The short- and long-term effect of duloxetine on painful physical symptoms in patients with generalized anxiety disorder: Results from three clinical trials

Generalized anxiety disorder (GAD) is associated with painful physical symptoms (PPS). These post hoc analyses of previous trial data assessed PPS and their response to duloxetine treatment in GAD patients. Studies 1 and 2 (n = 840) were 9- to 10-week efficacy trials; study 3 (n = 887) was a relapse prevention trial comprising a 26-week open-label treatment phase and a 26-week double-blind, placebo-controlled treatment continuation phase. Mean baseline visual analog scale scores (VAS, 0–100; n = 1727) ranged from 26 to 37 for overall pain, headache, back pain, shoulder pain, interference with daily activities, and time in pain while awake. In studies 1 and 2, improvement on all VAS scores was greater in duloxetine-treated than in placebo-treated patients (p ≤ 0.01). In study 3, pain symptoms worsened in responders switched to placebo compared with those maintained on duloxetine (p ≤ 0.02). In conclusion, duloxetine was efficacious in the short- and long-term treatment of PPS, which are common in GAD patients.     

Gabapentin as Add-On Therapy in Children with Refractory Partial Seizures: A 12-Week, Multicentre, Double-Blind, Placebo-Controlled Study

PURPOSE: To evaluate the efficacy and safety of gabapentin (Neurontin; GBP) as add-on therapy for refractory partial seizures in paediatric patients aged 3-12 years. METHODS: After a 6-week baseline period, 247 patients (54 centres) entered a 12-week double-blind phase and were randomized to receive either GBP (t.i.d., titrated to 23-35 mg/kg/ day) or placebo. Seizure activity and type were recorded daily. Efficacy variables included Response Ratio (RRatio), responder rate, and percentage change in frequency (PCH) for all partial seizures; PCH and RRatio for individual types of partial seizures; and investigator and parent/guardian global assessments of seizure frequency and patient well-being. RESULTS: RRatio for all partial seizures was significantly lower (better) for GBP-treated patients (p = 0.0407). Responder rate favored GBP, but the difference between treatment groups was not statistically significant. Median PCH for all partial seizures for the GBP treatment group (-17.0%) was better than that for the placebo group (-6.5%). Median PCH for specific seizure types showed GBP to be most effective in controlling complex partial seizures (-35%) and secondarily generalized seizures (-28%) when compared with placebo (-12%, +13%, respectively). A greater percentage of GBP-treated patients exhibited improvement according to investigator and parent/guardian global assessments, with a statistically significant difference observed in the parent/guardian global assessment of seizure-frequency reduction (p = 0.046). Three GBP patients and one placebo patient were seizure free during the double-blind treatment period. GBP was well tolerated. CONCLUSIONS: GBP was effective and well tolerated as an add-on therapy for partial seizures in paediatric patients with previously drug-resistant seizures.     

Pregabalin in the treatment of post‐traumatic peripheral neuropathic pain: a randomized double‐blind trial

Background: Pregabalin is effective in the treatment of peripheral and central neuropathic pain. This study evaluated pregabalin in the treatment of post‐traumatic peripheral neuropathic pain (including post‐surgical). Methods: Patients with a pain score ≥4 (0–10 scale) were randomized and treated with either flexible‐dose pregabalin 150–600 mg/day (n = 127) or placebo (n = 127) in an 8‐week double‐blind treatment period preceded by a 2‐week placebo run‐in. Results: Pregabalin was associated with a significantly greater improvement in the mean end‐point pain score vs. placebo; mean treatment difference was ?0.62 (95% CI ?1.09 to ?0.15) (P = 0.01). The average pregabalin dose at end‐point was ～326 mg/day. Pregabalin was also associated with significant improvements from baseline in pain‐related sleep interference, and the Medical Outcomes Study sleep scale sleep problems index and sleep disturbance subscale (all P < 0.001). In the all‐patient group (ITT), pregabalin was associated with a statistically significant improvement in the Hospital Anxiety and Depression Scale anxiety subscale (P < 0.05). In total, 29% of patients had moderate/severe baseline anxiety; treatment with pregabalin in this subset did not significantly improve anxiety. More patients reported global improvement at end‐point with pregabalin than with placebo (68% vs. 43%; overall P < 0.01). Adverse events led to discontinuation of 20% of patients from pregabalin and 7% from placebo. Mild or moderate dizziness and somnolence were the most common adverse events in the pregabalin group. Conclusion: Flexible‐dose pregabalin 150–600 mg/day was effective in relieving neuropathic pain, improving disturbed sleep, improving overall patient status, and was generally well tolerated in patients with post‐traumatic peripheral neuropathic pain.     

