Sleep Medicine

In discussions between health care providers and patients, the words “regularity” and “irregularity” come up primarily in reference to either constipation or menstrual cycles. However, the participants in a recent panel convened by the National Sleep Foundation think we should also be discussing irregularity when we are discussing sleep with our patients.

The sleep experts on the panel began by considering 40,000 papers that directly or tangentially dealt with the topic of irregular sleep patterns. The reviewers uncovered numerous references to an association between sleep irregularity and a wide variety of adverse health outcomes, including obesity and metabolic disorders, hypertension and other cardiovascular disorders, and elevations in several inflammatory markers. Not surprisingly, the investigators also found an abundance of references supporting an association between irregular sleep and a suite of mental health problems, including depression, mood disorders, lower self esteem, poor academic performance, and deficits in attention. For example, several of the studies the panel reviewed found that in college students, GPA was lower when their sleep pattern was irregular. There were some papers that found no significant association between irregular sleep and other adverse health outcomes, but none of the studies demonstrated an association with better or improved health outcomes.

There is currently no universally accepted definition of an irregular sleep pattern. The experts pointed to some papers that used a standard deviation of 1 hour from the patient’s usual bed time determined by averaging over an interval measured in weeks. You and I shouldn’t be surprised that irregular sleep is unhealthy, but the breadth of the panel’s findings is impressive.

Although it has been long in coming, sleep is finally beginning to get some attention by the media. The focus is usually on the optimal number of hours we need each night. This panel’s findings suggest that total sleep time is only part of the story, and may even be less important than the regularity of our sleep patterns.

For those of us in pediatrics, the place where irregularity raises its ugly head is with teenagers and weekends. Although the numbers are far from clear, the question remains of how effective is catch-up sleep after a week of too-early mornings and too-late bedtimes for the chronically under-slept adolescent.

In some studies in which patients had the demonstrable effects of sleep deprivation (e.g., metabolic and cardiovascular) there was some improvement when weekend sleep was extended by 1 or 2 hours, but none beyond 2 hours.

The panel’s findings, while certainly significant, merely add weight and nuance to the existing evidence of importance of sleep and the damage done by sleep deprivation. As one of the panel members has said, “Sleep is the third pillar of health, equally important as diet and exercise, if not more.” However, this message is not getting out, or at least it is not being heeded. Like obesity, our efforts as advisers to our patients isn’t working. Unfortunately, this is because our advice is often whispered and given halfheartedly.

There was some evidence of improvement as a result of the pandemic, when those fortunate enough to be able to work from home were taking advantage of the flexibility in their schedules and getting more sleep. But health care providers certainly can’t take responsibility for what was an accident of nature.

Those of you who have been reading Letters from Maine for the last 3 decades may tire of my beating the tired horse of sleep deprivation. But I will not be deterred. I see very little evidence among health care professionals in taking the importance of sleep seriously. Sure, they may include it buried in the list of potential contributors to their patient’s complaint, but I see very little effort to move it higher on their list of priorities and almost no movement toward making substantive recommendations and then reinforcing them with follow-up.

Like obesity, sleep deprivation is a societal problem. We can lay some of the blame on Thomas Edison, but until we as health care professionals take sleep deprivation seriously, we will be undertreating and mistreating our patients who would benefit from a serious discussion of their sleep habits. Until that time you will continue to read columns like this one when I encounter significant studies on the importance of sleep.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

In discussions between health care providers and patients, the words “regularity” and “irregularity” come up primarily in reference to either constipation or menstrual cycles. However, the participants in a recent panel convened by the National Sleep Foundation think we should also be discussing irregularity when we are discussing sleep with our patients.

The sleep experts on the panel began by considering 40,000 papers that directly or tangentially dealt with the topic of irregular sleep patterns. The reviewers uncovered numerous references to an association between sleep irregularity and a wide variety of adverse health outcomes, including obesity and metabolic disorders, hypertension and other cardiovascular disorders, and elevations in several inflammatory markers. Not surprisingly, the investigators also found an abundance of references supporting an association between irregular sleep and a suite of mental health problems, including depression, mood disorders, lower self esteem, poor academic performance, and deficits in attention. For example, several of the studies the panel reviewed found that in college students, GPA was lower when their sleep pattern was irregular. There were some papers that found no significant association between irregular sleep and other adverse health outcomes, but none of the studies demonstrated an association with better or improved health outcomes.

