Relationship of suboptimal and disordered sleep with cardiovascular disease and its risk factors - a narrative review.

Cardiovascular disease (CVD), including coronary heart disease and cerebrovascular disease, is already amongst the leading causes of morbidity and mortality worldwide, but its burden continues to rise. Over time, relevant risk factors for CVD have been identified, many of which are modifiable. More recently, the relationship of sleep and CVD has been of interest, specifically increased rates of disrupted and disordered sleep, which have been found to be associated with CVD. Longitudinal studies have linked sleep difficulties to a predisposition of vascular risk factors, suggesting a potential role for sleep improvement in primary and secondary CVD. In the present narrative review article, we summarize the current body of research linking suboptimal sleep (e.g. short/long sleep, fragmented sleep) as well as non-breathing-related sleep disorders (i.e. insomnia, restless legs syndrome/peripheral leg movements of sleep, narcolepsy) to modifiable CVD risk factors and CVD outcomes (morbidity and mortality).

Healthy Sleep Practices for Consumers of Home Total Parenteral Nutrition: A Mixed-Methods Community-Based Participatory Study.

Background: Consumers of overnight home parenteral nutrition (HPN) often experience sleep disruption; however, existing healthy sleep recommendations are widely inapplicable to consumers. Objectives: The aim of this mixed-methods, community-based participatory research study was to develop tailored recommendations on healthy sleep practices for HPN consumers. Methods: The multipart study involved the following: 1) an initial draft of sleep recommendations based on the evaluation of existing general sleep hygiene guidelines by an expert panel of clinicians and consumers with lived experience; 2) semi-structured focus groups with consumers and clinicians; 3) pre- and post-knowledge tests completed by consumers, and 4) final approval of the recommendations by the expert panel. Results: The literature synthesis resulted in 51 recommendations evaluated for relevance for HPN consumers. Focus groups with 20 HPN consumers and clinicians contributed additional recommendations based on lived experience. Ultimately, the final resource included recommendations spanning 4 sections: getting ready for bed, preparing the bedroom for sleep, daytime behaviors, and overall strategies for better sleep. Of the 36 recommendations, 58% were derived from existing general sleep hygiene guidelines, and the remaining 42% addressed sleep challenges experienced uniquely by consumers, including nocturnal polyuria, noise/light from medical equipment, and infusion schedules. Knowledge tests completed by 10 additional consumers indicated a modest increase in sleep health knowledge. Conclusions: The curated healthy sleep resource tailored for HPN consumers was facilitated by a multidisciplinary expert panel, a strategic collaboration with members of the HPN community and their clinicians, and in partnership with patient advocacy and support organizations. The wide distribution of these resources may improve the overall well-being of HPN consumers.

Improvement in sleep latency with extended-release once-nightly sodium oxybate for the treatment of adults with narcolepsy: Analysis from the phase 3 REST-ON clinical trial.

Background: In the REST-ON clinical trial (NCT02720744), mean sleep latency on the Maintenance of Wakefulness Test (MWT) was significantly improved with extended-release once-nightly sodium oxybate (ON-SXB) vs placebo (P < 0.001) in participants with narcolepsy. This post hoc analysis assessed response to treatment and improvement in excessive daytime sleepiness. Methods: Participants with narcolepsy aged ≥16 years were randomized 1:1 to receive ON-SXB (4.5 g, week 1; 6 g, weeks 2-3; 7.5 g, weeks 3-8; and 9 g, weeks 9-13) or placebo. Mean sleep latency on the MWT was measured across 5 trials of ≤30 min each. Post hoc assessments included percentage of participants whose sleep latency improved ≥5, ≥10, ≥15, and ≥20 min and with a mean sleep latency of 30 min. Results: Significantly more participants receiving ON-SXB vs placebo experienced increased mean sleep latency ≥5 min (all doses P < 0.001), ≥10 min (all doses P < 0.001), ≥15 min (6 and 7.5 g, P < 0.001; 9 g, P < 0.01), and ≥20 min (6 g, P < 0.01; 7.5 g, P < 0.001; 9 g, P < 0.05). More participants receiving ON-SXB had mean sleep latency of 30 min vs placebo (6 g, 5.7 % vs 0 %, respectively [P < 0.05]; 7.5 g, 10.5 % vs 1.3 % [P < 0.05]; 9 g, 13.2 % vs 5.1 % [P = 0.143]). Conclusions: Significantly more participants who received ON-SXB experienced increased mean sleep latency ≥5 to ≥20 min; at the 2 highest doses, >10 % remained awake for the entirety of the MWT. ON-SXB offers a once-at-bedtime treatment option for adults with narcolepsy.