A randomized,double-blind,placebo-controlled,parallel-group study to evaluate the efficacy and safety of osmotic-controlled release oral delivery system methylphenidate HCl in adults with attention-deficit/hyperactivity disorder in Japan

Objectives. To evaluate the safety and efficacy of osmotic-controlled release oral delivery system (OROS) methylphenidate (MPH) HCl in adults with attention-deficit/hyperactivity disorder (ADHD). Methods. In this study, 284 adults with ADHD were randomized to OROS MPH or placebo. During the 4-week titration period, patients were titrated from a starting dose of 18 mg once daily to an individually-optimized dose of up to 72 mg once daily in weekly 18-mg increments. Patients continued on their individualized dose during the 4-week efficacy assessment period. The primary efficacy endpoint was change in DSM-IV Total ADHD Symptoms subscale score of Conners’ Adult ADHD Rating Scale-Observer: Screening Version (CAARS-O:SV) from baseline to endpoint. Results. The mean change in DSM-IV Total ADHD Symptoms subscale score of CAARS-O:SV was significantly larger with OROS MPH compared with placebo (P < 0.0001, ANCOVA). Similar results were observed for the majority of secondary endpoints, including CAARS-O:SV total score and other subscale scores. Although treatment-emergent adverse events were reported more frequently in the OROS MPH group (81.8%) versus the placebo group (53.9%), OROS-MPH showed a well-tolerated safety profile overall. Conclusions. OROS MPH in a dose range of 18–72 mg once daily was effective and well-tolerated in adult patients with ADHD.     

Bupropion SR vs. Methylphenidate vs. Placebo for Attention Deficit Hyperactivity Disorder in Adults

Despite the increasing recognition of attention-deficit hyperactivity disorder (ADHD) in adults, there are few controlled trials demonstrating the effectiveness of pharmacological treatments, particularly with nonstimulants. One controlled trial found bupropion SR more effective than placebo in the treatment of ADHD adults. We conducted a controlled study to contrast the effectiveness of bupropion SR and methylphenidate to placebo in ADHD adults. A randomized, double-blind, parallel design was used in this study. Following a 7-day placebo lead-in, 30 ADHD (DSM-IV) subjects (18–60 years old) were randomized to bupropion, methylphenidate, or placebo for 7 weeks. Methylphenidate was titrated over 1 week to a maximum dose of 0.9 mg/kg/d divided into 3 doses while bupropion was titrated over 2 weeks to a maximum dose of 200 mg A.M. and 100 mg P.M. Response rates based on Clinical Global Impression improvement ratings in patients receiving bupropion, methylphenidate, and placebo were 64, 50, and 27%, respectively. The difference in response rates between active treatment and placebo was not statistically significant (p = 0.14). Neuropsychological testing demonstrated trends favoring drug treatment on measures of immediate recall and verbal fluency. While bupropion SR may be a viable clinical alternative for adults with ADHD, further investigation is needed.     

Lamotrigine for central poststroke pain: a randomized controlled trial

OBJECTIVE: Central poststroke pain (CPSP) is usually difficult to treat. Amitriptyline, the only oral preparation shown to be effective in a randomized controlled trial, is often associated with a range of side effects related to the many mechanisms of actions of tricyclic antidepressants. We investigated the effect of lamotrigine, a drug that reduces neuronal hyperexcitability, on poststroke pain. METHODS: Thirty consecutive patients with CPSP (median age 59 years, range 37 to 77; median pain duration 2.0 years, range 0.3 to 12) from two centers participated in a randomized, double-blind, placebo-controlled cross-over study. The study consisted of two 8-week treatment periods separated by 2 weeks of wash-out. The primary endpoint was the median value of the mean daily pain score during the last week of treatment while treated with 200 mg/d lamotrigine. Secondary endpoints were median pain scores while on lamotrigine 25 mg/d, 50 mg/d, and 100 mg/d; a global pain score; assessment of evoked pain; areas of spontaneous pain; and allodynia/dysesthesia. RESULTS: Lamotrigine 200 mg/d reduced the median pain score to 5, compared to 7 during placebo (p = 0.01) in the intent-to-treat population of 27 patients. No significant effect was obtained at lower doses. Twelve patients (44%) responded to the treatment. There was a uniform tendency to reduction of all secondary outcome measures, but lamotrigine only had significant effects on some of the secondary outcome measures. Lamotrigine was well tolerated with few and transient side effects. Two mild rashes occurred during lamotrigine treatment, one causing withdrawal from study. CONCLUSIONS: Oral lamotrigine 200 mg daily is a well tolerated and moderately effective treatment for central poststroke pain. Lamotrigine may be an alternative to tricyclic antidepressants in the treatment of CPSP.     

