Case of buprenorphine-associated central sleep apnea resolving with dose reduction.

Aside from respiratory suppression in overdose, full opioid agonist agents are known to cause sleep-disordered breathing (SDB). The increasing rates of opioid overdose in the United States have led to increasing use of medication-assisted treatments for opioid use disorders. Dose-dependent increase in SDB has been documented with methadone. There is emerging literature in the form of case reports providing evidence of buprenorphine and buprenorphine-naloxone contributing to sleep apnea. We report an additional case of a female patient developing central sleep apnea during initiation of buprenorphine-naloxone treatment. The condition resolved with dose reduction.

Uso de psicofármacos y riesgo de apnea del sueño en pacientes internados en hospital general / Psychotropic drugs and obstructive sleep apnea risk use in hospitalized medical patients

RESUMEN: Se realizó un estudio descriptivo observacional, de corte transversal, con el objetivo de identificar la asociación del consumo de psicofármacos y el aumento del riesgo de padecer apnea obstructiva del sueño (A.O.S.), en pacientes internados y bajo tratamiento con psicofármacos en Hospital General (Hospital Pasteur, Montevideo, Uruguay) durante julio-septiembre de 2019. Se aplicó el cuestionario STOP BANG, hallándose riesgo elevado de A.O.S en el 59,4% de la muestra, del cual 75,6% corresponde al sexo masculino y el 24,4% corresponde al sexo femenino. El riesgo elevado para A.O.S fue: 54,3% para pacientes en tratamiento con un solo psicofármaco y 71,4% con dos. El grupo de antipsicóticos fue el que se asoció con mayor frecuencia al riesgo elevado de A.O.S.

SUMMARY A cross-sectional study was conducted with the objective of identifying the link between psychotropic medications and an increased risk of suffering from obstructive sleep apnea (OSA) in patients under treatment with psychotropic medication who were hospitalized in General Hospital (Hospital Pasteur, Montevideo, Uruguay) during the July-September 2019 period. The STOP BANG questionnaire was applied, elevated risk of OSA was found in 59.4% of the sample, of which 75.6% were male, while 24.4% were female. The elevated risk of OSA was: 54.4% for patients under treatment with a single psychotropic medication and 71.4% for patients under treatment with two psychotropic medications. Antipsychotics were the most frequently group of psychotropic drugs linked to an elevated OSA risk.

Are High- or Low-dose SGLT2 Inhibitors Associated With Cardiovascular and Respiratory Adverse Events? A Meta-analysis.

ABSTRACT: The association between high-dose or low-dose sodium-glucose cotransporter 2 (SGLT2) inhibitors and various cardiovascular and respiratory serious adverse events (SAE) is unclear. Our meta-analysis aimed to define the association between high-dose or low-dose SGLT2 inhibitors and 86 kinds of cardiovascular SAE and 58 kinds of respiratory SAE. We included large cardiorenal outcome trials of SGLT2 inhibitors. Meta-analysis was conducted and stratified by the dose of SGLT2 inhibitors (high dose or low dose) to synthesize risk ratio (RR) and 95% confidence interval (CI). We included 9 trials. Compared with placebo, SGLT2 inhibitors used at high dose or low dose were associated with the decreased risks of 6 kinds of cardiovascular SAE [eg, bradycardia (RR, 0.60; 95% CI, 0.41-0.89), atrial fibrillation (RR, 0.79; 95% CI, 0.69-0.92), and hypertensive emergency (RR, 0.34; 95% CI, 0.15-0.78)] and 6 kinds of respiratory SAE [eg, asthma (RR, 0.59; 95% CI, 0.37-0.93), chronic obstructive pulmonary disease (RR 0.77, 95% CI 0.62-0.96), and sleep apnea syndrome (RR 0.37, 95% CI 0.17-0.81)]. SGLT2 inhibitors used at high dose or low dose did not show significant associations with 132 other cardiopulmonary SAE. For any outcome of interest, the subgroup difference according to the dose of SGLT2 inhibitors was not significant (Psubgroup > 0.05). SGLT2 inhibitors used at whether high dose or low dose are associated with the decreased risks of 12 cardiopulmonary disorders (eg, bradycardia, atrial fibrillation, hypertensive emergency, asthma, chronic obstructive pulmonary disease, and sleep apnea syndrome). These findings may suggest the potential efficacy of high- or low-dose SGLT2 inhibitors for the prevention and treatment of these cardiopulmonary disorders.

[Sleep disorders in patients with a neurocognitive disorder]. / Les troubles du sommeil chez les patients atteints d'un trouble neurocognitif.

