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Introduction The prevalence of epilepsy increases in elderly patients aged > 65 years, and treatment is challenging because clinical data are limited. Objective Our objective was to evaluate the safety of eslicarbazepine acetate (ESL) in patients aged ≥ 65 years versus non-elderly patients with focal seizures. Methods The safety data of seven phase II and III, double-blind, open-label, randomized clinical studies of ESL in adults were pooled. At least possibly related treatmentemergent adverse events (TEAEs) and ESL post-marketing adverse drug reactions (ADRs) were analyzed separately by age categories. Results The most frequently reported at least possibly related TEAEs in elderly (N = 120) versus non-elderly patients (N = 1863) were dizziness (10.8 vs. 20.3%), somnolence (9.2 vs. 12.6%), and hyponatremia (6.7 vs. 1.5%). Elderly patients presented a higher incidence of serious TEAEs (22.5 vs. 7.6%) and at least possibly related serious TEAEs (6.7 vs. 2.5%), probably because treatment was complicated by comorbidities and comedications. After an estimated cumulative exposure of over 2 million patient-months worldwide and 8 years of post-marketing surveillance, hyponatremia was the most frequently reported ADR (n = 232), accounting for 14.6% and 6.8% of the ADRs reported in elderly (n = 473) and non-elderly patients (n = 2406), respectively. This was followed by ADR/safety information such as drug–dose titration not performed (7.0 vs. 5.4%), product use in unapproved indication (4.9 vs. 1.9%), off-label use (3.4 vs. 2.2%), dizziness (3.4 vs. 3.5%), and seizure (2.1 vs. 5.8%). Conclusion No specific safety issue was identified from the pooled studies for elderly compared with non-elderly patients. After 8 years of post-marketing surveillance, the qualitative safety of ESL remains similar to that observed in the clinical studies. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01097-5.

Morphine infusion through Intrathecal Drug Delivery System (IDDS) is widely used to relieve refractory cancer pain. However, continuous escalation of morphine dose caused by opioid tolerance and/or progress of cancer was commonly observed. Combining morphine with medications of different analgesic mechanisms is applied to blunt the rate of morphine increase. The purpose of this study was to determine the analgesic efficacy and safety of combining gabapentin with morphine after IDDS implantation. This study compared patients that received IDDS implantation from January 1, 2017 to November 10, 2018 in our institute. Key outcomes included change in mean pain score, dose of morphine used in patients, percentage of patients with 30% and 50% reduction in mean pain score, Patient Global Impression of Change scores, breakthrough pain characters and side effects. 34 patients in the combination group (morphine + gabapentin) and 40 patients in the monotherapy group(morphine)were analyzed. The results showed that both therapy groups achieved similar analgesic efficacy, demonstrated by Numerical rating scale (2.42 ± 0.88 vs 2.57 ± 0.85; Combination vs Monotherapy), PGIC and responder status. Mean daily dose of morphine was significantly lower in combination group compared to monotherapy group (3.54 ± 1.29 mg vs 4.64 ± 1.28 mg, P = 0.007). More patients experienced dizziness and somnolence after receiving combination therapy compared to morphine-alone treatment although no statistical significance was found (P = 0.49). Addition of gabapentin achieved similar analgesic efficacy with lower dose of morphine compared to morphine alone accompanying with higher incidence of dizziness and somnolence.

Hypersomnia is a rare neurologic disorder characterized by an excessive daytime sleepiness with long naps, despite an undisturbed nocturnal sleep. The impaired daytime alertness and sleep inertia are different from general fatigue. This disorder is often classified as idiopathic. Here, we report the case of a young patient presenting both a mitochondrial disease and a hypersomnia. We discuss the links between the two pathologies and propose to systematically investigate personal and familial mitochondrial features in case of hypersomnia, to offer suitable genetic tests. Conversely, fatigue could be one of the complaints reported by patients with a confirmed mitochondrial disease, which is multifactorial. Sleep quality and somnolence should be examined in these patients as specific treatments exist for this debilitating disorder.

Driver drowsiness is the major cause of many traffic accidents. A study by the National Institute of Sleep and Vigilance showed that the majority of the accidents took place on fast tracks. 34% of these accidents are mainly due to lack of sleep. Indeed, the drowsiness of drivers appears mainly by a fall of vigilance with the appearance of various behaviors that represent clues for the decrease of reflexes like the presence of yawning, heaviness of the eyelids and the difficulty to keep the head in frontal position compared to the vision field. In this context, we are interested particularly in the proposal of new solutions allowing the automatic control of the driver drowsiness states. These solutions need to be non-invasive while being based only on the analysis of the visual indices. These indices are calculated starting from the spatiotemporal information of the contents of a video stream. The main goal of our work is to recognize driver abnormal behavior by analyzing the characteristics of the face. In fact, we have proposed a fusion system based on detection of yawn, detection of somnolence and the 3D head pose estimation. This fusion system is evaluated by the three databases and shows many success of our suggested approach.

To examine the safety, effectiveness, and patient-perceived benefit of treatment with olanzapine for nausea and vomiting (N/V) in patients with advanced cancer. We conducted a multicenter prospective observational study in a tertiary care setting (Trial registration number: UMIN000020493, date of registration: 2016/1/12). We measured the following: average nausea in the last 24 h using a Numeric Rating Scale (NRS: range 0–10) at baseline and day 2, patient-perceived treatment benefit (based on a 5-point verbal scale), and adverse events (AEs; using the Common Terminology Criteria for Adverse Events version 4). The 85 participants (45% men) had a mean age of 58.7±15.8 years. Major causes of N/V were opioids (44%) and chemotherapy (34%). All patients received a daily dose of olanzapine of 5 mg or less as first-line treatment (N=35) or second- or later-line treatment (N=50). Nausea NRS decreased from 6.1±2.2 to 1.8±2.0 (differences: −4.3, 95% CI −3.7 to −4.9, p

Cenobamate (XCOPRI®), a novel tetrazole alkyl carbamate derivative, is approved in the USA for use as monotherapy and adjunctive therapy in adults with focal seizures (also known as partial-onset seizures). Its use (within the recommended dosage of ≤ 400 mg/day) significantly reduced focal seizure frequency relative to the use of placebo in short-term (≤ 18 weeks) multinational, phase 2 studies in adults with focal seizures, with antiepileptic benefits appearing to be sustained over the longer-term (30 months). Cenobamate appears to have low abuse potential and to be generally well tolerated over the short- and longer-term (up to 79 months), with most treatment-emergent adverse events (TEAEs) being mild or moderate in severity. The most frequently reported TEAEs (somnolence, dizziness and fatigue) were CNS related, dose dependent and similar to those seen with other anti-seizure medications.

Antiseizure prophylaxis is required during busulfan administration for hematopoietic stem cell transplantation. However, antiseizure agents such as benzodiazepines and phenytoin may produce adverse effects through interaction with other drugs. We retrospectively assessed the prophylactic efficacy and safety of levetiracetam and clonazepam against busulfan-induced seizures between 2013 and 2018. Thirty patients (after 2015) received levetiracetam, and 13 patients (before 2015) received clonazepam in this study. Levetiracetam was well-tolerated and had a significantly lower frequency of adverse effects, such as somnolence, compared with clonazepam, although two patients in the levetiracetam group experienced seizures. Levetiracetam is a feasible option for preventing busulfan-induced seizures.

Objective This study evaluated clinical outcomes in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) treated with the α2-adrenoceptor agonist guanfacine extended-release (GXR) in routine Canadian clinical practice. Methods This retrospective chart review focused on patients with ADHD aged 6–17 years initiating treatment with GXR as monotherapy or adjunctive therapy. Patients were followed for up to 12 months after GXR initiation and, if they had received prior ADHD pharmacotherapy, for 12 months before GXR initiation. The primary outcome was change in ADHD symptoms and functionality based on physician assessments, classified as improvement, no change, or worsening relative to the time of GXR initiation. Treatment-emergent adverse events (TEAEs) were evaluated. Clinical outcomes were also analyzed post hoc according to whether GXR treatment was received as monotherapy or adjunctive therapy, and by select psychiatric comorbidities. Exploratory analyses were conducted in patients who had received prior ADHD pharmacotherapy to evaluate clinical outcomes after initiating GXR. Results Improvements in ADHD symptoms were reported for 232/330 (70.3%) patients. Functional improvements in school performance and home life were reported for 213/330 (64.5%) and 209/330 (63.3%) patients, respectively. The most frequent TEAEs (≥ 5%) were somnolence, headache, insomnia, presyncope, and decreased appetite. Improvements in ADHD symptoms were observed when GXR was received as either monotherapy (35/60 [58.3%]) or adjunctive therapy (197/270 [73.0%]). Improvements in ADHD symptoms and functionality were observed in the majority of patients with select psychiatric comorbidities. Among patients who had experienced worsening of symptoms with prior ADHD pharmacotherapy, 44/54 (81.5%) experienced symptom improvement, 33/44 (75.0%) who had previously experienced worsening of school performance improved, and 34/48 (70.8%) who had previously experienced worsening of home life improved. Conclusion In Canadian routine clinical practice, most children and adolescents with ADHD treated with GXR experienced improvements in ADHD symptoms and in functionality both at school and at home.