Gabapentin and cognition: a double blind, dose ranging, placebo controlled study in refractory epilepsy.

OBJECTIVE: To assess the effect of different doses of gabapentin (GBP) on cognitive function in treated epileptic patients. METHODS: Twenty seven patients with refractory partial seizures commenced a double blind, dose ranging, placebo controlled, crossover study of adjuvant GBP. Each treatment phase lasted three months, during which the dose of GBP or matched placebo was increased stepwise at intervals of four weeks (1200 mg/day, 1800 mg/day, and 2400 mg/day in three daily doses). Psychomotor and memory testing was carried out at the end of each four week period, at which time the patient also completed subjective measures of cognition, fatigue, worry, temper, and dysphoria. A visual analogue scale was used to assess drowsiness and a questionnaire was employed to gauge the severity of side effects. RESULTS: In the 21 patients completing the study, GBP produced a significant reduction in median monthly seizure frequency from 7 to 4.3 (P = 0.02), the decrease being most pronounced for secondarily generalised seizures (from 1.0 to 0.3, P = 0.01). Forty three per cent of patients reported a reduction in seizure frequency of at least 50% throughout all GBP doses. Mean (SD) plasma concentrations of GBP at 1200, 1800, and 2400 mg/day were 4.7 (2.6), 6.8 (3.8), and 8.6 (3.3) mg/l respectively. The drug had no effect on composite psychomotor and memory scores; nor was there alteration in any self assessment subscore. The mean drowsiness (P = 0.03) score was higher during treatment with 2400 mg GBP daily compared with matched placebo. Composite psychomotor (r = -0.47, P < 0.01), tiredness (r = 0.42, P < 0.01), and side effect (r = 0.61, P < 0.001) scores correlated significantly with seizure frequency but not with GBP dose. CONCLUSION: GBP is a well tolerated and effective antiepileptic drug which had no measurable effect on cognition but did produce sedation at the highest dose. This study also supports the suggestion that seizures can cause cognitive impairment.     

The effect of duloxetine on painful physical symptoms in depressed patients: do improvements in these symptoms result in higher remission rates?

BACKGROUND: Depression is a chronic disease consisting of emotional/psychological and physical symptoms. Emotional symptoms have been shown to respond to currently available antidepressants; however, physical symptoms may not be as responsive. It was hypothesized that resolution of both psychological and physical symptoms of depression would predict a higher percentage of patients achieving remission. METHOD: Efficacy data were pooled from 2 identical, but independent, 9-week randomized, double-blind clinical trials of duloxetine 60 mg q.d. (N = 251) and placebo (N = 261). All patients met diagnostic criteria for DSM-IV major depressive disorder, which was confirmed by the Mini-International Neuropsychiatric Interview. Efficacy measures included the 17-item Hamilton Rating Scale for Depression (HAM-D-17) total score, the HAM-D-17 Maier subscale, the Clinical Global Impressions-Severity of Illness (CGI-S) scale, the Patient Global Impression of Improvement (PGI-I) scale, the Somatic Symptom Inventory, the Quality of Life in Depression Scale, and Visual Analog Scales (VAS) for pain (overall pain, headaches, back pain, shoulder pain, interference with daily activities, and time in pain while awake). RESULTS: Duloxetine-treated patients demonstrated significantly greater improvement in overall pain (p =.016), back pain (p =.002), and shoulder pain (p =.021) at week 9 compared with patients receiving placebo. When treatment effects were pooled over all visits, patients receiving duloxetine, 60 mg q.d., exhibited significantly greater improvement than placebo-treated patients in 5 of the 6 assessed VAS pain measures. Approximately 50% of the improvement in overall pain was independent of improvement in HAM-D-17 total score. Assuming the same level of improvement in core emotional symptoms of depression (Maier subscale), improvement in overall pain severity was associated with higher estimated probabilities of remission (p <.001). The week 9 means for VAS overall pain severity were 13.0 for remitters (last observed value for HAM-D-17 was < or = 7) compared with 22.7 for nonremitters (p <.001), respectively, representing a greater than 3-fold improvement from baseline in remitters. The remission rate for pain responders (improvement in VAS overall pain from baseline to last observation > or = 50%) was twice that observed for pain nonresponders (36.2% vs. 17.8%, p <.001). Greater improvements in pain outcomes were associated with more favorable endpoint outcomes on the CGI-S and PGI-I scales. In addition, early favorable responses in VAS overall pain severity were associated with favorable endpoint outcomes. CONCLUSIONS: Treatment with duloxetine, 60 mg q.d., significantly reduced pain compared with placebo. Improvements in pain severity were attributable equally to the direct effect of duloxetine and to associated changes in depression severity. Improvement in painful physical symptoms was associated with higher remission rates even after accounting for improvement in core emotional symptoms.     

