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Restless legs syndrome (RLS) is a sensory-motor neurologic disorder present to a clinically significant degree in 2% to 3% of the adult population, more commonly with advancing age and in women, that dramatically affects sleep and quality of life. Addressing factors that worsen RLS (eg, iron deficiency, antidepressant or antihistamine administration, OSA) is an important first step in treatment. RLS can generally be well treated with medications such as the alpha

A scientific advisory panel of seven U.S. and Canadian sleep experts performed a clinical appraisal by comparing general medical opinion, assessed via a survey of practicing clinicians, regarding insomnia treatment, with the available scientific evidence. This clinical appraisal focuses on the specific statement, “Treatments for insomnia have uniformly been shown to significantly improve the associated daytime impairment seen with insomnia.” The advisory panel reviewed and discussed the available body of evidence within the published medical literature to determine what discrepancies may exist between the currently published evidence base and general medical opinion. The advisory panels’ evaluation of this statement was also compared with the results of a national survey of primary care physicians, psychiatrists, nurse practitioners, physician assistants, and sleep specialists in the United States. Contrary to general medical opinion, the expert advisory panel concluded that the medical literature did not support the statement. This gap highlights the need to educate the general medical community regarding insomnia treatment efficacy in pursuit of improved treatment outcomes.

Trazodone is one of the most commonly used prescription medications for insomnia; however, some recent clinical guidelines do not recommend its use for treating insomnia. This clinical appraisal critically reviews the scientific literature on trazodone as a first-line treatment for insomnia, with the focus statement “Trazodone should never be used as a first-line medication for insomnia.” In addition, field surveys were sent to practicing physicians, psychiatrists, and sleep specialists to assess general support for this statement. Subsequently, a meeting with a seven-member panel of key opinion leaders was held to discuss published evidence in support and against the statement. This paper reports on the evidence review, the panel discussion, and the panel’s and healthcare professionals’ ratings of the statement’s acceptability. While the majority of field survey responders disagreed with the statement, the majority of panel members agreed with the statement based on the limited published evidence supporting trazodone as a first-line agent as they understood the term “first-line agent”.

Insomnia and restless leg syndrome (RLS) are associated with increased risk for suicidal behavior (SB), which is often comorbid with mood or thought disorders; however, it is unclear whether these relationships are causal. We performed a two-sample Mendelian randomization study using summary-level genetic associations with insomnia symptoms and RLS against the outcomes of risk of major depressive disorder (MDD), bipolar disorder (BP), schizophrenia (SCZ), and SB. The inverse-variance weighted method was used in the main analysis. We performed replication and sensitivity analyses to examine the robustness of the results. We identified outcome cohorts for MDD (n = 170,756 cases/329,443 controls), BP (n = 20,352/31,358), SCZ (n = 69,369/236,642), SB-Cohort-2019 (n = 6569/14,996 all with MDD, BP or SCZ; and SB within individual disease categories), and SB-Cohort-2020 (n = 29,782/519,961). Genetically proxied liability to insomnia symptoms significantly associated with increased risk of MDD (odds ratio (OR) = 1.23, 95% confidence interval (CI) = 1.2–1.26, P = 1.37 × 10–61), BP (OR = 1.15, 95% CI = 1.07–1.23, P = 5.11 × 10–5), SB-Cohort-2019 (OR = 1.17, 95% CI = 1.07–1.27, P = 2.30 × 10–4), SB-Cohort-2019 in depressed patients (OR = 1.34, 95% CI = 1.16–1.54, P = 5.97 × 10–5), and SB-Cohort-2020 (OR = 1.24, 95% CI = 1.18–1.3, P = 1.47 × 10–18). Genetically proxied liability to RLS did not significantly influence the risk of any of the outcomes (all corrected P > 0.05). Results were replicated for insomnia with MDD and SB in Mass General Brigham Biobank and were consistent in multiple lines of sensitivity analyses. In conclusion, human genetic evidence supports for the first time a potentially independent and causal effect of insomnia on SB and encourages further clinical investigation of treatment of insomnia for prevention or treatment of SB.

OBJECTIVE: This study aimed to investigate the existence of a difference in quality of life (QOL) between individuals with and without significant subjective-objective discrepancy (SOD) in total sleep time (TST). METHODS: From the Sleep Heart Health Study (SHHS) 2, 2540 individuals who had completed polysomnography, a morning sleep survey, and the 36-item Short-Form Health Survey (SF-36) were included in the analyses. The participants were classified as normoestimators (estimation of TST < ± 60 min), underestimators (underestimation of TST ≥ 60 min), or overestimators (overestimation of TST ≥ 60 min). The standardized SF-36 QOL scores were compared among the three groups. An adjusted partial correlation analysis was conducted between SOD and QOL. RESULTS: Of the 2540 participants, 1617 (63.7%), 433 (17.0%), and 490 (19.3%) were assigned to the normoestimator, underestimator, and overestimator groups, respectively. The bodily pain and social functioning components of the SF-36 score were significantly lower in the underestimators than in the normoestimators, whereas the physical functioning component was significantly lower in the overestimators than in the normoestimators. The absolute value of SOD in the TST showed a significant negative correlation with the physical and mental components of the SF-36. CONCLUSIONS: QOL was significantly better in the normoestimator than in the other groups and linearly correlated with the absolute value of SOD. This study suggests that a high prevalence of positive and negative sleep misperception in a community population can be a potential factor associated with poor QOL and potential comorbidities.

Restless legs syndrome (RLS) is a syndrome characterized by unpleasant sensations associated with an urge to move the legs, with onset at rest, worse in the evening or at night, and transiently relieved by standing or walking. RLS is a clinical diagnosis, and common mimics of RLS include neuropathy, akathisia, and leg cramps. There is a bidirectional association between RLS and psychiatric disorders. RLS contributes to psychiatric comorbidity, especially anxiety, depression, and risk of self-harm or suicide, and RLS treatments can have iatrogenic behavioral effects, especially chronic dopaminergic drug. Conversely, serotonergic (e.g., SSRI, SNRI) and antihistamine (e.g., mirtazapine) drugs used to treat depression, chronic anxiety, and insomnia, have the potential to unmask or worsen RLS.