Life-limiting conditions in children in specialized pediatric palliative care (PPC) are manifold. The "Together for Short Lives" (TfSL) association established four disease categories, which represent the most common illness trajectories. Better understanding the palliative care needs and symptoms of children within these TfSL groups will result in improved anticipation of clinical problems and tailored care. During this retrospective single-center cohort study, 198 children, adolescents, and young adults (CAYAs) were in PPC. Mean age at referral was 8.7 years (range 0.0-25.0), mean duration of care 355 days (range 1-2754). One hundred six (53.5%) CAYAs died during the study period. Sixty-five (32.8%) CAYAs were assigned to TfSL-1, 13 (6.6%) to TfSL-2, 49 (24.7%) to TfSL-3, and 71 (35.9%) to TfSL-4. Home visits were conducted on average every 9.6 days in TfSL-1, 18.9 days in TfSL-2, 31.7 days in TfSL-3, and 31.8 days in TfSL-4 (p value 0.01).Conclusions: Intensity of palliative care significantly differed between the TfSL groups. Neurological and gastrointestinal symptoms were most prominent across all TfSL groups. Symptom cluster analysis showed distinct clusters in TfSL-1 (cluster 1, fatigue/lack of appetite/nausea/somnolence; cluster 2, dyspnea/fear/myoclonus/seizures/spasticity) and TfSL-3/4 (cluster 1, spasticity; cluster 2, all other symptoms).What is Known:• The four TfSL (together for short lives) groups represent the four most common illness trajectories of pediatric palliative care patients.• Better understanding the palliative care needs and symptoms of children within these four TfSL groups will result in improved anticipation of clinical problems and tailored care.What is New:• In our study, TfSL-1 represented the largest individual group of patients, also requiring the most intensive care (defined by the number of visits per days of care).• Symptom cluster analysis revealed distinct symptom clusters in TfSL-1 and TfSL-3/4, which can be used to anticipate clinically common challenges in these patients.

Satisfactory management of Parkinson’s disease is a challenge that requires a tailored approach for each individual. In the advanced phase of the disease, patients may experience motor complications despite optimized pharmacological therapy. Apomorphine, a short-acting D1- and D2-like receptor agonist, is the only drug proven to have an efficacy equal to that of levodopa, albeit with a shorter time to onset and effect duration. Clinical trials have shown that intermittent apomorphine injections provide rapid and effective relief from unpredictable “off” periods. Continuous apomorphine infusion reduced around 50% of the daily “off” time in several studies. Dopaminergic side effects such as nausea, somnolence and hypotonia, as well as administration site reactions, are often mild or treatable, but somnolence and skin reactions in particular can sometimes be reasons for premature discontinuation. We provide an overview of the pharmacological mechanism of action of the drug in light of its effects on Parkinson’s disease symptoms. We then summarize the evidence regarding the efficacy and tolerability of apomorphine, both in its established formulations (subcutaneous intermittent injection and continuous infusion) and in the new preparations currently under investigation.

Narcoleptics tend to have a low quality of life (QoL). Few studies have compared QoL in narcolepsy against other sleep disorders. The purpose of this study was to investigate QoL and its influential factors in narcolepsy patients compared to obstructive sleep apnea (OSA) with somnolence and primary insomnia. We enrolled 63 narcoleptics (33 type 1, 30 type 2), 49 patients with OSA with somnolence, and 87 insomniacs. All patients were diagnosed through detailed clinical face-to-face interviews and polysomnography and had no other comorbid sleep disorders or medical diseases. All patients completed the Korean-version of the Short-Form 36-Item Health Survey (K-SF36) and a series of standard sleep-related questionnaires. The QoL of the narcolepsy group was comparable to the OSA with somnolence and insomnia groups. There was no significant difference between type 1 and type 2 narcolepsy on the total score of the K-SF36. However, factors that had the most impact on QoL included anxiety followed by depressive mood for narcoleptics, depressive mood followed by severity of insomnia for OSA with somnolence, and insomnia severity followed by depressive mood for insomniacs. Mood disturbances, mainly anxiety, affected QoL most in narcolepsy patients. Excessive daytime sleepiness and nocturnal sleep disturbance did not directly affect QoL of narcoleptics. To improve QoL in narcoleptics, proper management of anxiety should be considered as part of the treatment.

BACKGROUND: Obstructive sleep apnea (OSA) often has a significant impact on health-related quality of life (HRQoL) with social and psychological implications. For most OSA patients, a reduction in their HRQoL is due to symptoms such as poor sleep quality, excessive daytime somnolence, and fatigue with differences between gender. PURPOSE: This study explores the CPAP treatment effect on self-perceived HRQoL related to gender, somnolence, and CPAP adherence. METHODS: Out of 1082 consecutive Italian outpatients, 125 (82 M) (60.3 ± 9.6 years) completed the prospective observational study and were evaluated at the first visit (T0), and the follow-up visit (T1). Two self-reported HRQoL questionnaires were administered: six subscales Psychological General Well-Being Index (PGWBI) and 12-Item Short-Form Health Survey (SF-12). RESULTS: Scores of PGWBI and SF-12 MCS improved from T0 to T1. Patients with CPAP use >= 4 h/night showed a significant improvement in all dimensions evaluated, except for SF-12 PCS. At T1, participants with ESS > 10 improved in all scores, except SF-12 PCS. Gender comparison shows better-perceived HRQoL in males at first visit and CPAP follow-up visit. Variation of PGWBI was significantly correlated with CPAP use, ESS at T0 and T1 (p < 0.0001; r2 = 0.26). CONCLUSIONS: This study provides evidence on the effectiveness of CPAP treatment on perceived HRQoL. Participants with greater adherence to therapy, greater sleepiness, and greater improvement of daytime sleepiness with CPAP therapy, reported a higher quality of life improvement. Gender comparison shows better-perceived HRQoL in males at first visit and CPAP follow-up, despite a more considerable improvement in females.

The purpose is to evaluate the effect and safety of ramelteon 8 mg/day for 8 weeks in the treatment of insomnia in patients with concurrent depression in an exploratory manner. This phase 4, open-label, exploratory study included outpatients aged 20 to

The objective of this manuscript is to describe the cardiovascular effects of the gabapentinoids gabapentin and pregabalin. The most frequent adverse effects of gabapentin and pregabalin affect the central nervous system, such as somnolence and fatigue. Additionally, pregabalin, and a much lesser extent, gabapentin, may adversely affect the cardiovascular system. Pregabalin induces peripheral edema and may cause or exacerbate heart failure. Pregabalin use has been associated with QTc prolongation in patients taking other QTc–prolonging agents, although the relative contributions of pregabalin to QTc prolongation may be minimal. Pregabalin and gabapentin have been associated with a dose-related increased risk of atrial fibrillation. Most evidence for adverse cardiovascular effects of gabapentinoids derives from case reports and observational studies. Clinicians should be aware of the potential for pregabalin and possibly gabapentin to contribute to cardiovascular dysfunction.

Background We report on the results of a Japanese postmarketing drug-use survey of suvorexant (Belsomra®) tablets. Methods A survey with a ≤ 6-month observation period after the start of administration was conducted, targeting insomnia patients who were treated with suvorexant for the first time in Japan. Information on the safety and efficacy of the drug product was collected. The evaluation period was July 21, 2015–August 12, 2017, and the target number of patients was 3428. Results The mean administration period for the safety analysis population of 3248 patients was 113 days. At 6 months after the start of treatment, 48.6% (1577/3248) of the patients had been continually receiving treatment, and 51.4% (1671/3248) of the patients discontinued/dropped out of treatment before 6 months. Among the patients who discontinued/dropped out of the treatment, more than 30% discontinued due to improvement. The mean treatment duration for those who had discontinued treatment for this reason was 62 days. The incidence rate of adverse drug reactions among those in the safety analysis population was 9.7%, and the common adverse drug reactions were somnolence (3.6%), insomnia (1.2%), dizziness (1.1%), and nightmare (0.8%), all of which are described in the product label. No additional noteworthy events were observed. In 2439 patients with a final overall global assessment of sleep judged by physicians, the ‘improved’ rate was 74.0%. Among 2424 patients who provided a final overall global assessment, the improvement rate was 73.2%, which was comparable with the improvement rate judged by physicians. Regarding clinical effects (based on patient diary data or physician’s assessment), reduction in median sleep latency and increase in median total sleep time (reduction from 60 to 50 min and increase from 300 to 360 min compared with baseline, respectively) were observed at 1 week after the start of treatment and onwards, and the effect was maintained after the start of treatment for 6 months. A similar effect was observed irrespective of age groups or reasons for using suvorexant. Conclusion This survey was an exploratory observational study without a control group; the interpretation of results may require the consideration of factors that may have caused bias in the results, such as demographic characteristics and effects of other drugs. However, the results suggest that suvorexant can be a useful drug in daily clinical practice for treating insomnia.