Quality of life in patients with personality disorders seen at an ordinary psychiatric outpatient clinic

Background

The most prominent feature of melancholic depression is a near-total loss of the capacity to derive pleasure from activities or other positive stimuli. Additional symptoms can include psychomotor disturbances, anorexia, excessive guilt, and early awakening from sleep. Melancholic patients may exhibit treatment responses and outcomes that differ from those of non-melancholic patients. Pooled data from double-blind, placebo-controlled studies were utilized to compare the efficacy of duloxetine in depressed patients with and without melancholic features.

Methods

Efficacy data were pooled from 8 double-blind, placebo-controlled clinical trials of duloxetine. The presence of melancholic features (DSM-IV criteria) was determined using results from the Mini International Neuropsychiatric Interview (MINI). Patients (aged ≥ 18 years) meeting DSM-IV criteria for major depressive disorder (MDD) received duloxetine (40–120 mg/d; melancholic, N = 759; non-melancholic, N = 379) or placebo (melancholic, N = 519; non-melancholic, N = 256) for up to 9 weeks. Efficacy measures included the 17-item Hamilton Rating Scale for Depression (HAMD₁₇) total score, HAMD₁₇ subscales (Maier, anxiety, retardation, sleep), the Clinical Global Impression of Severity (CGI-S) and Patient Global Impression of Improvement (PGI-I) scales, and Visual Analog Scales (VAS) for pain.

Results

In data from all 8 studies, duloxetine's advantage over placebo did not differ significantly between melancholic and non-melancholic patients (treatment-by-melancholic status interactions were not statistically significant). Duloxetine demonstrated significantly greater improvement in depressive symptom severity, compared with placebo, within both melancholic and non-melancholic cohorts (p ≤.001 for HAMD₁₇ total score, CGI-S and PGI-I). When analyzed by gender, the magnitude of improvement in efficacy outcomes did not differ significantly between duloxetine-treated male and female melancholic patients. In the two studies that assessed duloxetine 60 mg once-daily dosing, duloxetine-treated melancholic patients had significantly greater improvement compared with placebo on HAMD₁₇ total score, CGI-S, PGI-I, 3 of 4 subscales of the HAMD₁₇, and VAS overall pain severity (p <.01). Estimated probabilities of response and remission were significantly greater for melancholic patients receiving duloxetine 60 mg QD compared with placebo (response 74.7% vs. 42.2%, respectively, p <.001; remission 44.4% vs. 24.7%, respectively, p =.002

Conclusions

In this analysis of pooled data, the efficacy of duloxetine in patients with melancholic features did not differ significantly from that observed in non-melancholic patients.     