BACKGROUND AND PURPOSE Restless legs syndrome (RLS) has been suggested as a prodromal symptom of Parkinson disease (PD). Olfactory or taste dysfunction can also occur preceding PD diagnosis. However, whether RLS is associated with chemosensory dysfunction remains unknown. We thus aim to investigate the association between RLS and perceived olfactory and taste dysfunction. METHODS We performed a cross-sectional analysis including 90,337 Chinese adults free of neurodegenerative diseases in the Kailuan study in 2016. Presence of RLS was defined using revised RLS diagnostic criteria or the Cambridge-Hopkins questionnaire for RLS. Perceived olfactory and taste dysfunction was collected via a questionnaire. The association between RLS and perceived olfactory and taste dysfunction was assessed using logistic regression model, adjusting for potential cofounders such as age, sex, and medical history. RESULTS RLS was associated with high odds of having perceived olfactory and/or taste dysfunction (adjusted odds ratio = 5.92, 95% confidence interval = 3.11-11.3). The significant association persisted when using the Cambridge-Hopkins questionnaire (adjusted odds ratio = 5.55, 95% confidence interval = 2.37-13.0) or when excluding participants with major chronic diseases. CONCLUSIONS RLS was associated with increased odds of perceived olfactory and taste dysfunction.

Treatment for narcolepsy with sodium oxybate (SXB) has required twice-nightly dosing, at bedtime and 2.5-4 h later. This study evaluated the pharmacokinetics of FT218, an investigational, extended-release, once-nightly formulation of SXB (ON-SXB), vs twice-nightly SXB.In this phase 1, open-label study, healthy volunteers were randomized (1:1) to ON-SXB 6 g or twice-nightly SXB (two 3-g doses administered 4 h apart); minimum 3-day washout before crossover. Doses were administered 2 h post-evening meal. Blood samples for pharmacokinetic assessments were collected predose and up to 14 h after the first dose during each treatment period.Twenty-eight participants were enrolled (mean age, 39.6 years; 54% women; 93% white). Mean ± SEM area under the concentration-time curve for ON-SXB was 282.7 ± 30.2 μg·h/mL vs 273.3 ± 27.8 μg·h/mL for twice-nightly SXB. Geometric mean ratio (GMR; 90% CI) was 102.9 (98.0-108.0). Maximum γ-hydroxybutyrate (GHB) plasma concentration (CGHB exposure and C

Study Objectives The objective of this study was to assess the effectiveness of current treatment guidelines for restless legs syndrome (RLS) augmentation in patients on dopamine agonists (DAs) which recommend a cross-titration strategy to an alpha-2-delta ligand (A2D) and/or opioid. Methods Consecutive new consultations for RLS with both augmentation and active treatment with DAs at the time of initial assessment were included if followed >5 months. Clinical information from the semi-structured initial consultation, and subsequent visits until their most recent/final visit was extracted. Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I) scores were retrospectively determined by two independent evaluators. Results In the 63 patients with augmented RLS on DAs, followed for 5–59 months (mean = 28, SD = 14), the average age was 67.6 (SD = 9.8) and 63% were female. Mean duration of prior dopaminergic therapy was 11.6 years (SD = 6.7) and average pramipexole equivalent dose was 1.23 mg (SD = 1.22 mg). At baseline, RLS was “moderate-markedly” severe (CGI-S = 4.9). At the final/most recent visit, 78% (49/63) were classified as Responders (CGI-I ≤ 2, “Much” or “Very Much Improved”) with an average CGI-S of 2.4 (“borderline-mildly ill”). Responders (59%) were more likely to have discontinued DAs than Non-Responders (40%), and mean opioid doses were higher in Responders (39 vs 20 MME). No differences in baseline DA dose, final A2D dose, or iron therapy were observed between groups. Responders did have significantly more severe RLS, more sleep maintenance insomnia, and greater subjective daytime sleepiness at baseline (p < 0.05). Conclusions Guideline-based management is effective in most patients with augmented RLS on DAs.

Restless legs syndrome (RLS) is a chronic sensorimotor disorder diagnosed by clinical symptoms. It is challenging to translate the diagnostic self-reported features of RLS to animals. To help researchers design their experiments, a task force was convened to develop consensus guidelines for experimental readouts in RLS animal models. The RLS clinical diagnostic criteria were used as a starting point. After soliciting additional important clinical features of RLS, a consensus set of methods and outcome measures intent on capturing these features-in the absence of a face-to-face interview-was generated and subsequently prioritized by the task force. These were, in turn, translated into corresponding methods and outcome measures for research on laboratory rats and mice and used to generate the final recommendations. The task force recommended activity monitoring and polysomnography as principal tools in assessing RLS-like behavior in rodents. Data derived from these methods were determined to be the preferred surrogate measures for the urge to move, the principal defining feature of RLS. The same tools may be used to objectively demonstrate sleep-state features highly associated with RLS, such as sleep disturbance and number and periodicity of limb movements. Pharmacological challenges and dietary or other manipulations that affect iron availability are desirable to aggravate or improve RLS-like behavior and lend greater confidence that the animal model being proffered replicates key clinical features of RLS. These guidelines provide the first consensus experimental framework for researchers to use when developing new rodent models of RLS. © 2020 International Parkinson and Movement Disorder Society.

The growing availability, legality, and use of marijuana products in the USA has contributed to increased patient and clinician interest in the treatment of sleep disorders, especially insomnia and restless legs. What should clinicians know about these drugs and what should they tell patients that inquire about using them? Increasing numbers of studies are being published revealing clear subjective improvement of sleep-onset latency, subjective improvement of sleep disruptions, and subjective improvement of restless legs symptoms. However, objective findings are most often mixed, with some studies demonstrating improvement of sleep characteristics, and some demonstrating worsening. There is a trend for improvement in sleep with short-term use of marijuana products and a longer-term attenuation of effect, or possibly worsening. Evidence for their effectiveness in these disorders is robust from subjective patient reports but limited or mixed in objective measures. Discussions with patients should be individualized and risks and benefits weighed. Future large, randomized, placebo-controlled studies are needed to help clarify the discrepancy between subjective and objective measures.