Background The purpose of this study was to evaluate the post-marketing safety and effectiveness of aripiprazole in treating irritability in pediatric patients (6–17 years) with autism spectrum disorder (ASD) in actual clinical sites of Japan. Methods In this post-marketing surveillance, patients were enrolled into the multicenter, prospective, non-interventional, observational study for 52 weeks, and were dosed with aripiprazole (1–15 mg/day) under daily clinical settings in Japan. Results In 510 patients, the continuation rate of aripiprazole treatment was 84.6% at day 168 (week 24) and 78.1% at day 364 (week 52). Adverse drug reactions (ADRs) occurred in 22.7% of patients (n = 116), and the most common ADRs were somnolence (9.4%), followed by weight increased (3.3%). At week 4, the mean change from baseline in the irritability subscale score for the Aberrant Behavior Checklist Japanese version (ABC-J) was − 5.7 ± 6.8 (n = 288). Based on multiple regression analysis, comorbid attention deficit and hyperactivity did not affect the ABC-J irritability subscale score at endpoint. At week 24, the mean change from baseline for the Strengths and Difficulties Questionnaire was − 3.3 ± 4.9 (n = 215) for the total difficulties score and 0.6 ± 1.7 (n = 217) for the prosocial behavior subscale score. Conclusions Aripiprazole was well tolerated and effective in the long-term treatment of irritability associated with ASD in Japanese pediatric patients in the real-world clinical practice. Trial registration This surveillance was registered with Clinical Trial.gov (no. NCT03179787) on June 7, 2017 (retrospectively registered).

Background As inadequate pain communication contributes to difficulties in optimizing outcomes of outpatients, we investigated the effect of reinforced education using WeChat App to the opioid titration treatment of cancer-related pain in the outpatient setting. Methods We conducted a prospective study to compare reinforced education using Wechat with care as usual from February to December 2019. Patients in the reinforced education group received reinforced education via Wechat, while those in the control group received care as usual. Effect measurements for both groups are carried out with questionnaires at the baseline and 3 days later. Questionnaires include pain intensity (NRS), treatment-related adverse events, cancer-related quality of life (QOL), sleep (PSQI), satisfaction, anxiety (GAD-7) and depression (PHQ-9). Number of patients whose NRS reduced to less than three points in 24 h was the primary outcomes. Secondary outcomes included treatment-related adverse events, cancer-related quality of life, sleep, satisfaction, anxiety and depression. Results Although there was no significant difference regarding pain intensity (NRS) between the two groups at 72 h, the rate of NRS that reduced to less than three points in 24 h was significantly higher in the Wechat group than in the control group. Patients’ satisfaction was significantly higher in the Wechat group than in the control group. There was no significant difference between the two groups regarding the other findings at 72 h, including pain intensity (NRS), cancer-related quality of life (QOL), anxiety (GAD-7), depression (PHQ-9), and sleep (PSQI). However, no significant difference was found between the two groups for constipation, nausea, vomiting, dizziness, somnolence, pruritus, loss of consciousness, and death. Conclusions Our results indicated that receiving instructions delivered by Wechat resulted an increased number of patients with good pain control and better satisfaction. The study provided insight into the effectiveness of the reinforced education using a Wechat app delivered by a doctor to outpatients in the titration treatment of cancer-related pain. Trial registration This study was registered at chictr.org (Registration number: ChiCTR1900021150, Date of Registration: January 30, 2019).

The growing need for symptomatic treatment of post-traumatic neuropathic pain (PTNP) continues to be unmet. Studies evaluating the efficacy of pregabalin for reducing neuropathic pain following trauma and surgery yielded positive results over ≤ 8-week treatment. To assess the efficacy and tolerability of pregabalin over 3 months in patients with PTNP, a randomized, double-blind, placebo-controlled, parallel-group trial evaluated patients with PTNP at 101 centers in 11 countries—the longest, largest such trial. Adults diagnosed with PTNP were randomly assigned (1:1) to 15 weeks of pregabalin (flexibly dosed 150–600 mg/day) or matching placebo. Primary efficacy analysis was by mixed-model repeated measures comparing change from baseline to week 15 in weekly mean pain scores between active and placebo groups. Evaluable patients included 274 in the pregabalin group and 265 in the placebo group. Trauma was surgical in 49.6% of patients, non-surgical in the remainder. The primary efficacy analysis showed no statistically significant difference between pregabalin and placebo groups in the change from baseline to week 15 [mean difference, − 0.22 points (95% confidence interval, 0.54–0.10); p = 0.1823]. However, comparisons for key secondary outcome measures yielded p values

Mirogabalin is an α2δ ligand being developed to treat neuropathic pain. A small fraction of mirogabalin is metabolized by the liver, where hepatic impairment may affect exposure. The objective of this phase I, open-label single-dose study was to determine if mild or moderate hepatic impairment alters the pharmacokinetics of mirogabalin. Serial blood samples were collected for determination of maximum observed concentration, time to maximum concentration, and area under the concentration–time curve until the last quantifiable concentration of the active free form (A200-700) and inactive lactam metabolite (A204-4455) of mirogabalin. The A200-700 maximum observed concentration was similar in subjects with mild hepatic impairment but lower in subjects with moderate hepatic impairment vs. control subjects. The A204-4455 maximum observed concentration was lower in subjects with mild and moderate hepatic impairment vs. control groups. The A200-700 area under the concentration–time curve until the last quantifiable concentration was slightly lower in subjects with mild hepatic impairment and slightly higher in subjects with moderate hepatic impairment vs. control subjects. Peak A204-4455 levels were approximately 22% and 31% lower for subjects with mild and moderate hepatic impairment vs. control individuals, respectively. Exposure to A204-4455 was approximately 37% lower in subjects with mild hepatic impairment but unaffected in subjects with moderate hepatic impairment vs. control groups. Two subjects in the mild hepatic impairment group reported a treatment-emergent adverse event of mild somnolence. No serious or severe treatment-emergent adverse events, discontinuations as a result of treatment-emergent adverse events, or deaths were reported. Mild hepatic impairment resulted in lower A200-700 and A204-4455 exposure, while moderate hepatic impairment did not affect A200-700 exposure. Overall, mild-to-moderate hepatic impairment did not have a significant effect on mirogabalin exposure. A single 15-mg dose of mirogabalin was well tolerated by subjects with mild or moderate hepatic impairment.

Mirtazapine is commonly used to treat major depressive disorder. Due to its effects on multiple neurotransmitters, it has been investigated for possible benefits in patients with fibromyalgia. The objective of this systematic review is to assess the efficacy and safety of mirtazapine in the treatment of patients with fibromyalgia. Pubmed (1946-May 2018), Embase (1947-May 2018), CENTRAL, and ClinicalTrials.gov were queried using the search term combination: fibromyalgia, pain, chronic pain, neuralgia, neuropathic pain, chronic widespread pain, or chronic pain syndrome and mirtazapine. Studies appropriate to the objective were evaluated, including three randomized, placebo-controlled trials and one open-label trial, investigating the effect of mirtazapine in patients with fibromyalgia. In patients with fibromyalgia, treatment with mirtazapine resulted in improvements in pain, sleep, and quality of life. Study durations ranged from 6 to 13 weeks and studies used varying dosing strategies for mirtazapine. Minor occurrences of somnolence, weight gain, nasopharyngitis, dry mouth, and increased appetite were reported with mirtazapine use. Based on the reviewed literature, mirtazapine appears to be a promising therapy to improve pain, sleep, and quality of life in patients with fibromyalgia. These benefits were demonstrated in patients that were treatment naïve and those that had failed previous therapies. Additional clinical evidence through larger and longer length trials would be of benefit to further define the role of mirtazapine for patients with fibromyalgia.