INTRODUCTION: Sleep disorders are prevalent in patients with a neurocognitive disorder, and diagnosis and treatment in these patients remain challenging in clinical practice. METHODS: This narrative review offers a systematic approach to diagnose and treat sleep disorders in neurocognitive disorders. RESULTS: Alzheimer's disease is often associated with circadian rhythm disorders, chronic insomnia, and sleep apnea-hypopnea syndrome. Alpha-synucleinopathies (e.g., Parkinson's disease and Lewy body dementia) are often associated with a rapid eye movement sleep behavior disorder, restless legs syndrome, chronic insomnia, and sleep apnea-hypopnea syndrome. A focused history allows to diagnose most sleep disorders. Clinicians should ensure to gather the following information in all patients with a neurocognitive disorder: (1) the presence of difficulties falling asleep or staying asleep, (2) the impact of sleep disturbances on daily functioning (fatigue, sleepiness and other daytime consequences), and (3) abnormal movements in sleep. Sleep diaries and questionnaires can assist clinicians in screening for specific sleep disorders. Polysomnography is recommended if a rapid eye movement sleep behavior disorder or a sleep apnea-hypopnea syndrome are suspected. Sleep complaints should prompt clinicians to ensure that comorbidities interfering with sleep are properly managed. The main treatment for moderate to severe obstructive sleep apnea-hypopnea syndrome remains continuous positive airway pressure, as its efficacy has been demonstrated in patients with neurocognitive disorders. Medications should also be reviewed, and time of administration should be optimized (diuretics and stimulating medications in the morning, sedating medications in the evening). Importantly, cholinesterase inhibitors (especially donepezil) may trigger insomnia. Switching to morning dosing or to an alternative drug may help. Cognitive-behavioral therapy for insomnia is indicated to treat chronic insomnia in neurocognitive disorders. False beliefs regarding sleep should be addressed with the patient and their caregiver. The sleep environment should be optimized (decrease light exposure at night, minimize noise, avoid taking vital signs, etc.). Sleep restriction can be considered as patients with a neurocognitive disorder often spend too much time in bed. The need for naps should be assessed case by case as naps may contribute to insomnia in some patients but allow others to complete their diurnal activities. Trazodone (50mg) may also be used under certain circumstances in chronic insomnia. Recent evidence does not support a role for exogenous melatonin in patients with a neucognitive disorder and insomnia. Patients in long-term care facilities are often deprived of an adequate diurnal exposure to light. Increasing daytime exposure to light may improve sleep and mood. Patients with circadian rhythm disorders can also benefit from light therapy (morning bright light therapy in case of phase delay and evening bright light therapy in case of phase advance). Rapid eye movement sleep behavior disorder can lead to violent behaviors, and the sleeping environment should be secured (e.g., mattress on the floor, remove surrounding objects). Medication exacerbating this disorder should be stopped if possible. High dose melatonin (6 to 18mg) or low dose clonazepam (0.125-0.25mg) at bedtime may be used to reduce symptoms. Melatonin is preferred in first-line as it is generally well tolerated with few side effects. Patients with restless legs syndrome should be investigated for iron deficiency. Medication decreasing dopaminergic activity should be reduced or stopped if possible. Behavioral strategies such as exercise and leg massages may be beneficial. Low-dose dopamine agonists (such as pramipexole 0.125mg two hours before bedtime) can be used to treat the condition, but a prolonged treatment may paradoxically worsen the symptoms. Alpha-2-delta calcium channel ligands can also be used while monitoring for the risk of falls. CONCLUSION: Multiple and sustained nonpharmacological approaches are recommended for the treatment of sleep disturbances in patients with neurocognitive disorder. Pharmacological indications remain limited, and further randomized clinical trials integrating a multimodal approach are warranted to evaluate the treatment of sleep disorders in specific neurocognitive disorders.

Predictive Performance of Oximetry to Detect Sleep Apnea in Patients Taking Opioids.

