Luciano Ribeiro Pinto

Randomized, double‐blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment

The objective of the present study was to assess the toxicology of melatonin (10 mg), administered for 28 days to 40 volunteers randomly assigned to groups receiving either melatonin (N=30) or placebo (N=10) in a double‐blind fashion. The following measurements were performed: polysomnography (PSG), laboratory examinations, including complete blood count, urinalysis, sodium, potassium and calcium levels, total protein levels, albumin, blood glucose, triglycerides, total cholesterol, high‐density lipoprotein (HDL), low‐density lipoprotein (LDL), and very low‐density lipoprotein (VLDL), urea, creatinine, uric acid, glutamic‐oxalacetic transaminase (GOT), glutamic‐pyruvate transaminase (GPT), bilirubin, alkaline phosphatase, gama‐glutamic transaminase (GGT), T3, T4, TSH, LH/FSH, cortisol, and melatonin serum concentrations. In addition, the Epworth Somnolence Scale (ESS) and a sleep diary (SD) were also applied to the volunteers 1 wk before each PSG. In addition, the volunteers were asked about possible side effects (SE) that appeared during the treatment. The study was carried out according to the following timetable: Visit 0, filling out the term of consent and inclusion criteria; Visit 1, PSG, laboratory examinations, ESS, SD, melatonin serum concentrations; Visit 2, SD, melatonin serum concentrations, SE; Visit 3, melatonin serum concentrations, PSG, ESS, SE; Visit 4, laboratory examinations, SE, melatonin serum concentrations, SD; and Visit 5, PSG, ESS, SE. Analysis of the PSG showed a statistically significant reduction of stage 1 of sleep in the melatonin group. No other differences between the placebo and melatonin groups were obtained. In the present study we did not observe, according to the parameters analyzed, any toxicological effect that might compromise the use of melatonin at a dose of 10 mg for the period of time utilized in this study.

Mind-body interventions for the treatment of insomnia: a review

OBJECTIVE As insomnia is highly prevalent, and side effects of medication are well-known, mind-body interventions are increasingly being sought. The objective of this study is to present a narrative review regarding the effects of mind-body interventions for the treatment of insomnia. METHOD A PubMed search was conducted including only randomized, controlled trials in which the main objective was to treat insomnia. DISCUSSION Twelve studies were selected. In three of the studies, objective parameters (polysomnography) were analyzed. Mind-body interventions were able to improve sleep efficiency and total sleep time. Most can ameliorate sleep quality; some can reduce the use of hypnotic drugs in those who are dependent on these drugs. CONCLUSION According to the studies we selected, self-reported sleep was improved by all mind-body treatments, among them yoga, relaxation, Tai Chi Chih and music. Cognitive behavioral therapy seems to be the most effective mind-body intervention. Cognitive behavioral therapy was the only intervention that showed better results than medication. However, considering that only five of the twelve studies chosen reached a score of 3 in the Jadad scale, new studies with a higher methodological quality have to be conducted especially in mind-body interventions that belong to the complementary or alternative medicine field.

Acute effects of low doses of melatonin on the sleep of young healthy subjects

This study was undertaken to evaluate the acute effects of single low doses of melatonin given to healthy volunteers in the evening. Six healthy male volunteers (age range 22–24 years) participated in this study, after signing an informed consent form. They received in a double‐blind fashion placebo or 0.3 or 1.0 mg melatonin at three fixed times: 18:00, 20:00, and 21:00 hr. Polysomnographic recordings began immediately thereafter, with their being allowed to sleep. Prior to each experimental session and in the following morning, subjects completed a sleep quality questionnaire, the Profile of Mood States, the Stanford Sleepiness Scale, and underwent a visual reaction test. Significant decrease on sleep latencies was found following melatonin treatment at 18:00 and 20:00 hr. In addition, melatonin tended to improve sleep efficiency and to reduce intermittent wakefulness. However, at 21:00 hr, 0.3 mg melatonin increased latency to sleep onset and 1.0 mg melatonin had no effect on sleep variables. Furthermore, melatonin given at different times did not alter subjective sleepiness, mood, and reaction time in the following morning. The results from the present study support the notion that administration of low doses of melatonin, mimicking the nocturnal physiological concentration of this hormone may exert immediate sleep‐inducing effects.