Background Both Major Depressive Disorder (MDD) and Primary Insomnia (PI) have been linked to deficiencies in cortical γ-aminobutyric acid (GABA) and glutamate (Glu) thus suggesting a shared neurobiological link between these two conditions. The extent to which comorbid insomnia contributes to GABAergic or glutamatergic deficiencies in MDD remains unclear. Methods We used single-voxel proton magnetic resonance spectroscopy (1H MRS) at 4 Tesla to examine GABA+ and Glu relative to creatine (Cr) in the dorsal anterior cingulate cortex (dACC) and in the parieto-occipital cortex (POC) of 51 non-medicated adults with MDD, 24 adults with Primary Insomnia (PI), and 25 age- and sex-matched good sleeper controls (HC). Measures of depression severity and subjective and objective sleep quality were compared with 1H MRS metabolite measures. Results MDD subjects exhibited a 15% decrease in Glu/Cr in the dACC compared to HC. Within the MDD group, there was a trend inverse correlation between dACC Glu/Cr and anhedonia ratings. We observed no significant association between measures of sleep quality with dACC Glu/Cr in those with MDD. Limitations The protocol and data interpretation would have been enhanced by the recruitment of MDD subjects with a broader range of affect severity and a more comprehensive assessment of clinical features. Conclusions These findings support the role of cortical glutamatergic mechanisms in the pathophysiology of MDD. Insomnia severity did not further contribute to the relative deficiency of glutamatergic measures in MDD.

It remains unclear whether neurobiological dysfunction observed in major depressive disorder (MDD) and insomnia is an expression of common or independent bases. The present investigation sought to explore differences in heart rate variability (HRV)—a widely utilized biomarker of neurobiological functioning—among individuals with MDD, insomnia, and healthy controls, while awake and during distinct sleep stages (REM, N2), with the goal of improving our understanding of shared neurobiological factors in depression and insomnia. Participants were 73 adults who underwent home polysomnography. All N2 and REM sleep epochs with a duration greater than or equal to 5 min were identified for HRV analysis. Additionally, a single waking epoch was defined for each participant. From waking to N2 sleep, and waking to REM sleep, changes in HRV indices indicated participants experienced reductions in sympathetic arousal and increases in parasympathetic arousal. Contrary to hypotheses, however, no between group differences were observed in HRV. Though the present findings do not support the hypotheses of a shard neurobiological pathway between MDD and insomnia, more work is warranted to advance our understanding of the neurobiological bases of these common, debilitating, and frequently co-occurring psychiatric conditions, to improve early detection and identify novel intervention targets for these disorders.

BACKGROUND: Heart rate variability (HRV) is a widely utilized biomarker of autonomic regulatory functioning, and concomitant health or pathological states. A growing body of work is exploring HRV under sleeping conditions. Most of this literature utilizes either averaged HRV indices calculated from multiple sleep stage epochs, or averaged HRV throughout the night. Both approaches implicitly assume that HRV within sleep epoch types is consistent throughout the night. Given the robust literature indicating the existence of an endogenous cardiovascular circadian rhythm as well as the potential for effects for cumulative time asleep, we hypothesized that HRV would vary across distinct sleep epochs. METHODS: Participants underwent at least one night of home polysomnography that included electroencephalogram, electromyogram, and electrocardiogram (N = 73). All rapid eye movement (REM) and non-REM stage 2 (N2) sleep epochs with a duration greater than or equal to five minutes were identified for HRV analysis. Time and frequency domain indices of HRV were calculated for each sleep stage epoch. Linear mixed models were used to examine main effects of time on HRV indices for N2 and REM sleeps epochs respectively. RESULTS: Main effects of time were observed for all models. Patterns emerged for both the N2 and REM epochs, suggesting HRV indices are non-stationary (i.e., variable) across distinct sleep epochs through the course of the night. CONCLUSIONS: The present findings indicate HRV is non-stationary across sleep stage epochs. Aggregating HRV indices across sleep stage epochs likely obscures important transient effects and increases risk of type-I and type-II errors.

Study Objectives The neuropeptide orexin promotes wakefulness, modulates thermoregulation, increases after menopause, and is normalized in women receiving estrogen therapy, suggesting a role for orexin antagonism as a treatment for the vasomotor symptom (VMS)-associated insomnia disorder. We tested the efficacy of the dual orexin receptor antagonist suvorexant for chronic insomnia related to nighttime VMS. Methods In a double-blind, placebo-controlled trial, 56 women with chronic insomnia associated with nighttime VMS, Insomnia Severity Index (ISI) scores ≥15, and >30 min of diary-rated wake after sleep-onset (WASO) were randomized to receive oral suvorexant 10–20 mg (n = 27) or placebo (n = 29) nightly for 4 weeks. Analysis of within-person change in ISI was adjusted for baseline ISI and race. Results Mean baseline ISI scores were 18.1 (95% CI, 16.8 to 19.4) and 18.3 (95% CI, 17.2 to 19.5) in the suvorexant and placebo groups, respectively (p = .81). The average 4-week ISI within-person decrease from baseline was greater on suvorexant (−8.1 [95% CI, −10.2 to −6.0]) compared to placebo (−5.6 [95% CI, −7.4 to −3.9], p = .04). Compared to placebo, nighttime diary-rated VMS frequency was significantly reduced with suvorexant (p < .01). While diary-rated WASO and total sleep time trended toward improvement on suvorexant, findings were not significant after adjustment for multiple comparisons. Daytime VMS and other sleep-related outcomes did not differ between groups. Suvorexant was well tolerated. Conclusion These results suggest that suvorexant is likely a well-tolerated and efficacious treatment for VMS-associated insomnia disorder and reduces nighttime VMS. Antagonism of orexin receptors could provide a novel therapeutic option for midlife women with VMS-associated chronic insomnia. Clinical Trial Information Efficacy of Suvorexant in the Treatment of Hot Flash-associated Insomnia, https://clinicaltrials.gov/ct2/show/NCT03034018, ClinicalTrials.gov Identifier: NCT03034018.

Insomnia is a significant, highly prevalent, persistent public health problem but often remains undiagnosed and untreated. Current treatment practices are not always evidence-based. When insomnia is comorbid with anxiety or depression, treatment often targets that comorbid condition with the expectation that improvement of the mental health condition will generalize to sleep symptoms. An expert panel of seven members conducted a clinical appraisal of the literature regarding the treatment of insomnia when comorbid anxiety or depression are also present. The clinical appraisal consisted of the review, presentation, and assessment of current published evidence as it relates to the panel’s predetermined clinical focus statement, “Whenever chronic insomnia is associated with another condition, such as anxiety or depression, that psychiatric condition should be the only focus of treatment as the insomnia is most likely a symptom of the condition”. The results from an electronic national survey of US-based practicing physicians, psychiatrists, and sleep (N = 508) revealed that >40% of physicians agree “at least somewhat” that treatment of comorbid insomnia should focus solely on the psychiatric condition. Whereas 100% of the expert panel disagreed with the statement. Thus, an important gap exists between current clinical practices and evidence-based guidelines and more awareness is needed so that insomnia is treated distinctly from comorbid anxiety and depression.