BACKGROUND: Long-term use of opioids for treatment of chronic pain is associated with significant risks including worsening unrecognized or untreated sleep apnea that may increase morbidity and mortality. Overnight oximetry has been validated for predicting sleep apnea in surgical and sleep clinic patients. The objective of the study was to assess the predictive accuracy of oxygen desaturation index (ODI 4%) from home overnight oximetry when compared to apnea hypopnea index (AHI) from polysomnography for predicting sleep apnea in patients taking opioids for chronic pain. METHODS: This was a planned post hoc analysis of a prospective cohort study conducted at 5 pain clinics. Patient characteristics and daily morphine milligram equivalent (MME) dose were recorded. All consented patients underwent home overnight oximetry (PULSOX-300i, Konica Minolta Sensing, Inc, Osaka, Japan) and in-laboratory polysomnography. The predictive performance of ODI 4% from oximetry was assessed against AHI from polysomnography. RESULTS: Among 332 consented patients, 181 with polysomnography and overnight oximetry data were analyzed. The mean age and body mass index of 181 patients were 52 ± 13 years and 29 ± 6 kg/m2, respectively, with 40% men. The area under the receiver operating curve for ODI to predict moderate-to-severe sleep apnea (AHI ≥15 events/h) and severe sleep apnea (AHI ≥30 events/h) was 0.82 (95% confidence interval [CI], 0.75-0.88) and 0.87 (95% CI, 0.80-0.94). ODI ≥5 events/h had a sensitivity of 85% (95% CI, 74-92) and specificity of 57% (95% CI, 52-61) to predict moderate-to-severe sleep apnea. ODI ≥15 events/h had a sensitivity of 71% (95% CI, 55-83) and specificity of 88% (95% CI, 84-91) to predict severe sleep apnea. CONCLUSIONS: Overnight home oximetry has a high predictive performance in predicting moderate-to-severe and severe sleep apnea in patients on opioids for chronic pain. It is a useful additional tool for health care providers for the screening of sleep apnea in this high-risk group.

Opioids and sleep.

PURPOSE OF REVIEW: Summarize the effects of opioids on sleep including sleep architecture, sleep disordered breathing (SDB) and restless legs syndrome. RECENT FINDINGS: Opioids are associated with the development of central sleep apnea (CSA) and ataxic breathing. Recent reports suggest that adaptive servo-ventilation may be an effective treatment for CSA associated with opioids. SUMMARY: Opioids have multiple effects on sleep, sleep architecture and SDB. Although originally described with methadone use, most commonly used opioids have also been shown to affect sleep. In patients on chronic methadone, sleep architecture changes include decreases in N3 and REM sleep. However, in patients with chronic nonmalignant pain, opioids improve sleep quality and sleep time. Opioids, generally at a morphine equivalent dose more than 100 mg/day, are associated with an increased incidence of CSA and ataxic breathing as well as obstructive sleep apnea. Other risk factors may include concomitant use of other medications such as antidepressants, gabapentinoids and benzodiazepines. Opioid-induced CSA can be potentially treated with adaptive servo-ventilation. Finally, opioids are a potential therapeutic option for restless legs syndrome unresponsive to dopamine agonists and other medications. However, use in patients with restless legs syndrome should proceed with caution, taking into account the risk for dependence and development of SDB.

Sleep-disordered breathing in patients on opioids for chronic pain.

The past two decades has seen a substantial rise in the use of opioids for chronic pain, along with opioid-related mortality and adverse effects. A contributor to opioid-associated mortality is the high prevalence of moderate/severe sleep-disordered breathing, including central sleep apnea and obstructive sleep apnea, in patients with chronic pain. Although evidence-based treatments are available for sleep-disordered breathing, patients are not frequently assessed for sleep-disordered breathing in pain clinics. To aid healthcare providers in this area of clinical uncertainty, we present evidence on the interaction between opioids and sleep-disordered breathing, and the prevalence and predictive factors for sleep-disordered breathing in patients on opioids for chronic pain. We provide recommendations on how to evaluate patients on opioids for risk of moderate/severe sleep-disordered breathing in clinical care, which could lead to earlier use of therapeutic interventions for opioid-associated sleep-disordered breathing, such as opioid cessation or positive airway pressure therapy. This would improve quality of life and well-being of patients with chronic pain.

Intrathecal morphine and sleep apnoea severity in patients undergoing hip arthroplasty: a randomised, controlled, triple-blinded trial.

BACKGROUND: Intrathecal morphine prolongs analgesia after surgery, but has been implicated in postoperative respiratory depression or apnoeic episodes. However, this has not been investigated in a prospective trial using respiratory polygraphy. This randomised controlled triple-blinded trial tested the hypothesis that intrathecal morphine increases sleep apnoea severity, measured using respiratory polygraphy. METHODS: Sixty subjects undergoing hip arthroplasty under spinal anaesthesia received either 15 mg isobaric bupivacaine 0.5% with 0.5 ml normal saline 0.9% (control group) or 15 mg isobaric bupivacaine 0.5% with 0.5 ml intrathecal morphine 100 µg (intrathecal morphine group). Respiratory polygraphy was performed before surgery and on the first and third postoperative nights. The primary outcome was the apnoea-hypopnoea index in the supine position (supine AHI) on the first postoperative night. Secondary outcomes included supine AHI on the third postoperative night, oxygen desaturation index (ODI), and ventilatory frequency during the first and third postoperative nights. RESULTS: On the first postoperative night, mean (95% confidence interval) values for supine AHI were 20.6 (13.9-27.3) and 21.2 (12.4-30.0) events h-1 in the control and intrathecal morphine groups, respectively (P=0.90). There were no significant between-group differences for any of the secondary outcomes, except for a significantly higher central and mixed apnoea index preoperatively and significantly lower mean SpO2 on the third postoperative night in the control group. CONCLUSIONS: Intrathecal morphine did not increase sleep apnoea severity when measured using respiratory polygraphy. Of note, all patients had an increased number of apnoeic episodes on the third postoperative night. CLINICAL TRIAL REGISTRATION: NCT02566226.