New guidelines for diagnosis and treatment of insomnia

The Brazilian Sleep Association brought together specialists in sleep medicine, in order to develop new guidelines on the diagnosis and treatment of insomnias. The following subjects were discussed: concepts, clinical and psychosocial evaluations, recommendations for polysomnography, pharmacological treatment, behavioral and cognitive therapy, comorbidities and insomnia in children. Four levels of evidence were envisaged: standard, recommended, optional and not recommended. For diagnosing of insomnia, psychosocial and polysomnographic investigation were recommended. For non-pharmacological treatment, cognitive behavioral treatment was considered to be standard, while for pharmacological treatment, zolpidem was indicated as the standard drug because of its hypnotic profile, while zopiclone, trazodone and doxepin were recommended.A Associacao Brasileira de Sono reuniu especialistas em medicina do sono com o objetivo de desenvolver novas diretrizes no diagnostico e tratamento das insonias. Nos consideramos quatro niveis de evidencia: padrao, recomendado, opcional e nao recomendado. Os topicos abordados foram: conceito, avaliacao clinica e psicossocial, indicacao da polissonografia, tratamento farmacologico, terapia comportamental cognitiva, comorbidades e insonia na infância. Para o diagnostico da insonia, foi recomendada uma avaliacao psicossocial e a realizacao da polissonografia, enquanto que no que se refere ao tratamento, foi estabelecido como padrao a indicacao da terapia comportamental cognitiva, e, quanto ao tratamento farmacologico, foi indicado o uso do zolpidem como hipnotico padrao, e sendo recomendado o zopiclone, a trazodona e a doxepina.

Sleep perception in insomniacs, sleep-disordered breathing patients, and healthy volunteers – An important biologic parameter of sleep

BACKGROUND The mechanisms involved in sleep perception are not widely known. Therefore, we believe that investigating this phenomenon is the best way to understand some of the mechanisms involved in several sleep disturbances, particularly insomnias. OBJECTIVE The objective of our study was to evaluate sleep perception in insomniacs, sleep-disordered breathing (SDB) patients, and healthy volunteers. Our hypothesis was that insomniacs have less sleep perception than healthy individuals and patients with sleep respiratory disorders. METHODS We studied 199 individuals who were divided into the following four groups: (1) insomnia group; (2) patients with sleep-disordered breathing; (3) patients with insomnia complaints and an associated sleep respiratory disorder; and (4) healthy individuals with no sleep complaints. All patients were subjected to polysomnography (PSG) followed by a questionnaire addressing their perception about the previous nights sleep. In addition to analysis of all sleep parameters, we determined sleep perception as the percentage of the ratio between total sleep time perceived by the patient and the total sleep time obtained by PSG. RESULTS Sleep perception was significantly lower in insomnia patients than in sleep-disordered breathing patients or the normal group. In addition, no significant differences across the four groups were observed in sleep efficiency and total sleep time. CONCLUSIONS The results showed that the reported sleep perception of insomniacs is lower than that of sleep-disordered breathing patients or normal individuals. We believe that sleep perception is as important as other commonly measured parameters, such as sleep efficiency.

Diretrizes brasileiras para o tratamento da narcolepsia

This manuscript contains the conclusion of the consensus meeting of the Brazilian Sleep Association with Brazilian sleep specialists on the treatment of narcolepsy based on the review of medical literature from 1980 to 2010. The manuscript objectives were to reinforce the use of agents evaluated in randomized placebo-controlled trials and to issue consensus opinions on the use of other available medications as well as to inform about safety and adverse effects of these medications. Management of narcolepsy relies on several classes of drugs, namely, stimulants for excessive sleepiness, antidepressants for cataplexy and hypnotics for disturbed nocturnal sleep. Behavioral measures are likewise valuable and universally recommended. All therapeutic trials were analyzed according to their class of evidence. Recommendations concerning the treatment of each single symptom of narcolepsy as well as general recommendations were made. Modafinil is the first-line pharmacological treatment of excessive sleepiness. Second-line choices for the treatment of excessive sleepiness are slow-release metylphenidate followed by mazindol. The first-line treatments of cataplexy are the antidepressants, reboxetine, clomipramine, venlafaxine, desvenlafaxine or high doses of selective serotonin reuptake inibitors antidepressants. As for disturbed nocturnal sleep the best option is still hypnotics. Antidepressants and hypnotics are used to treat hypnagogic hallucinations and sleep paralysis.