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.

OBJECTIVE/BACKGROUND: X-linked adrenoleukodystrophy (ALD) is a neurodegenerative disease that causes progressive gait and balance problems. Leg discomfort, sleep disturbances, and pain contribute to daily disability. We sought to investigate the prevalence and severity of Restless Legs Syndrome (RLS) in patients with ALD. PATIENTS/METHODS: We administered questionnaires and conducted diagnostic telephone interviews to assess RLS severity. We retrospectively extracted data from neurological examinations, functional gait measures, and laboratory assessments. RESULTS AND CONCLUSIONS: Thirty-two adults with ALD (21 female, 11 male) were recruited to participate. Thirteen patients (40.6%) had RLS (10/21 females and 3/11 males). The median age of RLS onset was 35 years [IQR = 22 – 54]. Patients with RLS had more signs and symptoms related to myelopathy, but not the brain demyelination seen in ALD. This pilot study suggests a high prevalence of RLS in adults with ALD, which may contribute to sleep problems and impair quality of life.

Objective/background No research has yet assessed the impact of the coronavirus disease 2019 (COVID-19) pandemic on restless legs syndrome (RLS). We hypothesized that RLS symptom severity would be increased during the COVID-19 pandemic in a sample of patients with diagnosed RLS. Patients/methods The National RLS Opioid Registry is a longitudinal observational study of patients using opioid medications for treatment of RLS. Questionnaires assessing RLS symptom severity, medication dosages, sleep disturbance, depression, and anxiety are administered at baseline and at recurring 6-month surveys. Survey responses from the outset of the pandemic in April/May 2020 were compared to responses completed by other participants in January/February 2020 (between-subjects analysis), as well as responses by the same participants at baseline, approximately six months later in September 2020 through February 2021, and approximately one year later in March through June 2021 (within-subjects analyses). Results These analyses provide evidence for higher RLS symptom severity scores at the outset of the COVID-19 pandemic in the US. Symptom severity scores were still elevated on subsequent questionnaires completed over six months into the pandemic but had returned towards baseline by the spring of 2021. Participants with increases in RLS severity were significantly more likely than others to see increases in sleep disturbance, depression, and anxiety. Conclusions This is the first study demonstrating increased RLS symptom severity during the earliest stage of the COVID-19 pandemic. These findings warrant similar investigations in other patient populations and suggest that clinicians should attend to RLS symptoms during times of socioeconomic and/or political uncertainty.

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.

Restless legs syndrome (RLS) has a high prevalence in the elderly and can impact sleep quality and sleep quantity, reduce quality of life (QoL), and increase the risk of falls during episodes of night-time ambulation. In patients unable to verbalize their sensory symptoms, certain behavioral cues may help with the diagnosis. A state of brain iron deficiency could play a central role in the pathophysiology of RLS and be upstream to a series of dysfunctions that are not limited to the dopaminergic system. Management should initially emphasize lifestyle modifications and reduction of all possible iatrogenic contributors while maintaining a state of normal–high peripheral iron stores. Oral iron, in patients with ferritin levels

The European guideline for the diagnosis and treatment of insomnia (1) was developed by a task force of the European Sleep Research Society, which was composed of 27 experts with clinical experience on insomnia management from different European countries and the European Insomnia Network. The guideline focused on insomnia disorder as defined by ICD-10/ICSD-3. Its starting point was the previously published guideline by the German Sleep Society, which was revised and expanded based on a review of relevant meta-analyses of insomnia therapies published through June 2016. The scope of this guideline was to provide recommendations on the treatment of chronic insomnia disorder. This guideline was selected for review by the World Sleep Society (WSS) Insomnia Task Force and the WSS International Sleep Medicine Guidelines Committee. A task force of content experts from the WSS has reviewed this guideline specifically for its relevance and applicability to the practice of sleep medicine by sleep specialists that comprise its membership.

Sleep disorders such as narcolepsy can cause excessive daytime sleepiness (EDS). The diagnosis of narcolepsy is often delayed by years. Clinicians can improve the recognition of EDS and diagnosis of sleep disorders using screening tools such as the Epworth Sleepiness Scale and other tests. By following up with patients who present with EDS and continuing to assess until a cause is found, clinicians can lessen the time to diagnosis and initiate appropriate treatment. Fortunately, existing pharmacologic interventions are effective in reducing EDS for many patients, but elimination of EDS for most patients has not been achieved. Some interventions also show efficacy in cataplexy. Nonpharmacologic strategies should also be discussed with patients. Clinicians must monitor EDS during ongoing treatment so that residual symptoms can be addressed. Research suggests a causative role for hypocretin deficiency in narcolepsy, and treatments ameliorating this deficiency are needed. ​.

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, 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.

This systematic review and meta-analysis evaluated the diagnostic accuracy of screening instruments for restless legs syndrome (RLS) and reports sensitivity, specificity, positive (PPV) and negative predictive values (NPV). Searches for primary studies were conducted in electronic databases. Of the 1541 citations identified, 52 were included in the meta-analysis. The methodological quality of each study was evaluated using QUADAS-2. Only 14 studies assessed the reference standard in all participants or in all screen-positives and a selection of screen-negatives. Bivariate meta-analysis of these 14 studies estimated median sensitivity to be 0.88 (0.72-0.96) and specificity 0.90 (0.84-0.93); based on a population prevalence of 5%, the calculated PPV was 0.31 (0.27-0.34). For all 52 studies, with either full or partial verification of RLS status, we constructed best-case scenario sensitivities and specificities at pre-defined levels of prevalence: across all samples, when prevalence is 5%, the median best-case scenario PPV is 0.48 with significant between-study heterogeneity. No RLS screening instruments can currently be recommended for use without an expert clinical interview in epidemiological studies. For conditions with statistically low prevalence such as RLS, the specificity, not the sensitivity, of a screening instrument determines true prevalence. Therefore, future instruments should maximize specificity. We provide guidelines on RLS ascertainment in epidemiological studies that requires a two-step process with clinical interview following a screening test, and given the poor reporting quality of many RLS epidemiological studies, we include an RLS reporting checklist.

