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Evaluation of insomnia should include a complete medical and psychiatric history and assessment of sleep-related behaviors and symptoms. Therapies for persistent insomnia include cognitive behavioral therapy (considered the first-line treatment) and hypnotic medications. Foreword This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author’s clinical recommendations. Stage A 77-year-old overweight woman with hypertension and arthritis reports that she has had trouble sleeping for “as long as I can remember.” She has taken hypnotic medications nightly for almost 50 years; her medication was recently switched from lorazepam (1 mg), which had been successful, to trazodone (25 mg) by her primary care physician, who was concerned about her use of the former. She spends 9 hours in bed, from 11 p.m. to 8 a.m. She has only occasional difficulty falling asleep, but she awakens two to three times per night to urinate and lies in bed for over . . .

Nocturnal leg cramps (NLC) are common and poorly understood. To determine the prevalence of NLC and associations with cardiometabolic, sleep, and behavioral risk factors in the US population. Cross-sectional epidemiology. National Health and Nutrition Examination Survey, 2005-2006 and 2007-2008 waves. NLC were assessed with, \"In the past month, how often did you have leg cramps while trying to sleep?\" Responses were categorized as None, Mild, or Moderate-Severe. Demographics, medical history, sleep disturbances, and cardiometabolic risk factors were evaluated using the 2005-2006 dataset. Variables that demonstrated significant relationships to NLC after adjusting for age, sex, education, and BMI were assessed in the 2007-2008 dataset. Variables that were still significant were entered into a forward stepwise regression model combining both waves, to determine which variables best explained the variance in NLC. Prevalence was 24-25% reporting mild and 6% reporting moderate-severe NLC. NLC increased with age, lower education, unemployment, shorter sleep duration, all assessed sleep symptoms (nocturnal \"leg jerks\", snoring, snorting/gasping, difficulty falling asleep, difficulty maintaining sleep, non-restorative sleep, sleepiness, use of sleep medications), higher BMI, smoking, medical history (hypertension, heart failure, angina, stroke, arthritis, respiratory disease, and cancer), depression symptoms, and biomarkers (CRP, HbA1c, calcium, cadmium, red blood cells). Stepwise analysis showed that moderate-severe nocturnal leg cramps were associated with (in decreasing order of partial R2): leg jerks, poor overall health, arthritis, difficulty falling asleep, age, nonrestorative sleep, red blood cell count, lower education, angina, and difficulty maintaining sleep. Based on this first large, representative study, NLC occurring >5x per month are reported by 6% of the adult US population. Sleep disturbance symptoms and health conditions are associated with higher frequency of NLC, suggesting that NLC is a marker, and possibly contributor, to poor sleep and general health.

Abstract Study Objectives Sleep-related eating disorder (SRED) is a parasomnia characterized by partial arousals from sleep with compulsive consumption of food with impaired level of awareness and memory for the event. Small case series’ have demonstrated efficacy of topiramate in SRED. We conducted a placebo-controlled randomized clinical trial of topiramate to assess efficacy in SRED. Methods Thirty-four participants with an ICSD-2/ICSD-3 diagnosis of SRED with >6 months of symptoms and ≥3 sleep-related eating episodes per week were randomized to placebo or topiramate with flexible dosing to a maximum dosage of 300 mg for 13 weeks. Primary outcomes were percentage of nights with eating and Clinician Global Impression-Improvement (CGI-I). Intention-to-treat last observation carried forward (ITT LOCF) analysis was conducted. Results Mean age was 39.5 years, 74% were female, with mean duration of sleep-related eating of 13.7 years. SRED symptoms were significantly reduced with topiramate (74.7% to 33.2% nights/week; n = 15) compared to placebo (77.0% to 57.4%; n = 17) (p = 0.035). There were significantly more CGI-I responders on topiramate (71%) than placebo (27%) (p = 0.016). Level of wakefulness (r = −0.49) and memory for nighttime eating (r = −0.58) at baseline predicted topiramate response. The topiramate group lost significantly more weight than the placebo group (−8.5 lbs vs. +1.0 lbs, p = 0.001). The most common side effects were paresthesias and cognitive dysfunction. Conclusions This first randomized controlled trial demonstrating efficacy for treatment of SRED supports preliminary data on the use of topiramate for SRED. Side effects were prominent for topiramate. Limitations include a small sample size and a high drop-out rate in both study groups. Clinical Trial Information NCT00606411