Clinical Efficacy and Safety of Intravenous Ferric Carboxymaltose for Treatment of Restless Legs Syndrome: A Multicenter, Randomized, Placebo-controlled Clinical Trial.

STUDY OBJECTIVES: Iron therapy is associated with improvements in restless legs syndrome (RLS). This multicenter, randomized, double-blind study evaluated the effect of intravenous ferric carboxymaltose (FCM) on RLS. METHODS: A total of 209 adult patients with a baseline International Restless Legs Syndrome (IRLS) score ≥15 were randomized (1:1) to FCM (750 mg/15 mL) or placebo on study Days 0 and 5. Ongoing RLS medication was tapered starting on Day 5, with the goal of discontinuing treatment or achieving the lowest effective dose. Co-primary efficacy endpoints were change from baseline in IRLS total score and the proportion of patients rated as much/very much improved on the Clinical Global Impression-investigator (CGI-I) scale at Day 42 in the "As-Treated" population. RESULTS: The "As-Treated" population comprised 107 FCM and 101 placebo recipients; 88 (82.2%) and 68 (67.3%), respectively, completed the Day 42 assessment. The IRLS score reduction was significantly greater with FCM versus placebo: least-squares mean (95% confidence interval [CI]) -8.0 (-9.5, -6.4) versus -4.8 (-6.4, -3.1); P = 0.0036. No significant difference was observed in the proportion of FCM (35.5%) and placebo (28.7%) recipients with a CGI-I response (odds ratio 1.37 [95% CI: 0.76, 2.47]; P = 0.2987). Fewer patients treated with FCM (32.7%) than placebo (59.4%) received RLS interventions between Day 5 and study end (P = 0.0002). FCM was well tolerated. CONCLUSION: The IRLS score improved with intravenous FCM versus placebo, although the combination of both co-primary endpoints was not met. Potential methodological problems in the study design are discussed.

The Role of Circadian Rhythms and Sleep in Anorexia Nervosa.

Importance: Observational studies have associated anorexia nervosa with circadian rhythms and sleep traits. However, the direction of causality and the extent of confounding by psychosocial comorbidities in these associations are unknown. Objectives: To investigate the association between anorexia nervosa and circadian and sleep traits through mendelian randomization and to test the associations between a polygenic risk score (PRS) for anorexia nervosa and sleep disorders in a clinical biobank. Design, Setting, and Participants: This genetic association study used bidirectional 2-sample mendelian randomization with summary-level genetic associations between anorexia nervosa (from the Psychiatric Genomics Consortium) and chronotype and sleep traits (primarily from the UK Biobank). The inverse-variance weighted method, in addition to other sensitivity approaches, was used. From the clinical Mass General Brigham (MGB) Biobank (n = 47 082), a PRS for anorexia nervosa was calculated for each patient and associations were tested with prevalent sleep disorders derived from electronic health records. Patients were of European ancestry. All analyses were performed between February and August 2023. Exposures: Genetic instruments for anorexia nervosa, chronotype, daytime napping, daytime sleepiness, insomnia, and sleep duration. Main Outcomes and Measures: Chronotype, sleep traits, risk of anorexia nervosa, and sleep disorders derived from a clinical biobank. Results: The anorexia nervosa genome-wide association study included 16 992 cases (87.7%-97.4% female) and 55 525 controls (49.6%-63.4% female). Genetic liability for anorexia nervosa was associated with a more morning chronotype (ß = 0.039; 95% CI, 0.006-0.072), and conversely, genetic liability for morning chronotype was associated with increased risk of anorexia nervosa (ß = 0.178; 95% CI, 0.042-0.315). Associations were robust in sensitivity and secondary analyses. Genetic liability for insomnia was associated with increased risk of anorexia nervosa (ß = 0.369; 95% CI, 0.073-0.666); however, sensitivity analyses indicated bias due to horizontal pleiotropy. The MGB Biobank analysis included 47 082 participants with a mean (SD) age of 60.4 (17.0) years and 25 318 (53.8%) were female. A PRS for anorexia nervosa was associated with organic or persistent insomnia in the MGB Biobank (odds ratio, 1.10; 95% CI, 1.03-1.17). No associations were evident for anorexia nervosa with other sleep traits. Conclusions and Relevance: The results of this study suggest that in contrast to other metabo-psychiatric diseases, anorexia nervosa is a morningness eating disorder and further corroborate findings implicating insomnia in anorexia nervosa. Future studies in diverse populations and with subtypes of anorexia nervosa are warranted.