Restless legs syndrome (RLS) is a common disorder. The population prevalence is 1.5% to 2.7% in a subgroup of patients having more severe RLS with symptoms occurring 2 or more times a week and causing at least moderate distress. It is important for primary care physicians to be familiar with the disorder and its management. Much has changed in the management of RLS since our previous revised algorithm was published in 2013. This updated algorithm was written by members of the Scientific and Medical Advisory Board of the RLS Foundation based on scientific evidence and expert opinion. A literature search was performed using PubMed identifying all articles on RLS from 2012 to 2020. The management of RLS is considered under the following headings: General Considerations; Intermittent RLS; Chronic Persistent RLS; Refractory RLS; Special Circumstances; and Alternative, Investigative, and Potential Future Therapies. Nonpharmacologic approaches, including mental alerting activities, avoidance of substances or medications that may exacerbate RLS, and oral and intravenous iron supplementation, are outlined. The choice of an alpha2-delta ligand as first-line therapy for chronic persistent RLS with dopamine agonists as a second-line option is explained. We discuss the available drugs, the factors determining which to use, and their adverse effects. We define refractory RLS and describe management approaches, including combination therapy and the use of high-potency opioids. Treatment of RLS in pregnancy and childhood is discussed.

Sleep disorders such as narcolepsy can cause excessive daytime sleepiness (EDS). However, the diagnosis of narcolepsy is often delayed by years in both children and adults, reducing their quality of life. Clinicians can improve the recognition of EDS and diagnosis of sleep disorders using screening tools such as the Epworth Sleepiness Scale, collecting sleep histories, and using sleep laboratory tests. By following up with patients who present with EDS and continuing to assess until a cause is found, clinicians can lessen the time to diagnosis and the negative impact of narcolepsy by initiating appropriate treatment.

Background Venous thromboembolism (VTE) is a life-threatening disease, and some studies reported that benzodiazepine receptor agonist (BZRA) use could increase the risk of VTE, but this association lacks population-based evidence. Objectives To investigate the association between BZRA use and the risk of VTE. Patients/methods A nested case-control study analyzing Taiwan's claims database was conducted of patients with at least one new BZRA prescription on record from January 1, 2002, to December 31, 2012. We included new users who did not have any BZRA prescriptions in the preceding 2 years and identified cases with VTE and disease risk score matched control subjects. We used a logistic regression model to investigate the association between BZRA exposure and the risk of VTE. The exposure duration, dose, and classes of BZRAs were comprehensively evaluated. Results We identified 2800 VTE cases and 2800 matched controls. Current BZRA prescription (≤90 days) was associated with VTE occurrence (adjusted odds ratio [aOR]: 1.83; 95% confidence interval [CI], 1.62-2.06). The point estimates of benzodiazepine hypnotics (aOR: 2.00; 95% CI, 1.45-2.76) had a marginally higher risk of VTE than nonbenzodiazepine hypnotics (aOR: 1.39; 95% CI, 1.07-1.81). The VTE risk was increased with combination BZRA use, number of BZRA used, and a higher dose of BZRA. On examination of individual BZRA, the risk of VTE was higher with flunitrazepam use (aOR: 2.99; 95% CI, 1.43-6.28) than other BZRAs. Conclusions This study presents that current BZRA use may increase the risk of VTE. Also, benzodiazepine hypnotics, especially flunitrazepam, have a higher risk of VTE.

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

We aimed to identify the sleep electroencephalography (EEG) spectral power correlates of the subjective-objective discrepancy (SOD) of sleep onset latency (SOL) in major depressive disorder (MDD), primary insomnia (PI), and normal sleeping control (NSC) groups. We examined relative power values in standard frequency bands of the EEG spectra during the first Non-Rapid Eye Movement (NREM) sleep period as correlates of SOD of SOL between sleep diary and polysomnography in MDD (n = 36), PI (n = 19), and NSC (n = 23) groups. We also compared the relative spectral power of sleep EEG among MDD (n = 40), PI (n = 19), and NSC (n = 23) groups. SOD of SOL in MDD patients was positively correlated with relative sigma (r = 0.622, p corrected 0.001), beta power (r = 0.559, p corrected = 0.002), and alpha power (r = 0.469, p corrected = 0.024) in the first NREM sleep period. There was no significant difference of sleep EEG power spectra among the three groups. SOD was positively correlated with high frequency EEG in MDD. High frequency EEG power is thought to be associated with hyperarousal and memory consolidation, and future larger-scale studies may further elucidate the neurophysiological mechanisms underlying SOD of sleep onset duration.

The objective of the current review was to update the previous evidence-based medicine review of treatments for restless legs syndrome published in 2008. All randomized, controlled trials (level I) with a high quality score published between January 2007 and January 2017 were reviewed. Forty new studies qualified for efficacy review. Pregabalin, gabapentin enacarbil, and oxycodone/naloxone, which did not appear in the previous review, have accrued data to be considered efficacious. Likewise, new data enable the modification of the level of efficacy for rotigotine from likely efficacious to efficacious. Intravenous ferric carboxymaltose and pneumatic compression devices are considered likely efficacious in idiopathic restless legs syndrome. Bupropion and clonidine were reviewed, but the lack of data determined a rating of insufficient evidence for efficacy. The following interventions continue to be considered efficacious as in 2008: levodopa, ropinirole, pramipexole, cabergoline, pergolide, and gabapentin. Bromocriptine, oxycodone, carbamazepine, and valproic acid are considered likely efficacious. Oral iron is nonefficacious in iron-sufficient subjects, but its benefit for patients with low peripheral iron status has not been adequately evaluated. Restless legs syndrome augmentation has been identified as a significant long-term treatment complication for pramipexole more than pregabalin and possibly for all dopaminergic agents more than α2δ ligands. Therefore, special monitoring for augmentation is required for all dopaminergic medications as well as tramadol. Other drugs also require special safety monitoring: cabergoline, pergolide, oxycodone, methadone, tramadol, carbamazepine, and valproic acid. Finally, we also highlighted gaps and needs for future clinical research and studies of restless legs syndrome. © 2018 International Parkinson and Movement Disorder Society.