Restless legs syndrome (RLS) is a distinct disorder, differing from chronic pain in many ways. Refractory RLS is characterized by unresponsiveness to dopamine agonists or alpha-2-delta ligands due to inadequate efficacy, augmentation, or adverse effects. This may result in severely impaired quality of life, profound insomnia, and suicidal depression. Opioid therapy is a mainstay in the management of these patients. This article summarizes the basic science and clinical evidence in support of their use, including the positive result of a large controlled multicenter study of 306 subjects, and outlines an approach to their use in clinical practice. Treatable explanations for RLS refractoriness, such as low iron stores, and other therapeutic options, such as combination therapy, should be considered before prescribing opioids. The agents most commonly used are oxycodone and methadone, but tramadol, codeine, morphine, and hydrocodone can also be considered. Controlled-release medication should be used for evening dosage and short-acting drugs, if needed, during the day. Effective doses are considerably lower than used for chronic pain (oxycodone 10-30 mg daily; methadone 5-20 mg daily) and the risk of opioid use disorder is relatively low. However, sensible precautions should be undertaken, including assessing opioid risk with standard questionnaires, using an opioid contract, using urine drug screens, consulting state prescription drug monitoring programs, and frequent reevaluation of effectiveness and side effects. Opioid use in selected patients with refractory RLS may be life-transforming with favorable risk-benefit ratio.

Abstract Study Objectives Long-term dopamine agonist (DA) use in restless legs syndrome (RLS) is associated with augmentation, a dose-related symptom worsening leading to further dose escalation to manage RLS. This study investigated rates and factors of high-dose DA prescribing in US RLS patients. Methods This retrospective analysis examined data from a US longitudinal prescriptions database (October 2017–September 2018). Patients diagnosed with RLS (ICD-10 G255.81) without Parkinson’s disease who were prescribed ropinirole, pramipexole, and/or rotigotine were included. Daily DA dosage was categorized: LOW/MID (US Food and Drug Administration [FDA]-approved/guideline or slightly above FDA-approved [pramipexole]); HIGH (101%–149%); VERY HIGH (>150%). Patient counts were converted to US national estimates. Logistic regression of patient counts evaluated factors associated with HIGH/VERY HIGH DA dosing. Results Of 670,404 RLS patients (131,289,331 therapy days), 58.8% were prescribed DA therapy. Overall, 19.1% of RLS patients were prescribed DAs above maximum FDA-approved/guideline daily doses—over half of these were >150% maximum recommended doses; 67.6% of HIGH/VERY HIGH-dose prescriptions were pramipexole (OR [95% CI] pramipexole vs ropinirole, 5.8 [5.7 to 6.0]). The highest 1% of DA prescriptions were ≥10× the FDA-recommended maximum daily dose. Rates of HIGH/VERY HIGH DA dosing increased with patient age. Twice as many neurologists (31.1%) prescribed HIGH/VERY HIGH doses vs other specialties (OR [95% CI], 2.1 [1.2 to 2.0]). Conclusions Approximately 20% of DA-treated RLS patients were prescribed doses above the approved and guideline daily maximum. Pramipexole, Neurology as specialty, and patient age were independently associated with HIGH/VERY HIGH DA dosing. Increased education is warranted regarding risks of high-dose DA exposure in RLS.

Objective Night eating syndrome (NES) is an eating disorder characterized by evening hyperphagia. Despite having a prevalence comparable to some other eating disorders, NES remains sparsely investigated and poorly characterized. The present study examined the phenotypic and genetic associations for NES in the clinical Mass General Brigham Biobank. Method Cases of NES were identified through relevant billing codes for eating disorders (F50.89/F50.9) and subsequent chart review; patients likely without NES were set as controls. Other diagnoses were determined from billing codes and collapsed into one of 1,857 distinct phenotypes based on clinical similarity. NES associations with diagnoses were systematically conducted in phenome-wide association scans using logistic regression models with adjustments for age, sex, race, and ethnicity. Polygenic scores for six related traits, namely for anorexia nervosa, depression, insomnia, sleep apnea, obesity, and type 2 diabetes were tested for associations with NES among participants of European ancestry using adjusted logistic regression models. Results Phenome-wide scans comparing patients with NES against controls (cases n  = 88; controls n  = 64,539) identified associations with 159 clinical diagnoses spanning 13 broad disease groups including endocrine/metabolic and digestive diseases. Notable associations were evident for bariatric surgery, vitamin D deficiency, sleep disorders (sleep apnea, insomnia, and restless legs syndrome), and attention deficit hyperactivity disorder. The polygenic scores for insomnia and obesity were associated with higher odds of NES (insomnia: odds ratio [OR], 1.24; 95% CI, 1.07, 1.43; obesity: 1.98; 95% CI, 1.71, 2.28). Discussion Complementary phenome-wide and genetic exploratory analyses provided information on unique and shared features of NES, offering insights that may facilitate its precise definition, diagnosis, and the development of targeted therapeutic interventions.