Restless legs syndrome, neuroleptic-induced akathisia, and opioid-withdrawal restlessness: shared neuronal mechanisms?

Restlessness is a core symptom underlying restless legs syndrome (RLS), neuroleptic-induced akathisia, and opioid withdrawal. These three conditions also share other clinical components suggesting some overlap in their pathophysiology. Recent prospective studies demonstrate the frequent incidence of RLS-like symptoms during opioid withdrawal and supervised prescription opioid tapering. Based on the therapeutic role of µ-opioid receptor (MOR) agonists in the three clinical conditions and recent preclinical experimental data in rodents, we provide a coherent and unifying neurobiological basis for the restlessness observed in these three clinical syndromes and propose a heuristic hypothesis of a key role of the specific striatal neurons that express MORs in akathisia/restlessness.

Lack of Efficacy of Suvorexant in People with Insomnia and Poorly Controlled Type 2 Diabetes.

Objective/Background: Sleep disturbance is a common and underappreciated feature of diabetes and sleep may contribute to glycemic control in people with type 2 diabetes (T2D). We conducted a 3-month trial to examine the efficacy of suvorexant in improving sleep and health outcomes in people with suboptimally controlled T2D and insomnia. Participants/Methods: This parallel, double-blind, randomized placebo-controlled trial was conducted using the sequential parallel comparison design (SPCD). Sixty-nine people with poorly controlled T2D (HbA1c ≥ 6.5) were randomized to placebo and/or suvorexant (10-20 mg). The primary outcome was subjective total sleep time (sTST), and secondary outcomes were Insomnia Severity Index (ISI) score and wake time after sleep onset (WASO). Exploratory outcomes included sleep efficiency, hemoglobin A1c (HbA1c), and C-reactive protein (CRP). Exploratory analyses were conducted on relationships between sleep and diabetes outcomes. Results: There were no significant improvements in sTST (p = 0.27), ISI (p = 0.86), or WASO (p = 0.94) among participants taking suvorexant compared to placebo. There were also no significant changes in any of the exploratory endpoints. Improvements in sleep were associated with improvements in both objective (ie, HbA1c) and subjective (ie, Diabetes Distress Scale) measures of diabetes, as well as reductions in depressive symptoms, independent of treatment assignment. Conclusion: The study did not find evidence that suvorexant is efficacious for insomnia in people with poorly controlled T2D. The associations of improved sleep with improvements in both diabetes-related metrics and depressive symptoms across groups highlight the importance of identifying and treating sleeping difficulties in this population. CT Registration #: Nct03818581.

Insomnia and treatment-resistant depression.