Background The relationship between the use of benzodiazepine-receptor agonists (BZRAs) and the risk of hospitalization for pneumonia remains inconclusive. This study aimed to explore the association between BZRA use and hospitalization for pneumonia in a general population. Methods This population-based nested case-control study used Taiwan's National Health Insurance Research Database between 2002 and 2012. We included only new users who did not have any BZRA prescriptions on record in the preceding 2 years and identified 12,002 subjects who were hospitalized for pneumonia (International Classification of Diseases, Ninth Revision codes 480-486, and 507) and 12,002 disease risk score-matched control subjects. A logistic regression model was used to determine the association of BZRA use and hospitalization for pneumonia. The exposure date, dose-response relationship, and class of BZRAs were comprehensively assessed. Results Current BZRA exposure was associated with hospitalization for pneumonia (adjusted OR [aOR],1.86; 95% CI, 1.75-1.97). Benzodiazepine hypnotic agents (aOR, 2.42; 95% CI, 2.16-2.71) had a higher risk of pneumonia than did benzodiazepine anxiolytic agents (aOR, 1.53; 95% CI, 1.44-1.63) or nonbenzodiazepine hypnotic agents (aOR, 1.60; 95% CI, 1.46-1.76). The pneumonia risk was increased with ultrashort-acting and short- to intermediate-acting agents, a higher defined daily dose, and the number of BZRAs used. Among individual BZRAs examined, midazolam had a higher risk (aOR, 5.77; 95% CI, 4.31-7.73) of hospitalization for pneumonia than did the others. Conclusions This study suggests that there is a dose-response relationship between current BZRA use and the risk of hospitalization for pneumonia. In addition, benzodiazepine hypnotic agents, especially midazolam, present a greater risk of hospitalization for pneumonia. These findings reinforce the importance of a careful analysis of the benefits vs the risks of BZRA use.

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.

Introduction Restless Legs Syndrome (RLS) is a sensory-motor neurological disorder which is associated with sleep disturbance and emotional distress. Opioid medications are effective treatments for RLS, and a high percentage of patients undergoing opioid withdrawal exhibit symptoms of RLS. Despite the known connection between RLS and opioids, there has been no assessment of RLS in patients actively treated with buprenorphine and naloxone for opioid use disorder (OUD). Methods We conducted a study to determine the prevalence of RLS among patients with OUD at an outpatient buprenorphine and naloxone clinic at Lemuel Shattuck Hospital in Jamaica Plain, Massachusetts. With the help of nurses, participants completed questionnaires which inquired about demographic information, previous opioid use, current medications, and RLS. Patients were categorized as having RLS if, according to the Cambridge-Hopkins Questionnaire, they answered positively to the four essential RLS criteria and if common mimics were not endorsed. A final determination of RLS status in those with ambiguous answers to RLS mimics was made by a trained sleep medicine physician (JWW). Results Participants (n=129) were primarily male (n=86; 66.7%), white (n=101; 78.3%), and the median age was 37.5 years. Approximately half of the sample (n=59; 45.7%) used medications for depression and/or anxiety. The median duration of buprenorphine and naloxone use was 3 years. 13.2% were judged to have RLS. RLS symptoms tended to be of moderate severity, disturb sleep to a moderate degree, and occur 5–15 days per month. There were no significant demographic or clinical differences in those with and without RLS. Of the 103 participants without suspected RLS, 15.5% (n=16) were taking a non-opioid medication known to treat RLS symptoms (e.g. gabapentin). Only 1/17 people (5.9%) with RLS were taking a treatment that would control such symptoms. Conclusion Approximately 13% of this sample currently taking buprenorphine and naloxone for OUD had RLS. RLS can greatly interfere with sleep and quality of life, and those with untreated or partially treated symptoms may be motivated to use unprescribed opioids to control them. With this in mind, clinicians treating OUD should be aware that there are effective non-opioid medications that can treat RLS. Support (if any)

Restless legs syndrome (RLS) is a sensorimotor neurologic disorder characterized by an unpleasant urge to move the legs, often accompanied by leg dysesthesias. Symptoms predominate in the evening or at night and often cause significant distress and disruption of sleep. Several non-opioid classes of drugs provide initial relief from the symptoms of RLS. Among these, however, the efficacy of dopamine agonists can wane over time or even paradoxically 'augment' the severity of symptoms during the course of long-term treatment. Opioids can alleviate RLS symptoms, even in patients who have become refractory to, or do not tolerate, other drugs. In a carefully selected group of patients with severe RLS that has not been effectively managed with other therapies, opioids may be an appropriate treatment.

Patients with simple snoring (SS) often complain of poor sleep quality despite a normal apnoea-hypopnoea index (AHI). We aimed to identify the difference in power spectral density of electroencephalography (EEG) between patients with SS and those with obstructive sleep apnoea (OSA). We compared the absolute power spectral density values of standard EEG frequency bands between the SS (n = 42) and OSA (n = 129) groups during the non-rapid eye movement (NREM) sleep period, after controlling for age and sex. We also analysed partial correlation between AHI and the absolute values of the EEG frequency bands. The absolute power spectral density values in the beta and delta bands were higher in the OSA group than in the SS group. AHI also positively correlated with beta power in the OSA group as well as in the combined group (OSA + SS). In conclusion, higher delta and beta power during NREM sleep were found in the OSA group than in the SS group, and beta power was correlated with AHI. These findings are microstructural characteristics of sleep-related breathing disorders.