Suvorexant (MK-4305) is an orexin receptor antagonist approved for the treatment of insomnia in the USA and other regions. This randomized, double-blind, placebo-controlled, sequential-panel, Phase 1 trial assessed the safety, tolerability, and pharmacokinetic data following single and multiple dosing of suvorexant in healthy men (aged 18–45 years). Within allocated panels, subjects (n = 8) were randomized to receive nightly doses of suvorexant (10, 20, 40, 80, and 100 mg) administered orally for 14 days, or placebo. Safety assessments included daily adverse event (AE) monitoring; pharmacokinetic data were obtained through periodic sampling. Of 40 subjects randomized, 39 completed the trial. The incidence of any AEs in the 10 and 20 mg groups was 67 and 83%, respectively, while 100% of subjects reported AEs in the dose groups of 40, 80, and 100 mg and the placebo group. The most frequently reported AEs were somnolence (n = 19 subjects), fatigue (n = 17), and headache (n = 15). Following single and multiple dosing, median time to reach maximum observed concentration ranged from 1.5 to 4.0 h and the apparent terminal half-life ranged from 7.7 to 14.5 h. Across the investigated doses, accumulation ratios for the area under the concentration–time curve and the maximum observed concentration were independent of dose and ranged from 1.21 to 1.60 and 1.00 to 1.46, respectively. Suvorexant was generally well tolerated after single and multiple dosing for 14 days. The findings support the once-nightly dosing regimen.

Data are reported from SPD503-318, a phase 3, open-label, safety study of guanfacine extended release (GXR) in European children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Participants received dose-optimized GXR (1–7 mg/day) for up to 2 years. Of 215 enrolled participants, 214 were included in the safety population and 133 completed the study. Participants’ mean age was 11.7 years and 73.8% were male. Overall, 177 participants (82.7%) experienced a treatment-emergent adverse event (TEAE). TEAEs reported in at least 10% of participants were somnolence (36.0%), headache (28.5%), fatigue (20.1%), and nasopharyngitis (11.7%). Serious TEAEs were reported in 4.7% of participants and TEAEs leading to discontinuation were reported in 3.3% of participants. There were no deaths. Mean z-scores for BMI were stable throughout the study. The incidence of sedative TEAEs (somnolence, sedation, and hypersomnia) peaked during week 3 and decreased thereafter. Small changes from baseline to the final assessment in mean supine pulse [− 5.5 bpm (standard deviation, 12.98)] and blood pressure [systolic, 0.6 mmHg (9.32); diastolic, 0.2 mmHg (9.17)] were reported. ADHD symptoms initially decreased and remained significantly lower than baseline at study endpoint. At the final assessment, the mean change in ADHD-RS-IV total score from baseline was − 19.8 (standard error of mean, 0.84; nominal p

Background Phosphodiesterase 10A (PDE10A) is selectively expressed in medium spiny neurons of the striatum. TAK-063 is a selective inhibitor of PDE10A in clinical development for the treatment of schizophrenia. Objectives Safety, tolerability, and pharmacokinetics (PK) of TAK-063 were evaluated following multiple rising oral doses, and PK/adverse event (AE) models were developed to characterize the relationship between TAK-063 exposure and incidence of specific AEs. Methods Healthy Japanese subjects (HJS) aged 20–55 years and subjects with stable schizophrenia (SSS) aged 18–55 years were enrolled and randomized to either TAK-063 or placebo. Study medication was administered as a tablet once daily (at night) with food over a 7-day period. Results TAK-063 and placebo groups consisted of 62 and 15 subjects, respectively. A majority of subjects (71 of 77) completed the study. AEs were mostly of mild or moderate severity, and no deaths were reported. The most common AE was somnolence. For equivalent doses, the rate of extrapyramidal syndromes (EPS) was higher in SSS than in HJS. PK parameters were comparable between HJS and SSS at equivalent doses. The incidence of somnolence and EPS symptoms increased with exposure, and this was described with the PK/AE model. A maximum tolerated dose was not determined. Conclusions Multiple doses of TAK-063 were safe and well tolerated. PK/AE models characterized the incidence of somnolence and EPS with increasing TAK-063 exposure, and simulations suggested that a once-daily dose range of up to 30 mg would be suitable for future studies. ClinicalTrials.gov Identifier NCT01879722. Electronic supplementary material The online version of this article (doi:10.1007/s40268-017-0214-8) contains supplementary material, which is available to authorized users.

This review article aims to describe the strong association between sleep and epilepsy. Sleep disturbance or sleep disorders are frequently observed comorbid conditions in patients with epilepsy. Sleep state and circadian rhythm influence seizure frequency in patients with epilepsy. In fact, some sleep syndromes are categorized as sleep-related epilepsy. Furthermore, sleep deprivation strongly influences seizure occurrence. The magnitude of the effects of sleep on seizure occurrence is variable, as there are many types of epilepsy. On the other hand, epilepsy affects sleep via both seizure activity and the side effects of treatments administered for epilepsy. Epileptic seizures during sleep often disturb sleep and antiepileptic drugs can alter sleep architecture; some antiepileptic drugs even induce somnolence. Although the close relationship between sleep and epilepsy is evident, the mechanisms underlying this connection remain unknown. Further studies are necessary to elucidate these mechanisms.

Fatigue is a prevalent and debilitating side effect of docetaxel chemotherapy in metastatic prostate cancer. A better understanding of the kinetics and nature of docetaxel-related fatigue may provide a framework for intervention. This secondary analysis was performed using the MOTIF database, from a phase III, randomised, double-blind, placebo-controlled study of modafinil (200 mg/day for 15 days) for docetaxel-related fatigue in men with metastatic prostate cancer [1]. The pattern of fatigue was analysed using the MDASI (MD Anderson Symptom Inventory) score. The impact of modafinil, cumulative docetaxel exposure, age and smoking status on fatigue kinetics were explored. Fatigue-related symptoms were assessed using the SOMA6 (fatigue and related symptoms) subset of the SPHERE (Somatic and Psychological Health Report). Mood was tracked using the short form 36 health survey questionnaire (SF-36). Across four docetaxel cycles, fatigue scores were higher in the first week and decreased over weeks two and three. Whilst men randomised to modafinil had reduced fatigue scores, cumulative docetaxel had little impact. Younger men (55–68 years) had significantly reduced fatigue scores, whereas current and ex-smokers had higher scores. There was no significant change in mood status or haemoglobin across treatment cycles. Men described both ‘somnolence’ and ‘muscle fatigue’ contributing significantly to their symptom complex. Assessment and management of docetaxel-related fatigue remains an important challenge. Given the complex, multifactorial nature of fatigue, identification through structured interview and interventions targeted to specific ‘at risk’ groups may be the most beneficial. Understanding the temporal pattern (kinetics) and nature of fatigue is critical to guide this process.

Severe depression accounts for one-third of depressed patients. Increasing severity of depression usually hinders patients from achieving remission. This study evaluated the efficacy and safety of escitalopram in acute-phase treatment of severe major depressive disorder (MDD). A total of 225 participants with severe MDD (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria), with a current depressive episode and Montgomery-Asberg Depression Rating Scale (MADRS) score of ≥30 were enrolled. Participants received flexible dose escitalopram (10-20 mg/d) treatment for 8 weeks. Symptoms status was assessed by MADRS, Hamilton Depression Rating Scale (HAM-D-17), and Hamilton Anxiety Rating Scale (HAM-A). Quality of life was assessed by Short Form-12 (SF-12) and safety by adverse events, laboratory investigations, vital signs and physical findings. The remission (MADRS total score ≤ 10) rate in the intent-to-treat set (n = 207) was 72.9% at week 8. Significant improvement in symptoms compared to baseline, as evaluated by MADRS, HAMD-17 and HAMA scores at baseline, week 1, week 2, week 4, and week 8 (p 0.0001 for all), was noted. Mean (SD) reduction from baseline in MADRS total score was 26.6 (11.38). Improvements in SF-12 score were significant (p = 0.000) and positively related to symptom improvement and negatively related to treatment-emergent adverse events (TEAEs). TEAEs were reported in 28.38% of participants. Most common TEAEs (4%) were somnolence (9.0%), nausea (7.7%), hyperhidrosis (4.5%), dry mouth and dizziness (4.1% each). No serious TEAEs were reported. Escitalopram was effective and well-tolerated for acute-phase treatment of severe depression in Chinese population.