Aims/hypothesis Sleeping difficulty has been associated with type 2 diabetes in some prior studies. Whether the observed associations are independent of health behaviours, other cardiovascular risk factors or other sleep disorders is unclear. Methods We analysed data from 133,353 women without diabetes, cardiovascular disease and cancer at baseline in the Nurses’ Health Study (NHS, 2000–2010) and the NHSII (2001–2011). Sleeping difficulty was assessed as having difficulty falling or staying asleep ‘all of the time’ or ‘most of the time’ at baseline (2000 in NHS and 2001 in NHSII). Results We documented 6,407 incident cases of type 2 diabetes during up to 10 years of follow-up. After adjustment for lifestyle factors at baseline, comparing women with and without sleeping difficulty, the multivariate-adjusted HR (95% CI) for type 2 diabetes was 1.45 (95% CI 1.33, 1.58), which changed to 1.22 (95% CI 1.12, 1.34) after further adjustment for hypertension, depression and BMI based on the updated repeated measurements. Women who reported all four sleep conditions (sleeping difficulty, frequent snoring, sleep duration ≤6 h and sleep apnoea in NHS or rotating shift work in NHSII) had more than a fourfold increased likelihood of type 2 diabetes (HR 4.17, 95% CI 2.93, 5.91). Conclusions/interpretation Sleeping difficulty was significantly associated with type 2 diabetes. This association was partially explained by associations with hypertension, BMI and depression symptoms, and was particularly strong when combined with other sleep disorders. Our findings highlight the importance of sleep disturbance in the development and prevention of type 2 diabetes.

While evidence supports the benefits of medications for the treatment of chronic insomnia, there is ongoing debate regarding their appropriate duration of use. A panel of sleep experts conducted a clinical appraisal regarding the use of insomnia medications, as it relates to the evidence supporting the focus statement, “No insomnia medication should be used on a daily basis for durations longer than 3 weeks at a time”. The panelists’ assessment was also compared to findings from a national survey of practicing physicians, psychiatrists, and sleep specialists. Survey respondents revealed a wide range of opinions regarding the appropriateness of using the US Food and Drug Administration (FDA)-approved medications for the treatment of insomnia lasting more than 3 weeks. After discussion of the literature, the panel unanimously agreed that some classes of insomnia medications, such as non-benzodiazepines hypnotics, have been shown to be effective and safe for long-term use in the appropriate clinical setting. For eszopiclone, doxepin, ramelteon and the newer class of dual orexin receptor antagonists, the FDA label does not specify that their use should be of a limited duration. Thus, an evaluation of evidence supporting the long-term safety and efficacy of newer non-benzodiazepine hypnotics is timely and should be considered in practice recommendations for the duration of pharmacologic treatment of chronic insomnia.

Abstract Study Objectives Restless legs syndrome (RLS) is a sensory-motor neurological disorder. Low dose opioid medications are prescribed for treatment-refractory RLS. We describe baseline and 1-year longitudinal dosing and symptom outcomes for the National RLS Opioid Registry. Methods Individuals currently taking a prescribed opioid for diagnosed RLS are included in the registry. Information on initial and current opioid dosages, side effects, past and current concomitant RLS treatments, RLS severity, psychiatric history, and opioid abuse risk factors were collected at baseline. Follow-up online surveys were performed at 6 months and 1-year. Results Participants (n = 500) are primarily white, elderly, educated, and retired. Half of all subjects are on opioid monotherapy. Nearly 50% of all subjects are taking methadone, and one-quarter are taking oxycodone formulations. The median total daily opioid dose is 30.0 morphine milligram equivalents (MME). At baseline, three-quarters of registry participants had been taking a prescribed opioid for RLS for more than 1 year and one-third for more than 5 years, and had mild-moderate RLS symptoms. At 1-year follow-up, 31.2% increased dose (median = 10 MME) and 16.0% decreased dose of their opioid. An MME increase ≥25 was associated with: opioid use for non-RLS pain, <1 year of opioid use, opioid switch to methadone, and discontinuation of non-opioid RLS medications which, combined, accounted for 91.7% of those with 1-year follow-up increases ≥25 MME. Conclusions In refractory RLS, prescribed opioids are generally used at low doses with good efficacy. Longitudinally over 1 year, roughly one-third of participants increased their prescribed opioid dose, though generally by small amounts, with larger dose increases accounted for by predictable features.

Our understanding of the causes and natural course of restless legs syndrome (RLS) is incomplete. The lack of objective diagnostic biomarkers remains a challenge for clinical research and for the development of valid animal models. As a task force of preclinical and clinical scientists, we have previously defined face validity parameters for rodent models of RLS. In this article, we establish new guidelines for the construct validity of RLS rodent models. To do so, we first determined and agreed on the risk, and triggering factors and pathophysiological mechanisms that influence RLS expressivity. We then selected 20 items considered to have sufficient support in the literature, which we grouped by sex and genetic factors, iron-related mechanisms, electrophysiological mechanisms, dopaminergic mechanisms, exposure to medications active in the central nervous system, and others. These factors and biological mechanisms were then translated into rodent bioequivalents deemed to be most appropriate for a rodent model of RLS. We also identified parameters by which to assess and quantify these bioequivalents. Investigating these factors, both individually and in combination, will help to identify their specific roles in the expression of rodent RLS-like phenotypes, which should provide significant translational implications for the diagnosis and treatment of RLS.