Brazilian guidelines for the diagnosis of narcolepsy

This manuscript contains the conclusion of the consensus meeting on the diagnosis of narcolepsy based on the review of Medline publications between 1980-2010. Narcolepsy is a chronic disorder with age at onset between the first and second decade of life. Essential narcolepsy symptoms are cataplexy and excessive sleepiness. Cataplexy is defined as sudden, recurrent and reversible attacks of muscle weakness triggered by emotions. Accessory narcolepsy symptoms are hypnagogic hallucinations, sleep paralysis and nocturnal fragmented sleep. The clinical diagnosis according to the International Classification of Sleep Disorders is the presence of excessive sleepiness and cataplexy. A full in-lab polysomnography followed by a multiple sleep latency test is recommended for the confirmation of the diagnosis and co-morbidities. The presence of two sleep-onset REM period naps in the multiple sleep latency test is diagnostic for cataplexy-free narcolepsy. A positive HLA-DQB1*0602 with lower than 110pg/mL level of hypocretin-1 in the cerebrospinal fluid is required for the final diagnosis of cataplexy- and sleep-onset REM period -free narcolepsy.

Effects of different sleep deprivation protocols on sleep perception in healthy volunteers

OBJECTIVES To investigate whether different protocols of sleep deprivation modify sleep perception. METHODS The effects of total sleep deprivation (TD) and selective rapid eye movement (REM) sleep deprivation (RD) on sleep perception were analyzed in normal volunteers. Thirty-one healthy males with normal sleep were randomized to one of three conditions: (i) normal uninterrupted sleep; (ii) four nights of RD; or (iii) two nights of TD. Morning perception of total sleep time was evaluated for each condition. Sleep perception was estimated using total sleep time (in hours) as perceived by the volunteer divided by the total sleep time (in hours) measured by polysomnography (PSG). The final value of this calculation was defined as the perception index (PI). RESULTS There were no significant differences among the three groups of volunteers in the total sleep time measured by PSG or in the perception of total sleep time at baseline condition. Volunteers submitted to RD exhibited lower sleep PI scores as compared with controls during the sleep deprivation period (P <0.05). Both RD and TD groups showed PI similar to controls during the recovery period. CONCLUSION Selective REM sleep deprivation reduced the ability of healthy young volunteers to perceive their total sleep time when compared with time measured by PSG. The data reinforce the influence of sleep deprivation on sleep perception.

Rapid eye movements during paradoxical sleep in patients with cerebrovascular disease

Rapid eye movements that occur during paradoxical sleep are generated from the brainstem and are modulated by cerebral hemispheres. In an attempt to establish the participation of cerebral hemispheres on rapid eye movements, we carried out a quantitative study of eye movements density in patients bearing hemispheres vascular lesions. The polysomnographic recordings of 24 patients were compared to those of 24 healthy volunteers. Density of rapid eye movements was defined as the percentage of eye movements during the respective time of paradoxical sleep. Based on the present results, we concluded that: stroke patients with hemispheric lesions displayed increased density of rapid eye movements; there was no difference on the density of rapid eye movements according to the hemispheric lesion; higher density of rapid eye movements was observed in patients with anterior hemispheric lesion.

Eszopiclone versus zopiclone in the treatment of insomnia

OBJECTIVE: To determine the therapeutic effects of two selective GABA-A agonists, zopiclone and eszopiclone, in the treatment of insomnia. METHODS: This study comprised a phase III, single-center, randomized, double-blind, double-dummy, parallel-group, non-inferiority trial. Patients were randomized to receive zopiclone 7.5 mg or eszopiclone 3 mg, both orally, for four weeks. In total, 199 patients were evaluated during two visits and then followed for at least six weeks. The primary endpoint was the Insomnia Severity Index after four weeks of treatment. Secondary endpoints were obtained through polysomnography data, including total sleep time, sleep latency and sleep efficiency. The frequency of adverse events was also analyzed. ClinicalTrials.gov: NCT01100164. RESULTS: The primary efficacy analysis demonstrated the non-inferiority of eszopiclone over zopiclone. Analysis of objective parameters assessed by polysomnography showed that eszopiclone increased total sleep time and also improved sleep efficiency. The safety profile of both study treatments was similar and the most common events reported in both groups were dysgeusia, headache, dizziness, irritability and nausea. Adverse events were observed in 223 patients, 109 (85.2%) in the eszopiclone group and 114 (87.7%) in the zopiclone group. CONCLUSION: Based on the Insomnia Severity Index at the end of four weeks of treatment, eszopiclone demonstrated efficacy comparable to that of zopiclone in the treatment of insomnia, increasing total sleep time as well as sleep efficiency according to polysomnography.