Sex-related differences in the clinical profiles of some insomnia medications have been previously reported. To evaluate the clinical profile of suvorexant, a novel orexin receptor antagonist approved for treating insomnia at doses up to 20 mg, by sex subgroups. Efficacy analyses by sex were based on pooled data from two similar phase 3, randomized, double-blind, placebo-controlled, 3-month trials in elderly (≥65 years) and non-elderly (18–64 years) insomnia patients. Two age-adjusted (non-elderly/elderly) dose regimes of 40/30 and 20/15 mg were evaluated, with fewer patients assigned to 20/15 mg. Efficacy was assessed by patient-reported outcomes (N = 1264 women, 707 men) and by polysomnography endpoints in ~75% of patients. Safety analyses by sex (N = 1744 women, 1065 men) included pooled data from the two 3-month trials plus 3-month data from a safety trial of 40/30 mg. The sex subgroup efficacy analyses mirrored the improvements seen for suvorexant 40/30 and 20/15 mg over placebo on patient-reported outcomes and polysomnography sleep maintenance and onset endpoints in the primary analyses; 95% CIs excluded zero in favor of suvorexant for most endpoints in both sexes, and similar efficacy was observed between sexes (95% CIs overlapped). Suvorexant was well-tolerated in women and men, although women in all treatment groups (including placebo) reported more adverse events than men. The most frequent adverse event was somnolence (women: 11.1% for 40/30 mg, 8.5% for 20/15 mg, 2.3% for placebo; men: 10.1% for 40/30 mg, 3.4% for 20/15 mg, 4.2% for placebo). Suvorexant was generally effective and well-tolerated in both women and men with insomnia. ClinicalTrials.gov trial registration numbers: NCT01097616, NCT01097629, NCT01021813.

Somnolence is a common side effect of antipsychotics, although not all agents have the same sedative properties. Antipsychotic-induced somnolence can be managed by selecting a lower-risk agent, initiating treatment at a lower dose with a slower titration and minimizing the use of concurrent somnolence-inducing agents. Good sleep hygiene is also vital. Although data are limited, caffeine, bupropion and stimulants, such as modafinil, armodafinil, amphetamines and methylphenidate, may be useful in treating antipsychotic-induced somnolence.

Fatigue is a well-known risk factor for mood disturbances, decreased cognitive acuity, and impaired judgment. Sleep research in medical students typically focuses on sleep quantity, but less is known about the quality of a student’s sleep. The purpose of this investigation was to examine the subjective sleep quality and quantity of US medical students and to identify differences in sleep characteristics across demographic groups. Medical students (N = 860) representing 49 medical colleges completed the Medical Outcomes Study Sleep Scale and a demographic questionnaire between December 2015 and March 2016. Although participants reported obtaining nearly 7 h of sleep per night, the majority of students reported indicators of poor sleep quality. First and third year students reported higher rates of sleep-related problems compared to second and fourth year students. First and second year students reported the highest levels of sleep somnolence. Ethnic minority students reported significantly lower levels of sleep adequacy and sleep quantity and significantly higher levels of sleep somnolence than Caucasian students. Impaired sleep quality may contribute to fatigue in medical students even when sleep quantity seems adequate. Students appear to begin medical school with disrupted sleep patterns that may not improve until their final year of study. Education regarding proper sleep habits and the significant role of sleep quality in sustaining healthy sleep is especially important in the early stages of medical education. Minority, first year, and third year students may benefit the most from learning new behaviors that promote sufficient sleep quality during periods of sustained stress.

Somnolence is a common side effect of antipsychotics. To assess the incidence of this side effect, we performed a MEDLINE search for randomized, double-blinded, placebo- or active-controlled studies of adult patients treated with antipsychotics for schizophrenia, mania, bipolar depression, or bipolar disorder. We extracted rates of somnolence from original publications and pooled them based on the dose of each antipsychotic in the same psychiatric condition, then estimated the absolute risk increase (ARI) and the number needed to harm (NNH) of an antipsychotic relative to placebo or an active comparator in the same psychiatric condition. According to the ARI in acute schizophrenia, bipolar mania, and bipolar depression, antipsychotics can be classified as high somnolence (clozapine), moderate somnolence (olanzapine, perphenazine, quetiapine, risperidone, ziprasidone), and low somnolence (aripiprazole, asenapine, haloperidol, lurasidone, paliperidone, cariprazine). The risk of somnolence with blonanserin, brexpiprazole, chlorpromazine, iloperidone, sertindole, and zotepine needs further investigation. The rates of somnolence were positively correlated to dose and duration for some antipsychotics, but not for others. Many factors, including antipsychotic per se, the method used to measure somnolence, patient population, study design, and dosing schedule, might affect the incidence of antipsychotic-induced somnolence. The mechanisms of antipsychotic-induced somnolence are likely multifactorial, although the blockade of histamine 1 receptors and α1 receptors may play a major role. The management of antipsychotic-induced somnolence should include sleep hygiene education, choosing an antipsychotic with a lower risk for somnolence, starting at a lower dose with a slower titration based on psychiatric diagnoses, adjusting doses when necessary, and minimizing concurrent somnolence-prone agents. Since most cases of somnolence were mild to moderate, allowing tolerance to develop over at least 4 weeks is reasonable before discontinuing an antipsychotic.

Gabapentin enacarbil is an extended-release prodrug of gabapentin that is approved in the USA (Horizant(®)) and Japan (Regnite(®)) for the treatment of moderate to severe primary restless legs syndrome (RLS) in adults [featured indication]. This article summarizes pharmacological, efficacy and tolerability data relevant to the use of oral gabapentin enacarbil in this indication. In double-blind, multicentre trials, treatment with gabapentin enacarbil 600 mg/day for 12 weeks significantly improved the symptoms of moderate to severe primary RLS in adults. Gabapentin enacarbil also significantly improved RLS pain scores and generally improved sleep and mood outcomes. These data are supported by retrospective pooled analyses of three of these trials (XP081, PIVOT RLS I and PIVOT RLS II), with gabapentin enacarbil generally improving symptoms irrespective of disease severity, associated sleep disturbance or prior dopamine agonist use. Responses to gabapentin enacarbil were sustained in longer-term trials, with lower relapse rates in gabapentin enacarbil than placebo recipients in a longer-term maintenance study. Overall, in short and longer-term trials, relatively few patients discontinued treatment, adverse events were mostly mild to moderate in severity, and somnolence/sedation and dizziness were the most commonly reported adverse events. Notably, there were no reports of augmentation or QT-interval prolongation. Gabapentin enacarbil is an important agent for the treatment of adults with moderate to severe primary RLS.

Sleep disorders are not a part of a normal aging process. Sleep is a vital physiological process with important restorative functions that are essential for health, wellbeing, optimal daytime functioning, and longevity. Quite often, sleep-related complaints are neither reported by the patients nor investigated by the primary care provider. Sleep disorders are common in the elderly population due to coexisting medical conditions including cardiopulmonary, neuropsychiatric, and psychosocial issues. This situation is further accentuated by a wide variety of medications and habitual use of alcohol, nicotine, and caffeine use. Clinical consequences often include hyper somnolence, impaired intellect, disturbed cognition, increased risk of cardiopulmonary complications, and risk of falls. Inadequate sleep can compromise quality of life and cause significant social and economic burden for the caregiver. Diagnosis of sleep disorders in the elderly requires a high index of suspicion by a skilled and experienced physician. A multifaceted and comprehensive approach is required for successful management of this complex conglomerate of conditions.

Background and Objectives The first weeks of treatment with antipsychotics are important for the development of their long-term efficacy. The objective of this study was to identify factors related to early clinical effects and quality of life (QoL) improvements with quetiapine extended-release (XR). Methods Six hundred and sixty-five patients starting with quetiapine XR were followed up for 8 weeks (schizophrenia = 153, major depression = 200, bipolar depression = 252, other psychiatric conditions = 60). Clinical effects were assessed by the Clinical Global Impression of Change scale (CGI-C), QoL by the visual analog scale (VAS) of the EQ-5D (QoL-VAS), and adherence by the Moriksy scale. Adverse events were explored: movement disorders by the UKU and Simpson-Angus scales, weight gain by calibrated balances, and diurnal somnolence by the Epworth Somnolence Scale (ESS). Results The mean dose of quetiapine XR during follow-up was 195.6 ± 154.8 mg/day. CGI and QoL-VAS scores improved significantly at week 8 by 2.7 ± 0.1 points and 25.1 ± 0.9 points. Adverse events were observed in 34 and 26 % of patients at weeks 4 and 8, respectively. A significant reduction in ESS score was also observed at week 8. Factors independently associated with change in QoL-VAS ≥20 points (n = 292, 43 %) were female gender, more severe disease at baseline, higher antipsychotic dose during follow-up, and improvements in somnolence. Factors independently associated with clinically significant improvement (CGI-C ≥5, n = 610, 93 %) were greater change in QoL-VAS, less frequent movement disorders at baseline, and lack of adverse events during follow-up, especially somnolence. Conclusions Results from this real-setting, large observational study in Central America suggest that disease severity at baseline, gender, antipsychotic dose, and occurrence of adverse reactions has a significant impact on the early clinical effects of quetiapine XR. Fil: Molina, Luis. Clínica de Especialidades Altamira; Nicaragua Fil: Recinos, Byron. Universidad San Carlos de Guatemala; Guatemala Fil: Paz, Bezner. Hospital Juan de Dios de San Pedro; Honduras Fil: Rovelo, Mauricio. Instituto de Salud Mental; Honduras Fil: Elias Rodriguez, Fanny Elizabeth. Colonia Médica; El Salvador Fil: Calderón, José. Clínica de la Conducta; Panamá Fil: Arellano, Arturo. Corporación Farmacéutica Recalcine; Costa Rica Fil: Pomata, Santiago. Corporación Farmacéutica Recalcine; Costa Rica Fil: Rey, María Verónica. Etymos Consulting Group; Argentina Fil: Pérez Lloret, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; Argentina

