. Duloxetine was significantly better than routine care on the bodily pain subscale of the SF-36 (mean change: 1.5 vs -4.1; P= 0.021) and on the EQ-5D (mean change: -0.00 vs -0.09; P = 0.001). CONCLUSIONS Over 52 weeks of follow-up, treatment of these diabetic patients with duloxetine for peripheral neuropathic pain was associated with outcomes similar to, or significantly better than, that of routine care on most measures of tolerability, diabetic complications, and QOL.

Hepatic Effects of Duloxetine – III: Analysis of Hepatic Events Using External Data Sources

OBJECTIVE Present results from two hepatic safety studies conducted within 20 months after duloxetine launch. METHODS Signal detection based on spontaneous reports to the FDA adverse event reporting system (AERS) and on a comparison of duloxetine and venlafaxine in the i3 Drug Safety Aperio claims database, using measures of disproportionality and incidence rate ratio, respectively. RESULTS In AERS all antidepressants had some degree of association with hepatic injury, in that at least one hepatic event was disproportionately represented for each drug. Signals were detected for duloxetine cases analyzed against full and antidepressant-only backgrounds. These signals corresponded to labeled events or events investigated during ongoing surveillance. Using a duloxetine fatal-case series, disproportional representation of clinically serious events was detected relative to both backgrounds, but the signals were refuted upon independent expert panel case review. The Aperio study showed no difference in hepatic injury between duloxetine and venlafaxine initiators after proper control for baseline risks, suggesting differential prescribing of duloxetine, perhaps preferentially as second-line therapy in some initiators. CONCLUSIONS No new signals were identified in Aperio. New signals detected through AERS were refuted upon independently conducted case-level investigation. Hepatic signals arising from spontaneously reported data must be clarified through subsequent systematic investigation.

A double-blind, placebo-controlled study of edivoxetine as an adjunctive treatment for patients with major depressive disorder who are partial responders to selective serotonin reuptake inhibitor treatment

BACKGROUND This phase 2 study examined the efficacy and tolerability of edivoxetine, a highly selective norepinephrine reuptake inhibitor, as an adjunctive treatment for patients with major depressive disorder (MDD) who have a partial response to selective serotonin reuptake inhibitor (SSRI) treatment. METHODS Study design consisted of double-blind, 10-week therapy of adjunctive edivoxetine (6-18 mg once daily) or adjunctive placebo with SSRI. Inclusion/entry criteria included partial response to current SSRI by investigator opinion and a GRID 17-item Hamilton Rating Scale for Depression (HAMD17) total score ≥16. The primary efficacy measure was the Montgomery-Asberg Depression Rating Scale (MADRS). Safety measures included treatment-emergent adverse events (TEAE) and vital signs. RESULTS For the primary evaluable population (n=63 for adjunctive edivoxetine and n=68 for adjunctive placebo), the treatment groups did not differ significantly on the primary outcome of change from baseline to week 8 in the MADRS total score; the effect size of edivoxetine treatment was 0.26. Significant treatment differences, favoring adjunctive edivoxetine (p≤.05), were shown for improvements in role functioning and the functional impact of fatigue. For the adjunctive edivoxetine randomized group (N=111), the most frequent TEAEs were hyperhidrosis (7.2%), nausea (7.2%), erectile dysfunction (6.3%) and testicular pain (6.3%). Hemodynamic changes were observed in blood pressure and pulse rate between treatment groups. LIMITATIONS Study was underpowered for an alpha 2-sided 0.05 significance level for the primary outcome. CONCLUSIONS For patients with MDD who had a partial response to SSRIs, adjunctive edivoxetine treatment was not statistically superior to adjunctive placebo on the primary outcome measure. However, pending further study, improved functioning and remission rate suggest a potential role for edivoxetine for patients with depression.

Pain response profile of patients with fibromyalgia treated with duloxetine.

ObjectivesThis study examined the time course for minimal clinically significant improvement in pain severity during the initial 12 weeks of treatment in patients with fibromyalgia taking duloxetine. MethodsFour double-blind, placebo-controlled trials of duloxetine were pooled. Patients received duloxetine 60 mg/d, 120 mg/d, or placebo. Clinically significant treatment response (≥30% reduction in pain severity on the 24-hour average pain severity of the Brief Pain Inventory scale) was assessed over 12 weeks. ResultsAt endpoint, 46.9% of duloxetine 60-mg-, 48.6% of duloxetine 120-mg-, and 32.1% of placebo-treated patients (P<0.001 for both doses) had ≥30% improvement on average pain from baseline. The probabilities of achieving ≥30% response at Weeks 1, 2, 4, 8, and 12 among duloxetine 60-mg-treated patients were 27%, 44%, 45%, 47%, and 49%, respectively, and among duloxetine 120-mg-treated patients were 35%, 43%, 53%, 53%, and 51%, respectively (P<0.01 vs. placebo at each week, for both doses). Among patients who did not respond by Weeks 1, 2, 4, and 8, the percentages of duloxetine 60-mg-treated patients who achieved a response by the endpoint of the study were 36.9%, 29.8%, 28.9%, and 26.9%, respectively. DiscussionThis article examines the time course for minimal clinically significant improvement in pain severity in duloxetine-treated patients with fibromyalgia. It provides information about continued treatment in patients who do not initially respond to duloxetine. This information could potentially help physicians facing clinical decisions about management of fibromyalgia with duloxetine.