Response to placebo acupuncture in insomnia: a secondary analysis of three randomized controlled trials

ObjectiveTo determine the patient characteristics that are associated with a response to noninvasive placebo acupuncture for insomnia.MethodsWe performed a secondary analysis of three randomized, double-blind, placebo-controlled trials of acupuncture for primary insomnia and residual insomnia associated with major depression. A total of 86 participants were randomized to receive placebo acupuncture three times per week for three consecutive weeks. Outcome was assessed at 1-week posttreatment. Response was defined as an Insomnia Severity Index (ISI) score improved by eight points or more from baseline to 1-week posttreatment. Sociodemographic, clinical, and baseline characteristics including sleep diary-derived and actigraph-derived sleep parameters as predictors of placebo response were examined using univariate and multivariate logistic regression.ResultsThe effect size of placebo acupuncture was estimated at 0.18 for total sleep time, 0.08 for sleep efficiency, and 0.92 for ISI score. Eighteen (20.9%) of the 86 participants were responders. Responders had a higher ISI score (p = 0.03), higher sleep diary–derived total sleep time (p = 0.02), less discrepancy between sleep diary–derived and actigraph-derived total sleep time (p = 0.03), and higher expectation toward acupuncture (p = 0.03) at baseline compared to nonresponders. Multivariate regression analysis found that only ISI score remained significant (odds ratio = 1.23, 95% confidence interval = 1.02–1.50, p = 0.03).ConclusionsBaseline sleep parameters and perceived effectiveness were shown to predict the placebo response of acupuncture for insomnia. Although the study was limited by a small sample size, our findings highlighted the potential implication of sleep duration and sleep-state misperception in the treatment of insomnia.     

Duloxetine 60 mg once daily dosing versus placebo in the acute treatment of major depression

Existing therapies for major depressive disorder (MDD) have either limited efficacy and/or poor tolerability. The present study examined the effects of duloxetine, a potent and balanced dual reuptake inhibitor of serotonin (5-HT) and norepinephrine (NE), in patients with MDD. Adult patients (N=267) with MDD were randomly assigned to receive duloxetine (60 mg/day) or placebo in this 9-week, multi-center, double-blind, parallel-group clinical trial. Efficacy was evaluated using the 17-item Hamilton Depression Rating Scale (HAMD₁₇), Visual Analog Scales (VAS) for pain, Clinical Global Impression of Severity (CGI-S), Patient's Global Impression of Improvement (PGI-I), and Quality of Life in Depression Scale (QLDS). Safety was evaluated by assessing discontinuation rates, adverse event rates, vital signs, and laboratory tests. Duloxetine (60 mg QD) significantly reduced the HAMD₁₇ total score compared with placebo at the end of 9-week therapy. Estimated probabilities of response and remission were 65 and 43%, respectively, for duloxetine compared with 42 and 28% for placebo. Duloxetine also reduced overall pain, back pain, shoulder pain and time in pain while awake significantly more than placebo. Global measures of improvement, including PGI-I and QLDS, were significantly improved by duloxetine compared with placebo. Discontinuations due to adverse events were more frequent for duloxetine-treated patients (12.5%) than for placebo-treated patients (4.3%). Nausea, dry mouth, dizziness, and constipation were more frequent for duloxetine than placebo. There was no significant incidence of hypertension, nor any other safety issues. Duloxetine 60 mg administered once daily appears to be a safe and effective treatment for MDD.     

The partial positive allosteric GABAA receptor modulator EVT 201 is efficacious and safe in the treatment of adult primary insomnia patients