BACKGROUND: Take-home naloxone, an opioid antagonist, has become part of a multimodal approach to curbing opioid-related mortality. However, there is little information about the utility of take-home naloxone in pediatric patients. We report a case of opioid toxicity after exposure to methadone in a pediatric patient, which was successfully reversed with take-home naloxone. CASE: A previously healthy 22-month-old girl ingested an unknown amount of liquid methadone. The child became progressively somnolent. The mother administered intranasal naloxone at home with reversal of somnolence. The patient presented to the emergency department and had recurrence of symptoms. The patient was placed on a naloxone infusion and discharged from a tertiary care facility, uneventfully, 2 days after ingestion. RESULTS: To our knowledge, we report the first case of pediatric opioid toxicity reversed by take-home naloxone. In the setting of rising opioid-related mortality, providers and public health officials should consider expanding access of take-home naloxone for children at high risk for opioid overdose.

Thirty-one to 97 % of patients who undergo thoracotomy for lung cancer experience ipsilateral shoulder pain, marring the otherwise excellent relief provided by thoracic epidural analgesia. The aim of this study was to test whether the addition of pregabalin to the treatment for shoulder pain would provide a significant benefit. Twenty patients undergoing thoracic surgery for lung cancer were enrolled in the control group between May 2012 and December 2012, and 20 patients were enrolled in the pregabalin group between January 2013 and July 2013, consecutively. All patients had standard pre- and intraoperative care. Patients received pregabalin 150 mg po POD 1 and then non-steroidal anti-inflammatory drugs (NSAIDs) po 2 h later (pregabalin group), or they received only NSAIDs po at exactly the same times (control group). Pain severity was then measured using a 100-mm visual analog scale (VAS) scoring system. The VAS scores indicated that patients in the pregabalin group had significantly less shoulder pain on postoperative day (POD) 2 than those in the control group (control: 27.9 ± 28.1 vs. pregabalin: 11.8 ± 14.4; p = 0.030). No differences in pain were observed between the two groups on other POD. There were significant differences on only POD 2 in the patients with shoulder pain immediately after surgery. Three of the pregabalin-treated patients showed mild somnolence. Postoperative administration of pregabalin provided significant relief of postoperative shoulder pain during earlier POD after thoracic surgery for lung cancer when received multimodal analgesia in combination with NSAIDs.

Noninvasive mechanical ventilation (NIPPV) was originally used in patients with acute respiratory compromises or exacerbations of chronic respiratory diseases, as an alternative to the endotracheal tube. Over the past 30 years NIPPV has been also used during the night in patients with stable chronic lung disease such as obstructive sleep apnea, the overlap syndrome (COPD and obstructive sleep apnea), neuromuscular disorders, obesity-hypoventilation syndrome, and in other conditions such as sleep disorders associated with congestive heart failure (Cheyne–Stokes respiration). In this review we discuss the different types of NIPPV, the specific conditions in which they can be used and the indications, recommendations, and evidence supporting the efficacy of NIPPV. Obstructive sleep apnea syndrome (OSA) is characterized commonly by instability of upper airway during sleep, reduction or elimination of airflow, daytime hyper somnolence, and sleep disruption. It is a risk factor for cardiovascular and cerebrovascular disorders including hypertension, myocardial infarction and stroke. Optimizing patient acceptance and adherence to noninvasive ventilation treatment is challenging. The treatment of sleep-related disorders is a life-threatening condition. The optimal level of treatment should be determinated in a sleep laboratory. Side effects directly affecting the patient’s adherence to treatment are known. The most common are nasopharyngeal symptoms including increased congestion and rhinorrea; these effects are related to reduced humidity of inspired gas. Humidification of delivered gas may improve these symptoms. Sleep specialists should review the results of objective testing with the patient and educate the patient concerning the nature of the disorder and treatment options. General education on the impact of weight loss, sleep position, alcohol avoidance, risk factor modification, and medication effects should be discussed. The patient should be counseled on the risks and management of drowsy driving. Patient education should optimally be delivered as a part of a multidisciplinary chronic disease management team.

Pregabalin has a multidimensional effect across a range of disorders that have of a pathogenesis involving a CNS response of abnormal hyperexcitability. The high-affinity binding of pregabalin at α2δ proteins and the subsequent reduction in excessive release of several excitatory neurotransmitters appears to be responsible for the clinical benefits of pregabalin in treating fibromyalgia, neurological pain and generalized anxiety disorder. The use of pregabalin in these complex and difficult-to-treat conditions is associated with rapid and durable clinically significant improvements in several outcome measures relating to core symptoms, including pain, anxiety and sleep, and improvements in overall health status and health-related quality-of-life. The most common adverse events associated with the drug are dizziness and somnolence, which are generally mild to moderate in intensity and are tolerated by many patients.

Second-generation antipsychotics (SGAs) have been proven effective in treating several psychiatric conditions in children and adolescents. These atypical antipsychotic medications are being used with increasing frequency in Europe, the U.S., and Canada. We aim to expose short-term and long-term adverse effects (AEs) of SGAs in youth populations and to provide management recommendations for major adverse effects. These proposals are based on (1) an in-depth literature review of both short- and long-term studies on the use of SGAs in youth; (2) our own clinical experience in managing such treatment in this population; and (3) the work of the Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics in Children (CAMESA). AEs are frequent in youth treated with SGAs, and include primarily weight gain, metabolic and hormonal changes, somnolence, extrapyramidal syndrome, and QT modifications. However, frequency and type of AE vary according to compound, and each compound’s AE profile is specific. Acknowledgment of these distinct profiles should aid clinicians in making treatment decisions. After an SGA is prescribed, routine monitoring of AEs is recommended, and should an AE occur, clinical management recommendations should be followed. To date, there are no clinically validated monitoring recommendations.

Migrainous vertigo is a common cause of dizziness presenting to an otorhinolaryngology/otoneurology clinic. Although it causes a substantial burden to the individual and society there are no randomized controlled trails on prophylactic medication for this condition. Flunarizine, a calcium channel blocker has been used effectively in both migraine and vestibular conditions. This randomized control trial was undertaken in a tertiary academic referral center to evaluate the efficacy of flunarizine in patients with migrainous vertigo when compared to non-specific vestibular treatment of betahistine and vestibular exercises. The effect of flunarizine on two particularly disabling symptoms of vertigo and headache was studied. A total of 48 patients who were diagnosed with definitive migrainous vertigo completed the study of 12 weeks duration. Patients in arm A received 10-mg flunarizine daily along with betahistine 16 mg and paracetamol 1 gm during episodes, and arm B received only betahistine and paracetamol during episodes. Symptom scores were noted at the start of the study and at the end of 12 weeks. Analysis of the frequency of vertiginous episodes showed a significant difference between arm A and arm B (p = 0.010) and improvement in severity of vertigo between the two groups (p = 0.046). Headache frequency and severity did not improve to a significant degree in arm A as compared to arm B. The main side effects were weight gain and somnolence and this was not significantly different between the two groups. Flunarizine (10 mg) is effective in patients with migrainous vertigo who suffer from considerable vestibular symptoms.

Migraine pain is often preceded, accompanied and followed by dopaminergic symptoms (premonitory yawning and somnolence, accompanying nausea and vomiting, postdromal somnolence, euphoria and polyuria). After reviewing evidence from pharmacological, biochemical, genetic and animal experimental studies on the relationship between dopamine and migraine, and matching these data with patients' clinical features, we postulate that migraine attacks could be characterized by an ictal dopamine release in a subject with dopamine receptor hypersensitivity due to a chronic dopaminergic deficit synergistic to serotoninergic impairment. Our review suggests that when the attack begins, a low dopamine plasma concentration stimulates hypersensitive central presynaptic dopamine receptors thus causing prodromal symptoms such as yawning and somnolence. Increasing dopamine levels, though still insufficient to stop trigeminovascular activation, stimulate postsynaptic dopamine receptors thus inducing nausea, vomiting and hypotension. Finally, dopamine levels slowly return to baseline, giving rise to somnolence and fatigue, but, in some cases, continue to rise triggering postdromal symptoms such as euphoria and polyuria.