Depression and sleep disturbance are related closely with bidirectional relationship. The heterogenic diagnostic criteria of major depressive disorder composed by the myriad combination of symptoms including sleep disturbance. Insomnia is an identifiable risk factor for depression and the treatment of insomnia might be able to prevent subsequent major depressive episodes which draws psychiatrists' attention to the interface of psychiatry and sleep medicine field. It is important to identify occult sleep disturbance in patients with treatment-resistant depression to improve treatment outcome. New tools to objectively measure sleep at home environment represent a great march in clinical care and research modalities but need further validation before they can be applying widespread at sleep and depression intersection. Careful evaluation and measurement of the phenotype and nature of sleep disturbance will continue to advance understanding of the biological bases of psychiatric disorders and the connections with sleep.

Prevalence of Current Restless Legs Syndrome Symptoms Among Patients Treated with Buprenorphine/Naloxone for Opioid Use Disorder.

Objective: The purpose of this study was to determine the prevalence of Restless Legs Syndrome (RLS) in patients with Opioid Use Disorder (OUD) taking buprenorphine/naloxone maintenance therapy, and to assess symptom frequency, severity, and sleep disruption due to RLS. Methods: Surveys inquired about demographic information, amount of time on maintenance treatment, previous drug use, current prescribed medications and alcohol use, and RLS symptoms. Participants were determined to have definite, probable, possible, or no RLS symptoms based on pre-established criteria from the Cambridge-Hopkins Questionnaire. Results: The sample (n=129) was 33.3% female, 81.5% white, and the mean age was 40.6 years (SD=11.9). The median duration of buprenorphine/naloxone use was 3 years. 13.2% of participants had definite/probable RLS symptoms; these symptoms tended to be of moderate severity, occur at least 5-15 times a month, and disrupt sleep to a moderate degree. Of the 17 participants with definite/probable RLS symptoms, just four were taking a medication commonly used to alleviate RLS. An additional 7.0% had possible RLS symptoms. Conclusion: Relatively high rates of current RLS symptoms were observed; the prevalence of clinically significant RLS was notably higher than that seen in the general population or in previously assessed clinical populations. RLS is common in those acutely withdrawing from opioids, and our data demonstrate that these symptoms are present in a sizable portion of patients on OUD maintenance therapy. Most patients with definite/probable current RLS symptoms did not report taking prescribed medications that have established efficacy for RLS.

A Novel Home-Based Study of Circadian Rhythms: Design, Rationale, and Methods for the Circadia Study.

The Circadia Study (Circadia) is a novel "direct-to-participant" research study investigating the genetics of circadian rhythm disorders of advanced and delayed sleep phase and non-24 hour rhythms. The goals of the Circadia Study are twofold: (i) to create an easy-to-use toolkit for at-home circadian phase assessment for patients with circadian rhythm disorders through the use of novel in-home based surveys, tests, and collection kits; and (ii) create a richly phenotyped patient resource for genetic studies that will lead to new genetic loci associated with circadian rhythm disorders revealing possible loci of interest to target in the development of therapeutics for circadian rhythm disorders. Through these goals, we aim to broaden our understanding and elucidate the genetics of circadian rhythm disorders across a diverse patient population while increasing accessibility to circadian rhythm disorder diagnostics reducing health disparities through self-directed at-home dim light melatonin onset (DLMO) collections.

Self-Directed Home-Based Dim-Light Melatonin Onset Collection: The Circadia Pilot Study.

Study Objectives: To test the feasibility of a novel at-home salivary Dim Light Melatonin Onset (DLMO) assessment protocol to measure the endogenous circadian phase of 10 individuals ( 1 Advanced Sleep-Wake Phase Disorder patient (ASWPD), 4 Delayed Sleep-Wake Phase Disorder patients (DSWPD), and 5 controls). Methods: The study involved 10 participants (sex at birth: females = 9; male= 1), who ranged between 27 to 63 years old, with an average age of 38 years old. Our study population consisted of 7 individuals who identified as white and 3 who identified as Asian. Our participants were diverse in gender identity (woman = 7, male = 1, transgender = 1, nonbinary = 1, none = 1).The study tracked the sleep and activity patterns of 10 individuals over a 5-6 week period using self-reported online sleep diaries and objective actigraphy data. Participants completed two self-directed DLMO assessments, approximately one week apart, adhering to objective compliance measures. Participants completed the study entirely remotely: they completed all sleep diaries and other evaluations online and were mailed a kit with all materials needed to perform the actigraphy and at-home sample collections. Results: Salivary DLMO times were calculated for 8/10 participants using the Hockeystick method. DLMO times were on average 3 hours and 18 minutes earlier than self-reported sleep onset times (DSPD: 12:04 AM, controls: 9:55 PM.) Among the 6 participants for whom we calculated two separate DLMO times, DLMOs 1 and 2 were 96% correlated (p<0.0005.). Conclusions: Our results indicate that self-directed, at-home DLMO assessments are feasible and accurate. The current protocol may serve as a framework to reliably assess circadian phase in both clinical and general populations.

