Relationship of Suboptimal and Disordered Sleep with Cardiovascular Disease and Its Risk Factors - A Narrative Review.

BACKGROUND: 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. SUMMARY: 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 nonbreathing-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).

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.

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.

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.

Nicotinamide Adenine Dinucleotide Augmentation in Overweight or Obese Middle-Aged and Older Adults: A Physiologic Study.

CONTEXT: Nicotinamide adenine dinucleotide (NAD) levels decline with aging and age-related decline in NAD has been postulated to contribute to age-related diseases. OBJECTIVE: We evaluated the safety and physiologic effects of NAD augmentation by administering its precursor, ß-nicotinamide mononucleotide (MIB-626, Metro International Biotech, Worcester, MA), in adults at risk for age-related conditions. METHODS: Thirty overweight or obese adults, ≥ 45 years, were randomized in a 2:1 ratio to 2 MIB-626 tablets each containing 500 mg of microcrystalline ß-nicotinamide mononucleotide or placebo twice daily for 28 days. Study outcomes included safety; NAD and its metabolome; body weight; liver, muscle, and intra-abdominal fat; insulin sensitivity; blood pressure; lipids; physical performance, and muscle bioenergetics. RESULTS: Adverse events were similar between groups. MIB-626 treatment substantially increased circulating concentrations of NAD and its metabolites. Body weight (difference -1.9 [-3.3, -0.5] kg, P = .008); diastolic blood pressure (difference -7.01 [-13.44, -0.59] mmHg, P = .034); total cholesterol (difference -26.89 [-44.34, -9.44] mg/dL, P = .004), low-density lipoprotein (LDL) cholesterol (-18.73 [-31.85, -5.60] mg/dL, P = .007), and nonhigh-density lipoprotein cholesterol decreased significantly more in the MIB-626 group than placebo. Changes in muscle strength, muscle fatigability, aerobic capacity, and stair-climbing power did not differ significantly between groups. Insulin sensitivity and hepatic and intra-abdominal fat did not change in either group. CONCLUSIONS: MIB-626 administration in overweight or obese, middle-aged and older adults safely increased circulating NAD levels, and significantly reduced total LDL and non-HDL cholesterol, body weight, and diastolic blood pressure. These data provide the rationale for larger trials to assess the efficacy of NAD augmentation in improving cardiometabolic outcomes in older adults.

Restless legs syndrome severity in the National RLS Opioid Registry during the COVID-19 pandemic.

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.

The Long-Term Psychiatric and Cardiovascular Morbidity and Mortality of Restless Legs Syndrome and Periodic Limb Movements of Sleep.

Restless legs syndrome (RLS) is a sensory-motor neurological disorder that is associated with high levels of distress and sleep disturbance. Cross-sectional and longitudinal evidence suggests that individuals suffering from RLS may be at an increased risk of certain psychiatric illnesses and cardiovascular diseases. There also is evidence for increased mortality rates in RLS patients, although contrasting results do exist. Periodic limb movements of sleep (PLMS), repetitive leg movement observed in most RLS patients, and sleep disturbance may mediate the relationship between RLS and long-term morbidity. This article summarizes the literature investigating the potential consequences of both RLS and PLMS.

Baseline and 1-year longitudinal data from the National Restless Legs Syndrome Opioid Registry.

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

Topiramate reduces nocturnal eating in sleep-related eating disorder.

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.