Once-daily administration of the rotigotine transdermal patch (Neupro®) is effective in treating patients with early Parkinson’s disease (as monotherapy), advanced Parkinson’s disease (in combination with levodopa), inadequate morning motor control despite antiparkinsonian treatment (mostly in combination with levodopa), and moderate to severe idiopathic restless legs syndrome. Rotigotine is generally well tolerated, with the most common treatment-emergent adverse events being application-site reactions, gastrointestinal disturbances, somnolence and headache.

Efficacy and safety of 2 risperidone doses were evaluated in children and adolescents with autism. Patients (N = 96; 5-17 years), received risperidone (low-dose: 0.125 mg/day [20 to45 kg], 0.175 mg/day [45 kg] or high-dose: 1.25 mg/day [20 to45 kg], 1.75 mg/day [45 kg]) or placebo. Mean baseline (range 27-29) to endpoint change in Aberrant Behavior Checklist-Irritability (primary endpoint) was significantly greater in the high-dose-(-12.4 [6.5]; p 0.001), but not low-dose (-7.4 [8.1]; p = 0.164) group, versus placebo (-3.5 [10.7]). Clinical Global Impressions-Severity and Children's Yale-Brown Obsessive Compulsive Scale scores improved significantly only in the high-dose group, consistent with ABC-I results. Somnolence, sedation and increased appetite occurred more frequently in high-versus low-dose groups. Overall, increased appetite occurred most frequently.

Open-label extensions [studies SP516 (NCT00501969) and SP715 (NCT00594386)] of the CLEOPATRA-PD and PREFER studies were conducted to evaluate the safety, tolerability and efficacy of the dopaminergic agonist, rotigotine, over several years of follow-up in patients with advanced Parkinson’s disease (PD). Eligible subjects completing the double-blind trials received open-label adjunctive rotigotine (≤16 mg/24 h) for up to 4 and 6 years in Studies SP516 and SP715, respectively. Safety and tolerability were assessed using adverse events, vital signs and laboratory parameters, and efficacy assessed using the unified Parkinson’s disease rating scale (UPDRS). Of the 395 and 258 patients enrolled in the SP516 and SP715 studies, 48 and 45 % completed, respectively. Adverse events were typically dopaminergic effects [e.g., somnolence (18–25 %/patient-year), insomnia (5–7 %/patient-year), dyskinesias (4–8 %/patient-year) and hallucinations (4–8 %/patient-year)], or related to the transdermal application of a patch (application site reactions: 14–15 %/patient-year). There were no clinically relevant changes in vital signs or laboratory parameters in either study. Mean UPDRS part II (activities of daily living) and part III (motor function) total scores improved from double-blind baseline during dose titration, then gradually declined over the maintenance period. In study SP516, mean UPDRS part II and III total scores were 0.8 points above and 2.8 points below double-blind baseline, respectively, at end of treatment. In study SP715, mean UPDRS part II and III total scores were 4.1 points above and 0.2 points below baseline, respectively, at end of treatment. In these open-label studies, adjunctive rotigotine was efficacious with an acceptable safety and tolerability profile in patients with advanced PD for up to 6 years.

International audience; Narcolepsy type 1 (NT1) and type 2 (NT2) are two rare neurological diseases, classified as central disorders of hypersomnolence. The pathophysiology of NT1 is well known; it is caused by the selective destruction of hypocretin (Hcrt) neurons, by a highly suspected autoimmune process. On the contrary, little is known about NT2 etiology, sharing with NT1 somnolence and signs of dysregulation of rapid eye movement (REM) sleep, but not cataplexy. Management strategies are rather codified, at least in adults, with a lifelong treatment required in NT1, whereas no pharmacological study focused only on NT2 patients, with sometimes spontaneous improvement or disappearance of their symptoms. We recommend that medications and guidelines in NT2 should be the same as for NT1 (except for cataplexy), but the benefit risk ratio should be reassessed regularly. The main symptom in both diseases is a disabling excessive daytime sleepiness (EDS). First-line medications should be stimulants such as modafinil, armodafinil, or sodium oxybate, second-line methylphenidate and pitolisant, where available, and amphetamines as third-line therapy. Sodium oxybate has the advantage to be also effective to manage the fragmented nocturnal sleep, another common symptom in NT1. We advise to wait a few weeks with a stimulant drug before starting an anticataplectic treatment in NT1, except for severe cataplexy. Furthermore, cataplexy treatment should not be systematic. First-line strategy is the use of sodium oxybate, the only drug approved for cataplexy and EDS in adults. However, antidepressant agents such as venlafaxine are also commonly used, with few adverse effects and a good efficacy, although based on expert consensus only. A clinically relevant tool is required to quantify the severity of narcolepsy, subjective symptoms, and their consequences, to monitor the treatment efficacy, and to finally optimize narcolepsy management. In the future, Hcrt replacement or Hcrt agonists will certainly be options to treat NT1, but for now the different peptides do not cross easily the blood brain barrier. Immune-based therapies are other possibilities in NT1, at disease onset, with already some successful attempts to slow down or stop the autoimmune process.

Background This multicenter, double-blind, placebo-controlled study assessed the efficacy of rotigotine transdermal patch on apathy and motor symptoms in patients with Parkinson’s disease (PD). Methods Patients with PD-associated apathy (Unified Parkinson's Disease Rating Scale [UPDRS] I item 4 [motivation] ≥2 and patient-rated Apathy Scale [AS] ≥14) were randomized 1:1:1 to “low-dose” rotigotine (≤6 mg/24 h for early PD [those not receiving levodopa] or ≤8 mg/24 h for advanced PD [those receiving levodopa]), “high-dose” rotigotine (≤8 mg/24 h for early PD or ≤16 mg/24 h for advanced PD), or placebo, and maintained at optimal/maximal dose for 12 weeks. Coprimary efficacy variables were: change from baseline to End of Maintenance in patient-rated AS and UPDRS II + III total score. Recruitment was stopped after an interim futility analysis; therefore, all p values are exploratory. Results Of 122 patients randomized, 81.1 % completed the study (placebo, n = 32/40 [80.0 %]; low-dose rotigotine, n = 30/41 [73.2 %]; high-dose rotigotine, n = 37/41 [90.2 %]). No treatment difference was observed in the change in patient-rated AS (least squares mean [95 % confidence interval (CI)] difference: low-dose, 0.04 [−2.42, 2.50], p =0.977; high-dose, −0.22 [−2.61, 2.18], p = 0.859). Rotigotine improved UPDRS II + III total scores versus placebo (least squares mean [95 % CI] treatment difference: low-dose, −7.29 [−12.30, −2.28], p = 0.005; high-dose, −6.06 [−10.90, −1.21], p = 0.015), and the “mood/apathy” domain of the Non-Motor Symptom Scale as rated by the investigator (secondary outcome). The most frequent adverse events in rotigotine-treated patients were application site reactions, somnolence, and nausea. Conclusions Rotigotine did not improve PD-associated apathy as rated by the patient but provided clinically relevant improvement in motor control and activities of daily living. Trial registration ClinicalTrials.gov identifier NCT01782222. Trial registration date: January 30, 2013. Electronic supplementary material The online version of this article (doi:10.1186/s12883-016-0610-7) contains supplementary material, which is available to authorized users.

Oral gabapentin enacarbil is approved in adult patients for the treatment of moderate to severe primary restless legs syndrome (RLS) [featured indication] and the management of postherpetic neuralgia. In the 12-week Patient Improvements in Vital Outcomes following Treatment (PIVOT) RLS I and II trials in adult patients with moderate to severe primary RLS (n > 500 total evaluable), once-daily gabapentin enacarbil 600 or 1,200 mg significantly improved mean International Restless Legs Scale (IRLS) total scores compared with placebo, with significantly higher investigator-rated Clinical Global Impression-Improvement (CGI-I) responder rates in gabapentin enacarbil groups than in placebo groups. Improvements in other sleep outcomes (assessed using various scales) also generally favoured gabapentin enacarbil treatment. These data are supported by results from a polysomnography, crossover (two 4-week treatment periods) trial (n > 100 evaluable). Improvements in RLS symptoms with gabapentin enacarbil were maintained in a 52-week extension study of clinical trials, including PIVOT RLS I and II. The longer-term efficacy of gabapentin enacarbil in patients with moderate to severe RLS was also demonstrated in the 36-week PIVOT RLS Maintenance study and a 52-week noncomparative study conducted in Japan. Gabapentin enacarbil was generally well tolerated in adult patients with RLS participating in short- and longer-term clinical trials. The most common treatment-emergent adverse events were somnolence/sedation and dizziness. Most adverse events were of mild to moderate severity, with relatively few patients discontinuing treatment because of an adverse event.