Efficacy and safety of tonic motor activation (TOMAC) for medication-refractory restless legs syndrome: a randomized clinical trial.

STUDY OBJECTIVES: The purpose of this study was to evaluate the efficacy and safety/tolerability of bilateral high-frequency tonic motor activation (TOMAC) in patients with medication-refractory restless legs syndrome (RLS). METHODS: RESTFUL was a multicenter, randomized, double-blind, sham-controlled trial in adults with medication-refractory moderate-to-severe primary RLS. Participants were randomized 1:1 to active or sham TOMAC for a double-blind, 4-week stage 1 and all received active TOMAC during open-label, 4-week stage 2. The primary endpoint was the Clinical Global Impressions-Improvement (CGI-I) responder rate at the end of stage 1. Key secondary endpoints included change to International RLS Study Group (IRLS) total score from study entry to the end of stage 1. RESULTS: A total of 133 participants were enrolled. CGI-I responder rate at the end of stage 1 was significantly greater for the active versus sham group (45% vs. 16%; Difference = 28%; 95% CI 14% to 43%; p = .00011). At the end of stage 2, CGI-I responder rate further increased to 61% for the active group. IRLS change at the end of stage 1 improved for the active versus sham group (-7.2 vs. -3.8; difference = -3.4; 95% CI -1.4 to -5.4; p = .00093). There were no severe or serious device-related adverse events (AEs). The most common AEs were mild discomfort and mild administration site irritation which resolved rapidly and reduced in prevalence over time. CONCLUSIONS: TOMAC was safe, well tolerated, and reduced symptoms of RLS in medication-refractory patients. TOMAC is a promising new treatment for this population. CLINICAL TRIAL: Noninvasive Peripheral Nerve Stimulation for Medication-Refractory Primary RLS (The RESTFUL Study); clinicaltrials.gov/ct2/show/NCT04874155; Registered at ClinicalTrials.gov with the identifier number NCT04874155.

Do Insomnia Treatments Improve Daytime Function?

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.

Disrupted white matter integrity in primary insomnia and major depressive disorder: relationships to sleep quality and depression severity.

This study examined the integrity of white matter tracts in 25 participants with primary insomnia (PI), 50 participants with major depressive disorder (MDD), and 25 healthy controls. Seven white matter tracts, selected based on prior research, were quantified by fractional anisotropy (FA) as well as by related measures of diffusivity using diffusion tensor imaging (DTI) on a 3-T scanner. All 100 participants were free of significant medical, psychiatric (excluding the MDD group) and sleep disorders (excluding the PI group), were free of central nervous system medications, and completed an extensive clinical assessment. Subjective and objective sleep measures revealed significant sleep disruption in both the PI and MDD groups. Relative to the controls, both the PI and MDD groups demonstrated impaired integrity in three of the seven white matter tracts: the genu of the corpus callosum (GenuCC), the superior longitudinal fasciculus (SLF), and the inferior longitudinal fasciculus (ILF). We demonstrated reduced FA in the GenuCC, reduced FA and reduced axial diffusivity (AD) in the SLF, as well as reduced AD and radial diffusivity in the ILF. Finally, in an exploratory analysis of the combined cohorts, FA in the GenuCC and FA in the SLF were negatively correlated with depression severity and positively correlated with total sleep time. Abnormalities documented in the GenuCC, SLF and ILF, and present in both the PI and MDD groups may suggest some shared neurobiology.