Intranasal Leptin Prevents Opioid-induced Sleep-disordered Breathing in Obese Mice.

Respiratory depression is the main cause of morbidity and mortality associated with opioids. Obesity increases opioid-related mortality, which is mostly related to comorbid obstructive sleep apnea. Naloxone, a µ-opioid receptor blocker, is an effective antidote, but it reverses analgesia. Like humans with obesity, mice with diet-induced obesity hypoventilate during sleep and develop obstructive sleep apnea, which can be treated with intranasal leptin. We hypothesized that intranasal leptin reverses opioid-induced sleep-disordered breathing in obese mice without decreasing analgesia. To test this hypothesis, mice with diet-induced obesity were treated with morphine at 10 mg/kg subcutaneously and with leptin or placebo intranasally. Sleep and breathing were recorded by barometric plethysmography, and pain sensitivity was measured by the tail-flick test. Excitatory postsynaptic currents were recorded in vitro from hypoglossal motor neurons after the application of the µ-opioid receptor agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin and leptin. Morphine dramatically increased the frequency of apneas and greatly increased the severity of hypoventilation and obstructive sleep apnea. Leptin decreased the frequency of apneas, improved obstructive sleep apnea, and completely reversed hypoventilation, whereas morphine analgesia was enhanced. Our in vitro studies demonstrated that [D-Ala2, N-MePhe4, Gly-ol]-enkephalin reduced the frequency of excitatory postsynaptic currents in hypoglossal motoneurons and that application of leptin restored excitatory synaptic neurotransmission. Our findings suggest that intranasal leptin may prevent opioid respiratory depression during sleep in patients with obesity receiving opioids without reducing analgesia.

Alpha-1 Adrenergic-Antagonist Use Increases the Risk of Sleep Apnea: A Nationwide Population-Based Cohort Study.

STUDY OBJECTIVES: Decreased upper-airway muscle responsiveness is one of the major phenotypes of obstructive sleep apnea. Use of α1-adrenergic antagonists is correlated with decreased muscle responsiveness in animal studies, but this association has not yet been demonstrated in humans. This study examined whether use of α1-adrenergic antagonists is an independent risk factor for sleep apnea in humans. METHODS: Data for this retrospective cohort study were obtained from the National Health Insurance Research Database from Taiwan. Between 2000 and 2012, 25,466 patients with hypertension and 18,930 patients without hypertension were enrolled. These groups were divided into α1-adrenergic antagonist users and nonusers, matched by age, sex, and index year. Individuals were monitored for diagnosis of sleep apnea until 2013. RESULTS: After adjusting for propensity score and potential confounders, including age, geographic location, enrollee category, income, urbanization level, comorbidities, and medication, the adjusted hazard ratios (HRs) for development of sleep apnea with α1-adrenergic antagonist use were 2.38 (95% confidence interval [CI] 1.82-3.10) and 2.82 (95% CI 1.79-4.44) in the hypertension and nonhypertension groups, respectively. Similarly, the adjusted HRs for development of severe sleep apnea with α1-adrenergic antagonist use were 2.74 (95% CI 1.78-4.22) and 4.23 (95% CI 1.57-11.40) in hypertension and nonhypertension patient groups, respectively. The interaction between α1-adrenergic-antagonist user and patients with hypertension was tested using multivariable Cox regression. The results showed that there are positive additive interactions for developing sleep apnea and severe sleep apnea, respectively. CONCLUSIONS: Our study suggests that patients with hypertension using α1-adrenergic antagonists have a higher risk of sleep apnea. Routine sleep apnea screening would be beneficial for patients with hypertension who take α1-adrenergic antagonists.

Chronic Opioid Therapy and Sleep: An American Academy of Sleep Medicine Position Statement.