Two well-studied conditions of peripheral neuropathic pain are postherpetic neuralgia (PHN) and painful diabetic peripheral neuropathy (DPN). Several pregabalin trials for peripheral neuropathic pain have been conducted in the West, but limited data are available for Japan. As ethnicity may influence health risks, differences may be evident in safety data from pregabalin trials in Japan and in the West. The objectives of this review were to compare large pooled safety data from randomized controlled trials evaluating pregabalin for the treatment of PHN or DPN in the West with data from two (one PHN, N = 371; one DPN, N = 314) similar trials in Japan. Longer-term safety data from Japanese open-label extension studies were also reviewed in these neuropathic pain populations. Published and unpublished Pfizer-supported pregabalin trials were identified and sourced from internal Pfizer records. A PubMed search to check for inclusiveness was conducted on 2 November 2011 using the following criteria: 'diabetic peripheral neuropathy' OR 'postherpetic neuralgia' OR 'neuropathic pain' AND 'pregabalin', with limits set for clinical and randomized controlled trials published in English. Five PHN trials (N = 1250) and nine DPN trials (N = 2554) were identified as suitable for inclusion based on methodological comparability. Descriptive safety data from the original trials were reviewed and the most commonly reported adverse events (AEs; dizziness, somnolence, peripheral oedema and weight gain) were identified to be of primary interest. The majority of AEs were of mild to moderate severity in Japanese and Western populations. The most commonly reported AE data (all-causality) with pregabalin (regardless of dose) in Japan (dizziness: PHN = 31.1%; DPN = 24.6%, and somnolence: PHN = 28.6%; DPN = 25.7%) were compared with pooled data from the Western trials (dizziness: PHN = 24.9%; DPN = 23.0%, and somnolence: PHN = 15.1%; DPN = 13.4%). Further assessment of these pooled AE (all-causality) data showed that dizziness and somnolence appeared early in the course of pregabalin treatment, but resolved before the end of the treatment in the majority of PHN and DPN patients (maximum duration of trials was 13 weeks). The slightly higher incidence of dizziness and somnolence in the two Japanese trials than that seen in the Western trials may reflect an increased exposure to pregabalin per fixed dose due to the lower mean bodyweight of the Japanese versus Western populations (on a mg/kg basis). However, of the participants who experienced these AEs (all-causality), the proportion who withdrew from the trials in Japan (dizziness: PHN = 23.5%; DPN = 18.2%, and somnolence: PHN = 10.3%; DPN = 10.9%) were comparable with the proportion who withdrew from trials in the West (dizziness: PHN = 16.0%; DPN = 29.3%, and somnolence: PHN = 19.4%; DPN = 34.2%). In Japan, 12.5% (PHN) and 15.1% (DPN) of patients experienced peripheral oedema as an AE (all-causality) compared with 8.8% (PHN) and 10.3% (DPN) in the West. Weight gain as an AE (all-causality) was experienced in 11.7% (PHN) and 13.4% (DPN) of patients in Japan compared with 3.8% (PHN) and 7.0% (DPN) in the West, but stabilized with continued treatment. Despite the lower mean bodyweight in Japanese versus Western patients, the PHN and DPN patients in Japan had stable blood glucose and HbA(1c) levels throughout the trials. The results of this review indicate safety outcomes in pregabalin trials are comparable between patients in Japan and those in the West. While managing peripheral neuropathic pain with pregabalin treatment, all patients should be observed closely for the incidence of dizziness and somnolence, especially at the beginning of treatment. These patients should also be monitored for evidence of peripheral oedema and weight gain during stable treatment, regardless of the source of neuropathic pain.

Restless legs syndrome (RLS) is a common neurological movement disorder that is often seen in multiple sclerosis patients. However, the association between RLS and multiple sclerosis (MS) is still unclear and RLS is not considered as one of the MS symptoms. This study was conducted to assess the frequency of RLS and its associated factors in patients with MS. This was a cross-sectional study conducted during January and April 2010. A total of 205 patients diagnosed with multiple sclerosis (164 females, 41 males, mean age 32.8 ± 8.9 years) were enrolled in the study and underwent a medical history interview and a neurological examination. The diagnosis of RLS was based on International Restless Legs Syndrome Study Group Criteria. 57 patients (27.8 %) met the RLS diagnostic criteria. In 90.1 % of the patients, the onset of RLS was simultaneous with or followed by MS onset. There was no significant difference between patients with and without RLS in respect of age, gender, disease duration, and MS pattern. There was an increased inci- dence of leg jerks before sleep in patients with RLS (P = 0.04). In patients suffering from RLS, there is greater complaint of insomnia (P = 0.03). Body mass index, history of anemia, excessive day-time somnolence, consuming caffeine containing beverages, pregnancy numbers, smoking, and alcohol consumption were not associated with the presence of RLS. This study revealed high prevalence of RLS in MS patients. Screening of RLS in these patients should be always considered in order to improve management of MS.

Background: Agitation and aggression are common neuropsychiatric symptoms of Alzheimer’s disease (AD) with a negative impact on caregivers. Objective: The aim of the study was to determine whether changes in agitation and aggression would follow memantine treatment and, if so, be associated with changes in nursing burden in institutionalized patients with moderate to severe AD. Study Design: This was a 3-month open-label trial of memantine. Setting: The setting was two long-term care facilities. Patients: Thirty-one institutionalized patients with moderate to severe AD and significant behavioural and psychiatric symptoms were included in the study. Intervention: Memantine was titrated to a target dose of 10mg twice daily. Main Outcome Measure: Effectiveness was assessed by the change in the Neuropsychiatric Inventory-Nursing Home (NPI-NH) agitation/aggression subscale and Clinical Global Impression of Change (CGI-C) scale using the intent-to-treat population. To establish caregiver impact, the effect on nursing burden was measured by the Modified Nursing Care Assessment Scale (primary outcome). As a secondary analysis, the caregiver distress subscale of the NPI-NH was examined, as well as changes in as required (pro re nata [prn]) psychotropic medication use. Results: Twenty-four patients completed the study. A significant decrease in agitation and aggression (F-test with 3 and 90 degrees of freedom [F3.90] = 3.721, p = 0.014) was demonstrated following memantine, with 48% of patients improving (either much improved or minimally improved) on the CGI-C scale. In addition, nursing burden (t-test with 30 degrees of freedom [t30] = 3.02, p = 0.005), caregiver distress (F3.90 = 4.125, p = 0.009) and the use of prn psychotropics decreased following memantine treatment (Z = −1.99, p = 0.046). Fourteen patients experienced at least one adverse event during memantine treatment. The most common adverse event associated with treatment was somnolence (n = 5). Conclusion: The results of this study suggest that the decreased agitated and aggressive behaviour in institutionalized patients with moderate to severe AD following treatment with memantine was accompanied by improvements in nursing burden and decreased psychotropic use. These findings should be confirmed in a larger, controlled trial. ClinicalTrials.gov Identifier: NCT00401167

It is costly and time-consuming to conduct the standard manual titration to identify an effective pressure before continuous positive airway pressure (CPAP) treatment for obstructive sleep apnea (OSA) patients. Automatic titration is cheaper and more easily available than manual titration. The purpose of this systematic review was to evaluate the effect of automatic titration in identifying a pressure and on the improvement of apnea/hyponea index (AHI) and somnolence, the change of sleep quality, and the acceptance and compliance of CPAP treatment, compared with the manual titration. A systematic search was made of the PubMed, EMBASE, Cochrane Library, SCI, China Academic Journals Full-text Databases, Chinese Biomedical Literature Database, Chinese Scientific Journals Databases and Chinese Medical Association Journals. Randomized controlled trials comparing automatic titration and manual titration were reviewed. Studies were pooled to yield odds ratios (OR) or mean differences (MD) with 95% confidence intervals (CI). Ten trials involving 849 patients met the inclusion criteria. It is hard to identify a trend in the pressures determined by either automatic or manual titration. Automatic titration can improve the AHI (MD = 0.03/h, 95% CI = −4.48 to 4.53) and Epworth sleepiness scale (SMD = −0.02, 95% CI = −0.34 to 0.31,) as effectively as the manual titration. There is no difference between sleep architecture under automatic titration or manual titration. The acceptance of CPAP treatment (OR = 0.96, 95% CI = 0.60 to 1.55) and the compliance with treatment (MD = −0.04, 95% CI = −0.17 to 0.10) after automatic titration is not different from manual titration. Automatic titration is as effective as standard manual titration in improving AHI, somnolence while maintaining sleep quality similar to the standard method. In addition, automatic titration has the same effect on the acceptance and compliance of CPAP treatment as manual titration. With the potential advantage of time and cost savings, automatic titration was recommended to be applied in identifying a proper pressure for CPAP treatment instead of manual titration in clinical practice.