Should Trazodone Be First-Line Therapy for Insomnia? A Clinical Suitability Appraisal.

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".

What Should Be the Focus of Treatment When Insomnia Disorder Is Comorbid with Depression or Anxiety Disorder?

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.

Long-Term Use of Insomnia Medications: An Appraisal of the Current Clinical and Scientific Evidence.

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.

Long-term Safety, Dose Stability, and Efficacy of Opioids for Patients With Restless Legs Syndrome in the National RLS Opioid Registry.

BACKGROUND AND OBJECTIVES: Restless legs syndrome (RLS) is a sensory-motor neurologic disorder. Low-dose opioids are prescribed for patients with refractory or augmented RLS. The long-term safety, dose stability, and efficacy of these medications for RLS treatment is still unclear. In this study, we report the 2-year longitudinal data in a sample of patients treated with opioids for RLS in the community. METHODS: The National RLS Opioid Registry is an observational longitudinal study consisting of individuals taking a prescribed opioid for diagnosed and confirmed RLS, most of whom experienced augmented symptoms from dopamine agonists. Information on opioid dosages, side effects, past and current concomitant RLS treatments, RLS severity, psychiatric symptoms, and opioid abuse risk factors was collected at initial Registry entry and every 6 months thereafter by surveys on REDCap. No feedback or intervention was provided by the study staff to local providers. RESULTS: Registry participants (n = 448) with 2-year longitudinal data available were mostly White, female, older than 60 years, and, at Registry entry, had been on opioids for a median of 1-3 years at a mean morphine milligram equivalent (MME) of 38.4 (SD = 43.5). No change in RLS severity in the overall cohort was observed over the 2-year follow-up period. The median change in daily opioid dose from baseline to 2 years was 0 MME (interquartile range = 0-10). While 41.1% of participants increased their dose during the follow-up period (median increase = 10 MME), 58.9% decreased their dose or saw no change. Only 8% and 4% saw increases of >25 MME and >50 MME, respectively. Ninety-five percent of those who increased opioid dose >25 or >50 MME had one of the following features: switching opioids, discontinuation of nonopioid RLS treatment medications, at least mild insomnia at baseline, a history of depression, male sex, younger than 45 years, and opioid use for comorbid pain. DISCUSSION: Low-dose opioid medications continue to adequately control symptoms of refractory RLS over 2 years of follow-up in most of the participants. A minority of patients did see larger dose increases, which were invariably associated with a limited number of factors, most notably changes in opioid and nonopioid RLS medications and opioid use for a non-RLS condition. Continued longitudinal observations will provide insight into the long-term safety and efficacy of opioid treatment of severe, augmented RLS. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that opioid doses increase in roughly 40% of patients, in most by small amounts, over a 2-year period when prescribed for adult refractory restless leg syndrome.

Randomized, crossover, open-label study of the relative bioavailability and safety of FT218, a once-nightly sodium oxybate formulation: Phase 1 study in healthy volunteers.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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 (Cmax) was 65.8 ± 4.0 µg/mL for ON-SXB vs 77.1 ± 4.9 µg/mL for twice-nightly SXB (GMR [90% CI], 88.3 [80.5-97.0]). The GMR (90% CI) for GHB plasma concentrations 8 h post dose (C8h) for ON-SXB vs twice-nightly SXB was 61.7 (45.8-83.0). The most frequently reported adverse events were the same for ON-SXB and twice-nightly SXB (nausea, dizziness, somnolence, vomiting). CONCLUSIONS: GHB exposure and Cmax with one 6-g dose of ON-SXB were bioequivalent to those with two 3-g doses of twice-nightly SXB, whereas C8h was lower with ON-SXB. If approved, ON-SXB will provide a single bedtime oxybate option, with clinically relevant pharmacologic exposure during the entire sleep period.