A randomized, double-blind, placebo-controlled trial of duloxetine for the treatment of pain in patients with multiple sclerosis.

BACKGROUND: Patients with multiple sclerosis (MS) often report neuropathic pain (NP-MS). The purpose of this study was to assess the efficacy and tolerability of duloxetine as treatment for NP-MS. METHODS: In this study, 239 adults with NP-MS (duloxetine = 118, placebo = 121) were randomized to duloxetine 60 mg (30 mg for 1 week, then 60 mg for 5 weeks) or placebo once daily for a 6-week acute therapy phase, followed by a 12-week open-label extension phase (duloxetine 30 to 120 mg/day). Eligible patients had MS for ≥ 1 year and a score ≥ 4 on daily average pain intensity (API) ratings for ≥ 4 of 7 days immediately before randomization. Patients rated API daily on an 11-point numeric scale (0 [no pain] to 10 [worst possible pain]) in an electronic diary. The primary efficacy measure, change in weekly API ratings, was analyzed longitudinally with a mixed-model repeated-measures analysis. Completion, reasons for discontinuation, and treatment-emergent adverse event incidence were compared by Fisher's exact test. RESULTS: Duloxetine-treated patients had statistically greater mean improvement in API vs. placebo at Week 6 (-1.83 vs. -1.07, P = 0.001). Treatment completion did not significantly differ between groups. Discontinuation due to adverse events was statistically greater for duloxetine vs. placebo (13.6% vs. 4.1%, P = 0.012). Decreased appetite was reported significantly more often by duloxetine-treated patients (5.9% vs. 0%, P = 0.007). CONCLUSIONS: This study found analgesic efficacy of duloxetine for NP-MS. Duloxetine is not approved for treatment of this condition. The duloxetine safety profile of this study was consistent with the known profile in other patient populations.

Duloxetine, pregabalin, and duloxetine plus gabapentin for diabetic peripheral neuropathic pain management in patients with inadequate pain response to gabapentin: an open-label, randomized, noninferiority comparison.

OBJECTIVE: To determine whether duloxetine is noninferior to (as good as) pregabalin in the treatment of pain associated with diabetic peripheral neuropathy. PATIENTS AND METHODS: We performed a 12-week, open-label study of patients with diabetic peripheral neuropathic pain who had been treated with gabapentin (≥ 900 mg/d) and had an inadequate response (defined as a daily pain score of ≥ 4 on a numerical rating scale [0-10 points]). The first patient was enrolled on September 28, 2006, and the last patient visit occurred on August 26, 2009. Patients were randomized to duloxetine monotherapy (n=138), pregabalin monotherapy (n=134), or a combination of duloxetine and gabapentin (n=135). The primary objective was a noninferiority comparison between duloxetine and pregabalin on improvement in the weekly mean of the diary-based daily pain score (0- to 10-point scale) at end point. Noninferiority would be declared if the mean improvement for duloxetine was no worse than the mean improvement for pregabalin, within statistical variability, by a margin of -0.8 unit. RESULTS: The mean change in the pain rating at end point was -2.6 for duloxetine and -2.1 for pregabalin. The 97.5% lower confidence limit was a -0.05 difference in means, establishing noninferiority. As to adverse effects, nausea, insomnia, hyperhidrosis, and decreased appetite were more frequent with duloxetine than pregabalin; insomnia, more frequent with duloxetine than duloxetine plus gabapentin; peripheral edema, more frequent with pregabalin than with duloxetine; and nausea, hyperhidrosis, decreased appetite, and vomiting, more frequent with duloxetine plus gabapentin than with pregabalin. CONCLUSION: Duloxetine was noninferior to pregabalin for the treatment of pain in patients with diabetic peripheral neuropathy who had an inadequate pain response to gabapentin. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00385671.

Effects of atomoxetine on attention-deficit/hyperactivity disorder in clinical pediatric treatment settings: a naturalistic study.