Key Points Questions Is restless legs syndrome associated with a high risk of suicide and self-harm? Findings In a cohort study that included 169 373 participants, individuals with restless legs syndrome had a higher risk of suicide and self-harm compared with age- and sex-matched participants without restless legs syndrome, and the increased risk was independent of common diseases and conditions. Meaning Restless legs syndrome was associated with an increased risk of suicide and self-harm., This cohort study of commercially insured US individuals examines the association between restless legs syndrome and risk of suicide and self-harm., Importance Restless legs syndrome (RLS) is a common neurologic disorder that has been previously found to be associated with higher odds of suicidal ideation. In the context of the increasing suicide rate in the United States, the evidence regarding the association between RLS and the risk of suicide and self-harm is limited. Objective To investigate the association between RLS and risk of suicide and self-harm. Design, Setting, and Participants This cohort study was performed using Truven Health MarketScan national claims data from 2006 to 2014; the baseline data were from 2006 to 2008, and the follow-up data covered 6 years (January 1, 2009, to December 31, 2014). Included were 24 179 nonpregnant participants with RLS and 145 194 age- and sex-matched participants without RLS at baseline (2006-2008), who were free of suicide, self-harm, cardiovascular disease, or cancer at study baseline. Data analysis was performed from February 1, 2018, to January 1, 2019. Exposure Diagnosis of RLS, as identified by the International Classification of Diseases, Ninth Revision code. Main Outcomes and Measures Incident suicide and self-harm event, identified by the International Classification of Diseases, Ninth Revision diagnosis code. Results Among 169 373 participants in the current analysis, the mean (SD) age was 49.4 (9.1) years; 53 426 (31.5%) participants were men. During a mean (SD) follow-up duration of 5.2 (2.2) years, 119 incident suicide and self-harm cases were identified. Individuals with RLS had a higher risk of suicide or self-harm compared with those without RLS (adjusted hazard ratio, 2.66; 95% CI, 1.70-4.15), after adjusting for lifestyle factors (eg, alcohol and obesity), presence of chronic diseases (eg, depression, insomnia, diabetes, chronic kidney disease, peripheral neuropathy, iron-deficiency anemia, and Parkinson disease), and use of medications. Excluding those with depression, insomnia, obstructive sleep apnea, and other common chronic conditions, the significant association between RLS and suicide or self-harm persisted (adjusted hazard ratio, 4.14; 95% CI, 2.17-7.92). Conclusions and Relevance Restless legs syndrome was associated with a high risk of suicide and self-harm, and the risk was independent of most identified diseases and conditions.

Study ObjectivesBoth periodic limb movements during sleep (PLMS) and arousals are associated with sympathetic nervous system activation and may be arrhythmogenic. We hypothesize a temporal relationship exists between individual PLMS, particularly with arousal, and nonsustained ventricular tachycardia (NSVT) events.MethodsA bidirectional time-stratified case-crossover design was used to assess temporal associations between PLMS and NSVT during sleep in 49 Osteoporotic Fractures in Men Sleep Study participants with NSVT in a community-based cohort (n = 2,911). Sleep time was divided into approximate 30-min segments. For each NSVT (n = 141), we selected a preceding 30-s hazard period and three randomly chosen 30-s control periods from sleep within the same segment and evaluated for PLMS, respiratory events, minimum saturation, and arousals. Odds ratios and 95% confidence intervals—OR (95% CI)—were determined by conditional logistic regression; covariates included EEG arousals, minimum saturation, and respiratory events in the same hazard/control period.ResultsParticipants with NSVT were 79.5 ± 6.2 years with a PLMS index of 32.1 (IQR: 10.1, 61.4) and apnea–hypopnea index of 17.1 (IQR: 9.4, 26.1). PLMS without arousal were not significantly associated with NSVT (OR = 0.80, 95% CI: 0.41–1.59). PLMS with arousal were associated with NSVT in unadjusted analyses (OR = 2.50, 95% CI: 1.11–5.65) and after adjustment (OR = 2.31, 95% CI: 1.02–5.25). Arousals associated with PLMS were associated with NSVT in unadjusted (OR = 2.84, 95% CI: 1.23–6.56) and adjusted analyses (OR = 2.61, 95% CI: 1.13–6.05).ConclusionsPLMS with (but not without) arousals are temporally associated with a greater than twofold higher odds of subsequent NSVT episodes. PLMS-related arousals may be physiologically important ventricular arrhythmia triggers.Clinical Trial RegistrationClinicalTrials.gov, NCT00070681.

Introduction Augmentation is a management dilemma in RLS patients on dopaminergic therapy. Understanding the clinical characteristics of such patients may assist in better management strategies. Methods Consecutive new consultations for RLS from 4/2016-6/2020 were identified from a single tertiary referral center in Boston, USA. Patients were included in this analysis if they had augmentation and current treatment with a dopamine agonist. Clinical information from initial consultation was collected. RLS severity at time of consultation was determined retrospectively with a modified IRLSSG severity score (0–12), assessing RLS symptom frequency (0–4), duration (0–4), and severity (0–4). Results Out of 209 referrals with RLS, 105 patients had augmentation, of whom 88 were on dopamine agonists at initial evaluation. Average age was 67 years (SD 11 years, range 39–88); 62 were female (59%). Mean duration of RLS symptoms was 27 years (SD 20), and 91% had symptoms > 10 years. Mean duration of dopamine agonist therapy was 11 years; 72% had previously been treated with pramipexole, 65% with ropinirole, 73% with rotigotine, and 16% with levodopa; 72% of patients had been treated with alpha-2-delta ligands, and 28% with opioids. Common comorbidities included obstructive sleep apnea (47%), obesity (49%), and depression (44%). Serotonergic medications were currently used by 25%. Of the 88 augmented patients on dopamine agonist therapy, 97% had earlier onset of symptoms and 33% had symptoms in both morning and afternoon; 53% reported anatomical extension. The mean modified IRLSSG score was 8.4 (SD 3.2). 66% of patients had either ferritin Conclusion Higher than FDA-recommended dopamine agonist dosing and high prevalence of iron deficiency in patients with augmented RLS represent a treatment gap in the care of RLS patients in the community. Controlled studies of guideline-based therapy are indicated to determine optimal management of augmented RLS. Support (if any) Baszucki Brain Research Fund

Introduction Restless Legs Syndrome (RLS) is a sensory-motor neurological disorder which is associated with sleep disturbance and emotional distress. Low dose opioid medications are prescribed for treatment-refractory RLS. We now report two-year longitudinal data from the National RLS Opioid Registry, a national sample of patients using opioids for RLS. Methods Individuals (n=500) taking a prescribed opioid for diagnosed RLS were enrolled in the registry from 12/2017–9/2019. Information on initial and current opioid dosages, side effects, past and current RLS treatments, and RLS severity was collected by interview at baseline. Follow-up online surveys were performed at six-month intervals for two years. Results At the time of analysis, 325 participants had reached two years since enrollment and completed the two-year survey (retention rate=95.3%). There were no mean changes from baseline in RLS symptom severity, sleep, or mood measures. Opioid dose changes from baseline to one- and two-year follow-up were: unchanged (51.2%, 43.1%), increased dose (29.7%, 36.7%), decreased dose (19.1%, 20.2%). Only 7.9% of participants increased dose from baseline at both one and two years. The median dose increase from baseline to two-years was just 10 morphine milligram equivalents (MME). Dose increases of >25 MME occurred in 7.3% of participants (vs 5.2% at one-year) and were independently associated with use of an opioid for a comorbid pain condition in addition to RLS (OR 5.91, p=0.02), discontinuing a non-opioid RLS medication (OR 4.26, p=0.01), and age of 55 or younger at baseline (OR 3.60, p=0.01). Being on an opioid medication for Conclusion Prescribed opioid doses remained relatively stable over the two years following enrollment into the registry. Of the 37% of participants that increased dose, over half increased by 10 MME or less. Individuals at the start of opioid treatment for RLS do not see elevated rates of dose increase past the first year of use. Future longitudinal data will improve our understanding of the efficacy and tolerability of opioids for RLS. Support (if any) The RLS Foundation, Baszucki Brain Research Fund, Florence Petrlik Family Foundation, Diane and Richard Brainerd, and Steven Silin