Objective: To evaluate polysomnographic (PSG) and self-reported measures of the efficacy and safety of EVT 201 in patients with primary insomnia.Patients and methods: Following clinical and PSG screening, 75 patients (mean age: 45.1 ± 11.2y; 50f, 25m) meeting DSM-IV criteria for primary insomnia entered this crossover study and were randomly assigned to double-blind treatment sequences of 1.5 mg or 2.5 mg EVT 201, or placebo using a balanced Latin square design. For each study condition study medication was administered on two consecutive nights and PSG and self-reported data were collected. Safety assessments included physical examination, clinical laboratory measures, electrocardiogram, documentation of adverse events, and the digit symbol substitution test (DSST) and self-reported sleepiness/alertness ratings to detect residual sedation. Data were collected at five US sleep laboratories. Efficacy analyses were performed for the 67 patients completing the study. Safety analyses included all 75 randomized patients.Results: On PSG measures compared to placebo, EVT 201 1.5 mg and 2.5 mg increased total sleep time (TST; 33.1, 45.0 min; both p < 0.0001), reduced wake after sleep onset (WASO; −16.7, −25.7 min; both p < 0.0001), reduced latency to persistent sleep (LPS; −17.0, −20.7 min; both p < 0.0001), and reduced the number of awakenings (−1.2, −2.6; both p < 0.0001). Significant reduction of wake time was seen with 1.5 mg during each of the first three quarters of the night (p < 0.0001–0.002), and with 2.5 mg in all four quarters (p < 0.0001–0.0005). Both doses also improved all key self-reported measures of sleep including total sleep time (rTST; 51.9, 51.1 min; both p < 0.0001), wake after sleep onset (rWASO; −29.3, −29.6 min; both p < 0.0001), sleep latency (rSL; −24.0 min, p < 0.004; −25.1 min, p < 0.0002), and number of awakenings (rNAW; −1.1, −1.2; both p < 0.0001). Sleep quality was also improved by both doses. Self-rated sleepiness in the morning did not differ from placebo for either dose; however, there was a small negative effect on the DSST for both doses. Both doses had similar effects on sleep architecture including an increase in Stage 2 sleep and REM latency and a small, but significant decrease in REM (REM −5.7, −8.3 min; p = 0.0175, p = 0.0006). No effect on other sleep architecture parameters, including SWS, was seen. EVT 201 was well tolerated. No serious or unexpected adverse events were reported.Conclusion: This first study of EVT 201 in adult patients with primary insomnia demonstrated improved measures of sleep onset and sleep maintenance, including during the third and fourth quarters of the night. Adverse events were infrequent and all were mild to moderate in severity.     

Hypericum extract LI 160 and fluoxetine in mild to moderate depression

Efficacy and tolerability of Hypericum LI 160 was compared to fluoxetine and placebo in mild to moderate Major Depression (DSM–IV) in a 4–week randomized, double–blind trial. One hundred and sixtythree outpatients from 15 general practitioner centers received either 900 mg Hypericum LI 160, 20 mg fluoxetine, or placebo daily. Amelioration was measured by the Hamilton and the Montgomery–Åsberg Depression scales. Response and remission rates and global ratings by investigators and patients were measured. Adverse event reports, laboratory screening, vital signs, physical exams and ECG were collected. No significant differences could be observed regarding efficacy measures except for remission rate (Hypericum 24%; fluoxetine 28%; placebo 7 %). Hypericum was significantly better tolerated than fluoxetine. Hypericum LI 160 or fluoxetine were not more effective in short–term treatment in mild to moderate depression than placebo.     

Efficacy of pitolisant in patients with high burden of narcolepsy symptoms: pooled analysis of short-term,placebo-controlled studies

Study objectiveTo evaluate the efficacy of pitolisant, a histamine 3 (H₃)-receptor antagonist/inverse agonist, in adult patients with high burden of narcolepsy symptoms.MethodsData were pooled from two randomized, placebo-controlled, 7- or 8-week studies of pitolisant (titrated to a potential maximum dose of 35.6 mg/day) in adults with narcolepsy. Analyses included three independent patient subgroups: Epworth Sleepiness Scale (ESS) baseline score ≥16, Maintenance of Wakefulness Test (MWT) sleep latency ≤8 min, and ≥15 cataplexy attacks per week.ResultsThe analysis populations included 118 patients for ESS (pitolisant, n = 60; placebo, n = 58), 105 for MWT (pitolisant, n = 59; placebo, n = 46), and 31 for cataplexy (pitolisant, n = 20; placebo, n = 11). On the ESS, least-squares mean change from baseline was significantly greater for pitolisant (−6.1) compared with placebo (−2.3; P < 0.001). Significantly more pitolisant-treated patients were classified as treatment responders: ESS score reduction ≥3, 69.0% in the pitolisant group versus 35.1% in the placebo group (P = 0.001); final ESS score ≤10, 36.2% versus 10.5%, respectively (P = 0.005). On the MWT, mean sleep latency increased from 3.5 min to 10.4 min with pitolisant and from 3.4 min to 6.8 min with placebo (P = 0.017). Least-squares mean change in the weekly rate of cataplexy was significantly greater for pitolisant (−14.5; baseline, 23.9; final, 9.4) compared with placebo (−0.1; baseline, 23.1; final, 23.0; P = 0.004). Headache was the most common adverse event with pitolisant.ConclusionsPitolisant, at once-daily doses up to 35.6 mg, was efficacious for reducing excessive daytime sleepiness and cataplexy in patients with severe narcolepsy symptom burden.     