None: There is a complex relationship among opioids, sleep and daytime function. Patients and medical providers should be aware that chronic opioid therapy can alter sleep architecture and sleep quality as well as contribute to daytime sleepiness. It is also important for medical providers to be cognizant of other adverse effects of chronic opioid use including the impact on respiratory function during sleep. Opioids are associated with several types of sleep-disordered breathing, including sleep-related hypoventilation, central sleep apnea (CSA), and obstructive sleep apnea (OSA). Appropriate screening, diagnostic testing, and treatment of opioid-associated sleep-disordered breathing can improve patients' health and quality of life. Collaboration among medical providers is encouraged to provide high quality, patient-centered care for people who are treated with chronic opioid therapy.

The association of coffee consumption and oxygen desaturation index during sleep among Japanese male workers.

BACKGROUND AND OBJECTIVE: Coffee is a major caffeine-containing food source that can be used for treatment of apnea in prematurity. However, few studies have examined the association between coffee consumption and sleep-disordered breathing (SDB). We investigated whether coffee consumption is associated with the oxygen desaturation index (ODI) as a marker of SDB among middle-aged Japanese male workers. METHODS: The subjects were 1126 male local government workers aged 22-59 who participated in SDB screening in 2011-2012. Daily coffee consumption was assessed by a self-administered questionnaire. We measured 3% oxygen desaturation (3%ODI) during a night's sleep using a pulse oximeter. A general linear model was used to calculate the multivariate-adjusted means of 3%ODI per quartile of coffee consumption. We further analyzed the data after stratifying by overweight and current smoking status. RESULTS: A inverse association between coffee consumption and 3%ODI was found. The multivariate-adjusted mean of 3%ODI for the lowest and highest coffee consumption groups were 11.9 times/h and 10.6 times/h (p for trend = 0.06), respectively; 14.6 and 11.5 times/h (p for trend = 0.01) in overweight participants; and 12.7 and 11.0 times/h (p for trend = 0.06) in non-smokers. No associations were found in non-overweight and smoking workers. CONCLUSIONS: Our results suggest that higher coffee consumption was associated with lower 3% ODI as a marker of SDB in overweight and non-smoking workers.

Drug-Induced Sleep-Disordered Breathing and Ventilatory Impairment.

This article describes current knowledge about drug entities that have the potential to induce, aggravate, or modify sleep-disordered breathing. The drug effects on sleep-disordered breathing may vary by patient age, gender, and comorbidity. In general, the clinical relevance of drug-induced sleep-disordered breathing is increasing in sleep medicine and the evidence in the field is growing in parallel.

Effects of Chronic Opioid Use on Sleep and Wake.

Chronic use of opioids negatively affects sleep on 2 levels: sleep architecture and breathing. Patients suffer from a variety of daytime sequelae. There may be a bidirectional relationship between poor sleep quality, sleep-disordered breathing, and daytime function. Opioids are a potential cause of incident depression. The best therapeutic option is withdrawal of opioids, which proves difficult. Positive airway pressure devices are considered first-line treatment for sleep-related breathing disorders. New generation positive pressure servo ventilators are increasingly popular as a treatment option for opioid-induced sleep-disordered breathing. Treatments to improve sleep quality, sleep-related breathing disorders, and quality of life in patients who use opioids chronically are discussed.

Sleep apnea and pesticide exposure in a study of US farmers.

INTRODUCTION: Carbamate and organophosphate pesticides inhibit acetylcholinesterase, and poisoning leads to respiratory depression. Thus, involvement in sleep apnea is plausible, but no data exist at lower levels of exposure. Other pesticides could impact sleep apnea by different mechanisms but have not been studied. Our study examines the associations between pesticide exposure and sleep apnea among pesticide applicators from a US farming population. PARTICIPANTS AND METHODS: We analyzed data from 1569 male pesticide applicators, mostly farmers, from an asthma case-control study nested within the prospective Agricultural Health Study. On questionnaires, participants reported use of specific pesticides and physician diagnosis plus prescribed treatments for sleep apnea. We used multivariable logistic regression to estimate associations between ever use of 63 pesticides and sleep apnea (234 cases, 1335 noncases). RESULTS: The most notable association was for carbofuran, a carbamate (100 exposed cases, odds ratio 1.83, 95% confidence interval 1.34-2.51, P=.0002). Carbofuran use began before reported onset of sleep apnea in all cases. DISCUSSION: This study adds to the known adverse health outcomes of exposure to carbofuran, a pesticide canceled in the United States in 2009 for most agricultural purposes but persists in the environment and remains in use in some other countries. CONCLUSIONS: We conducted the first epidemiological study investigating the association of pesticide exposure and sleep apnea. Our results in a male agricultural population suggests that exposure to carbofuran is positively associated with sleep apnea.