BACKGROUND: Observational studies involving atomoxetine hydrochloride in the treatment of attention-deficit/hyperactivity disorder (ADHD) complement randomized controlled trials by assessing treatment effects in a usual-care setting and including a more heterogeneous patient population. OBJECTIVE: To provide data on the effectiveness of atomoxetine in a naturalistic treatment setting according to both physician and parent ratings. DESIGN AND METHODS: A prospective, observational (non-interventional), longitudinal, open-label study of patients (N = 627; mean age = 11 years) with ADHD (from 60 physicians' offices in the United States and Puerto Rico) whose physicians had decided to prescribe atomoxetine either as initial treatment or after trying another ADHD treatment (e.g., stimulants, antidepressants). Patients with a baseline visit and one post-baseline visit for up to 1 year were eligible. Atomoxetine administration, dosing, and timing of follow-up visits were at each physician's discretion. Physicians evaluated the effectiveness of atomoxetine using a single-item rating scale: the Physician Global Impression: ADHD Severity (PGI-ADHD-S) scale. RESULTS: The average reported duration of treatment was 21.2 (range 0-89) weeks. Over this period, treatment significantly lowered ADHD severity compared with baseline, with a mean change of -0.91 (95% confidence interval: -1.00 to -0.82; p < 0.001) on the PGI-ADHD-S scale. Physician-rated improvement was more marked in patients with more severe ADHD at baseline (p < 0.001). Most patients (59-69%) experienced consistent symptom control at all times of the day. ADHD severity was improved similarly in patients across comorbid conditions (e.g., anxiety, depression, learning disorders), chief complaints (e.g., school problems, emotional problems), and prior treatment with stimulants or other medications. By parent reports, 49% of patients had improved grades following atomoxetine therapy while 35% stayed the same, and improvement in behavior (according to parents' ratings) occurred in 49% of patients following atomoxetine therapy, whereas 31% stayed the same. CONCLUSION: Data captured in this study support the conclusion that atomoxetine was effective in reducing symptom severity, and improving progress toward treatment goals, in children and adolescents with ADHD treated in a naturalistic treatment setting. However, given the open-label, observational (non-interventional) design of this study, certain biases cannot be excluded.

Once-daily atomoxetine treatment for children with attention-deficit/hyperactivity disorder, including an assessment of evening and morning behavior: a double-blind, placebo-controlled trial.

OBJECTIVES: Atomoxetine seems to be as effective for treating attention-deficit/hyperactivity disorder (ADHD) when the daily dose is administered once in the morning as when the dose is divided and administered in the morning and evening. In the present study, the efficacy of atomoxetine administered once daily among children with ADHD was assessed throughout the day, including the evening and early morning. Another goal was to determine how early in treatment it was possible to discern a specific effect of the drug on ADHD symptoms. METHODS: This study was a randomized, multicenter, double-blind, placebo-controlled trial conducted at 12 outpatient sites in the United States. A total of 197 children, 6 to 12 years of age, who had been diagnosed as having ADHD, on the basis of the Diagnostic and Statistical Manual of Mental Disorders (4th ed.) criteria, were randomized to receive 8 weeks of treatment with atomoxetine or placebo, dosed once daily in the mornings. ADHD symptoms were assessed with parent and investigator rating scales. The primary outcome measure was the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored total score. Daily parent assessments of children's home behaviors in the evening and early morning were recorded with an electronic data entry system. This instrument measures 11 specific morning or evening activities, including getting up and out of bed, doing or completing homework, and sitting through dinner. RESULTS: Seventy-one percent of the children enrolled were male, 69% met criteria for the combined subtype (both inattentive and hyperactive/impulsive symptoms), and the most common psychiatric comorbidity was oppositional defiant disorder (35%). Once-daily atomoxetine (final mean daily dose of 1.3 mg/kg) was significantly more effective than placebo in treating core symptoms of ADHD. Mean reductions in the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored total score were significantly greater for patients randomized to atomoxetine, beginning at the first visit after the initiation of treatment and continuing at all subsequent visits. Both inattentive and hyperactive/impulsive symptom clusters were significantly reduced with atomoxetine, compared with placebo. With continued treatment and dose titrations, core symptoms of ADHD continued to decrease throughout the 8-week study. Mean reductions in the daily parent assessment total scores for patients randomized to atomoxetine were superior during the first week, beginning with the first day of dosing, and were also superior at endpoint. Efficacy outcomes for the evening hours for atomoxetine-treated patients were superior to those for placebo-treated patients, as assessed with 2 different assessment scales. Decreases in the daily parent assessment morning subscores at endpoint showed a significant reduction in symptoms that lasted into the mornings. Rates of discontinuations attributable to adverse events were <5% for both groups. Adverse events reported significantly more frequently with atomoxetine were decreased appetite, somnolence, and fatigue. CONCLUSIONS: Among children 6 to 12 of age who had been diagnosed as having ADHD, once-daily administration of atomoxetine in the morning provided safe, rapid, continuous, symptom relief that lasted not only into the evening hours but also into the morning hours. Atomoxetine treatment was safe and well tolerated.