Fenfluramine in the treatment of Dravet syndrome: Results of a third randomized,placebo-controlled clinical trial

Objective

This study was undertaken to assess the safety and efficacy of fenfluramine in the treatment of convulsive seizures in patients with Dravet syndrome.

Methods

This multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial enrolled patients with Dravet syndrome, aged 2–18 years with poorly controlled convulsive seizures, provided they were not also receiving stiripentol. Eligible patients who had ≥6 convulsive seizures during the 6-week baseline period were randomized to placebo, fenfluramine .2 mg/kg/day, or fenfluramine .7 mg/kg/day (1:1:1 ratio) administered orally (maximum dose = 26 mg/day). Doses were titrated over 2 weeks and maintained for an additional 12 weeks. The primary endpoint was a comparison of the monthly convulsive seizure frequency (MCSF) during baseline and during the combined titration–maintenance period in patients given fenfluramine .7 mg/kg/day versus patients given placebo.

Results

A total of 169 patients were screened, and 143 were randomized to treatment. Mean age was 9.3 ± 4.7 years (±SD), 51% were male, and median baseline MCSF in the three groups ranged 12.7–18.0 per 28 days. Patients treated with fenfluramine .7 mg/kg/day demonstrated a 64.8% (95% confidence interval = 51.8%–74.2%) greater reduction in MCSF compared with placebo (p < .0001). Following fenfluramine .7 mg/kg/day, 72.9% of patients had a ≥50% reduction in MCSF compared with 6.3% in the placebo group (p < .0001). The median longest seizure-free interval was 30 days in the fenfluramine .7 mg/kg/day group compared with 10 days in the placebo group (p < .0001). The most common adverse events (>15% in any group) were decreased appetite, somnolence, pyrexia, and decreased blood glucose. All occurred in higher frequency in fenfluramine groups than placebo. No evidence of valvular heart disease or pulmonary artery hypertension was detected.

Significance

The results of this third phase 3 clinical trial provide further evidence of the magnitude and durability of the antiseizure response of fenfluramine in children with Dravet syndrome.     

Gabapentin increases slow-wave sleep in normal adults

PURPOSE: The older antiepileptic drugs (AEDs) have a variety of effects on sleep, including marked reduction in rapid-eye-movement (REM) sleep, slow-wave sleep (SWS), and sleep latency, and an increase in light sleep. The effects of the newer AEDs on sleep are unknown. Our purpose was to study the effect of gabapentin (GBP) on sleep. METHODS: Ten healthy adults and nine controls were the subjects of this study. All underwent baseline and follow-up polysomnography (PSG) and completed sleep questionnaires. After baseline, the treated group received GBP titrated to 1,800 mg daily. Polygraphic variables and Epworth Sleepiness Scale (ESS) scores, a subjective measure of sleep propensity, were compared by using the Wilcoxon signed rank test. RESULTS: Nine of the treated subjects achieved the target dose; one was studied with 1,500 mg daily because of dizziness experienced at the higher dose. GBP-treated subjects had an increase in SWS compared with baseline. No difference in the ESS or other polygraphic variables was observed. However, a minor reduction in arousals, awakenings, and stage shifts was observed in treated subjects. CONCLUSIONS: GBP appears to be less disruptive to sleep than are some of the older AEDs. These findings may underlie the drug's therapeutic effect in the treatment of disorders associated with sleep disruption.     

Rotigotine effects on early morning motor function and sleep in Parkinson's disease: A double‐blind,randomized, placebo‐controlled study (RECOVER)