Background We examined the short- and long-term efficacy and tolerability of a cross-titration algorithm from oral dopamine agonists to the rotigotine transdermal patch in patients dissatisfied with their restless legs syndrome (RLS) treatment, predominantly with mild augmentation. Methods Patients with RLS ( n = 20) were recruited at a single site. The cross-titration consisted of decreasing oral dopaminergic agents (ropinirole by 1 mg or pramipexole by 0.25 mg) and increasing rotigotine by 1 mg every two days. Efficacy and adverse events (AEs) were assessed at one, three, six and 12 months after the switch. Results Patients had moderate–severe RLS symptoms at the baseline (mean international restless legs syndrome (IRLS) score 19.4 ± 5.5); 85% had augmentation and 45% reported afternoon RLS symptoms. The baseline mean pramipexole equivalent dose was 0.6 ± 0.3 mg. At Week 5, 85% (17/20) had successfully switched from their oral dopamine agonist to rotigotine (mean dose 2.5 ± 0.6 mg; change in IRLS score: −6.7 ± 8.4, p = 0.002); 14 patients were CGI-I responders (much or very much improved). Three patients withdrew due to lack of efficacy. Twelve months after cross-titration, 10 patients continued on rotigotine, of whom four required either higher doses of rotigotine or supplemental RLS medication compared with their optimal Week 5 dose; five patients withdrew due to AEs and two due to lack of efficacy. Conclusion A cross-titration to rotigotine was efficacious after five weeks in 70% of patients dissatisfied with RLS treatment, most of whom had mild augmentation. At one year following the medication switch, 50% had discontinued rotigotine due to lack of continued efficacy or side effects.

STUDY OBJECTIVES To examine whether patients with restless legs syndrome demonstrate specific alterations in cardiovascular autonomic control. METHODS Patients with moderate-severe restless legs syndrome (n = 20, 80% female) and controls (n = 20) matched for age, sex, body mass index, and free of hypertension and cardiovascular disease were enrolled. We assessed cardiovagal baroreflex gain via the modified Oxford technique, sympathetically mediated vascular responses to isometric exercise to fatigue, bradycardiac response to Valsalva maneuver, and respiratory sinus arrhythmia during paced breathing. Standard electrocardiography, beat-by-beat arterial pressure, respiration, and popliteal blood flow velocity were recorded continuously. RESULTS Resting blood pressure and heart rate were similar between groups. However, baroreflex gain averaged 14.3 ± 1.4 msec/mm Hg in restless legs syndrome and was lower than in controls (22.6 ± 3.5 msec/mm Hg, P = 0.04). Hemodynamic responses to isometric exercise were similar between groups, though participants with restless legs syndrome had lower leg blood flow (P < 0.001), with greater leg vascular resistance (P < 0.0001), before and during isometric exercise. Respiratory sinus arrhythmia and Valsalva ratios were similar between groups. Neither baroreflex gain nor vascular resistance was correlated with sleep duration, sleep quality, or symptom duration. CONCLUSION Patients with restless legs syndrome demonstrate compromised cardiovagal control, specific to the arterial baroreflex, with greater peripheral vascular resistance, potentially due to heightened sympathetic outflow. These autonomic alterations may directly relate to the higher prevalence of cardiovascular disease in restless legs syndrome.

Introduction Dopamine agonists (DAs) have been first-line therapy for restless legs syndrome (RLS) for 30 years. Long-term DA use is associated with augmentation, a dose-related iatrogenic worsening of RLS, which results in a vicious cycle of escalating DA dosing to manage worsening symptoms. The objective of this study was to investigate rates of high-dose DA prescribing in patients with RLS nationally. Methods Patients with a diagnosis of RLS (ICD-10 G255.81), and no diagnosis of Parkinson’s disease, treated with rotigotine, pramipexole, and ropinirole, alone or in combination for >180 days, were identified from National Prescription Audit database from October 2017-September 2018. Daily total dosage was grouped into low (FDA-approved) and high (above FDA-approved) dose ranges, respectively (rotigotine: >0-≤3mg/>3mg; pramipexole: >0-≤0.75mg/>0.75mg; ropinirole: >0-≤4mg/>4mg). When DAs were used in combination with each other, dose-equivalent algorithms were used (rotigotine/ropinirole/pramipexole, 1:1:4). Results Prescriptions for 244,423 patients meeting inclusion criteria were sampled, constituting 71,181,466 therapy days. For all patients on DA therapy for RLS, 23.5% (57,552/244,423) were prescribed higher than FDA-recommended doses. For patients on DA monotherapy, high-dose prescriptions were provided to 42.7% (819/1919) on rotigotine, 40.7% (38,342/94,275) on pramipexole, and 11.5% (16,900/146,355) on ropinirole. Nearly one-quarter (23.2%) of all pramipexole monotherapy prescriptions were for very high dosages (>1.25 mg). For patients on DA combination therapy, high-dose prescriptions were provided to 79.6% (1,491/1,874). Conclusion Roughly 25% of RLS patients treated with DAs were prescribed doses above FDA and expert guideline-recommended maximum doses. Patients on DA combination therapy had substantially higher rates of cumulative high-dose prescriptions. High-dosage DA use is likely due to dose escalation in response to augmentation, risking further augmentation and adverse events such as impulse control disorders. Prescriber education on risks of high-dose DA prescribing for RLS is important. Support Arbor Pharmaceuticals, LLC