In a multinational, double‐blind, placebo‐controlled trial (NCT00474058), 287 subjects with Parkinson's disease (PD) and unsatisfactory early‐morning motor symptom control were randomized 2:1 to receive rotigotine (2–16 mg/24 hr [n = 190]) or placebo (n = 97). Treatment was titrated to optimal dose over 1–8 weeks with subsequent dose maintenance for 4 weeks. Early‐morning motor function and nocturnal sleep disturbance were assessed as coprimary efficacy endpoints using the Unified Parkinson's Disease Rating Scale (UPDRS) Part III (Motor Examination) measured in the early morning prior to any medication intake and the modified Parkinson's Disease Sleep Scale (PDSS‐2) (mean change from baseline to end of maintenance [EOM], last observation carried forward). At EOM, mean UPDRS Part III score had decreased by ?7.0 points with rotigotine (from a baseline of 29.6 [standard deviation (SD) 12.3] and by ?3.9 points with placebo (baseline 32.0 [13.3]). Mean PDSS‐2 total score had decreased by ?5.9 points with rotigotine (from a baseline of 19.3 [SD 9.3]) and by ?1.9 points with placebo (baseline 20.5 [10.4]). This represented a significantly greater improvement with rotigotine compared with placebo on both the UPDRS Part III (treatment difference: ?3.55 [95% confidence interval (CI) ?5.37, ?1.73]; P = 0.0002) and PDSS‐2 (treatment difference: ?4.26 [95% CI ?6.08, ?2.45]; P < 0.0001). The most frequently reported adverse events were nausea (placebo, 9%; rotigotine, 21%), application site reactions (placebo, 4%; rotigotine, 15%), and dizziness (placebo, 6%; rotigotine 10%). Twenty‐four‐hour transdermal delivery of rotigotine to PD patients with early‐morning motor dysfunction resulted in significant benefits in control of both motor function and nocturnal sleep disturbances. © 2010 Movement Disorder Society     

Oxcarbazepine in painful diabetic neuropathy: results of a dose-ranging study

OBJECTIVES: To evaluate the efficacy and safety of oxcarbazepine in patients with diabetic neuropathy in a multicenter, double-blind, placebo-controlled, dose-ranging 16-week study. METHODS: A total of 347 patients were randomized to oxcarbazepine 600 mg/day (n = 83), 1,200 mg/day (n = 87), 1,800 mg/day (n = 88), or placebo (n = 89). The primary efficacy variable was change in mean visual analog scale (VAS) score from baseline to the last week of the study. RESULTS: No difference between any oxcarbazepine group and the placebo group was noted for the primary efficacy variable. Both the 1,200- and 1,800-mg/day groups showed a trend toward statistical significance (P = 0.101, P = 0.096, respectively). Statistically significant differences were found between the oxcarbazepine 1,200-mg/day (P = 0.038) and 1,800-mg/day (P = 0.005) groups and placebo in the overall mean weekly VAS scores for the entire double-blind treatment phase. CONCLUSIONS: Although the primary efficacy variable did not reach statistical significance, patients taking oxcarbazepine 1,200 and 1,800 mg/day showed improvements in VAS scores compared with placebo. Oxcarbazepine may provide clinically meaningful pain relief in patients with painful diabetic neuropathy.     

Topiramate effects on the EEG and alertness in healthy volunteers: a different profile of antiepileptic drug neurotoxicity

OBJECTIVE: Previous quantitative EEG (QEEG) studies of carbamazepine (CBZ), oxcarbazepine (OXC), and phenytoin (PHT) revealed a pattern of EEG slowing and an increase in drowsiness on the awake maintenance task (AMT). EEG slowing has been shown to correlate with negative effects on cognitive tests. Topiramate (TPM) is a novel AED with relatively large negative effects on cognitive function. We tested the hypothesis that TPM would induce significant slowing of EEG background rhythms and an increase in AMT drowsiness. METHODS: Forty healthy volunteers were randomized to TPM, gabapentin (GBP), or placebo. Doses were escalated as tolerated to a maximum of 400mg/day for TPM or 3600 mg/day for GBP, over a 10-week period, followed by a minimum 2-week plateau period. Volunteers underwent an EEG, cognitive tests, and the AMT prior to starting an AED and again 12 weeks later. The EEG was captured using a structured recording protocol and quantified using the fast Fourier transform. Four target measures were derived from the averaged occipital electrodes (peak frequency of the dominant posterior rhythm, median frequency, percentage theta, and percentage delta). Test-retest changes for all measures were scored against similar test-retest distributions previously obtained from untreated healthy volunteers. RESULTS: TPM produced no significant change in any of the four target EEG measures or on the AMT, even though several target cognitive tests revealed moderate or greater negative effects. There were also no significant changes in the placebo group. GBP slowed the peak and median frequency EEG measures and increased the percentage of theta and delta activity. Neither TPM, GBP, nor placebo caused a significant increase in drowsiness on the AMT. CONCLUSIONS: TPM has a unique neurotoxicity profile. It has no effect on EEG background measures or on the AMT, but induces moderate to large negative changes in many cognitive test scores. This profile differs from those of CBZ, OXC, PHT, and GBP.