There is currently no universally accepted definition of an irregular sleep pattern. The experts pointed to some papers that used a standard deviation of 1 hour from the patient’s usual bed time determined by averaging over an interval measured in weeks. You and I shouldn’t be surprised that irregular sleep is unhealthy, but the breadth of the panel’s findings is impressive.

Although it has been long in coming, sleep is finally beginning to get some attention by the media. The focus is usually on the optimal number of hours we need each night. This panel’s findings suggest that total sleep time is only part of the story, and may even be less important than the regularity of our sleep patterns.

For those of us in pediatrics, the place where irregularity raises its ugly head is with teenagers and weekends. Although the numbers are far from clear, the question remains of how effective is catch-up sleep after a week of too-early mornings and too-late bedtimes for the chronically under-slept adolescent.

In some studies in which patients had the demonstrable effects of sleep deprivation (e.g., metabolic and cardiovascular) there was some improvement when weekend sleep was extended by 1 or 2 hours, but none beyond 2 hours.

The panel’s findings, while certainly significant, merely add weight and nuance to the existing evidence of importance of sleep and the damage done by sleep deprivation. As one of the panel members has said, “Sleep is the third pillar of health, equally important as diet and exercise, if not more.” However, this message is not getting out, or at least it is not being heeded. Like obesity, our efforts as advisers to our patients isn’t working. Unfortunately, this is because our advice is often whispered and given halfheartedly.

There was some evidence of improvement as a result of the pandemic, when those fortunate enough to be able to work from home were taking advantage of the flexibility in their schedules and getting more sleep. But health care providers certainly can’t take responsibility for what was an accident of nature.

Those of you who have been reading Letters from Maine for the last 3 decades may tire of my beating the tired horse of sleep deprivation. But I will not be deterred. I see very little evidence among health care professionals in taking the importance of sleep seriously. Sure, they may include it buried in the list of potential contributors to their patient’s complaint, but I see very little effort to move it higher on their list of priorities and almost no movement toward making substantive recommendations and then reinforcing them with follow-up.

Like obesity, sleep deprivation is a societal problem. We can lay some of the blame on Thomas Edison, but until we as health care professionals take sleep deprivation seriously, we will be undertreating and mistreating our patients who would benefit from a serious discussion of their sleep habits. Until that time you will continue to read columns like this one when I encounter significant studies on the importance of sleep.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

In discussions between health care providers and patients, the words “regularity” and “irregularity” come up primarily in reference to either constipation or menstrual cycles. However, the participants in a recent panel convened by the National Sleep Foundation think we should also be discussing irregularity when we are discussing sleep with our patients.

The sleep experts on the panel began by considering 40,000 papers that directly or tangentially dealt with the topic of irregular sleep patterns. The reviewers uncovered numerous references to an association between sleep irregularity and a wide variety of adverse health outcomes, including obesity and metabolic disorders, hypertension and other cardiovascular disorders, and elevations in several inflammatory markers. Not surprisingly, the investigators also found an abundance of references supporting an association between irregular sleep and a suite of mental health problems, including depression, mood disorders, lower self esteem, poor academic performance, and deficits in attention. For example, several of the studies the panel reviewed found that in college students, GPA was lower when their sleep pattern was irregular. There were some papers that found no significant association between irregular sleep and other adverse health outcomes, but none of the studies demonstrated an association with better or improved health outcomes.

There is currently no universally accepted definition of an irregular sleep pattern. The experts pointed to some papers that used a standard deviation of 1 hour from the patient’s usual bed time determined by averaging over an interval measured in weeks. You and I shouldn’t be surprised that irregular sleep is unhealthy, but the breadth of the panel’s findings is impressive.

Although it has been long in coming, sleep is finally beginning to get some attention by the media. The focus is usually on the optimal number of hours we need each night. This panel’s findings suggest that total sleep time is only part of the story, and may even be less important than the regularity of our sleep patterns.

For those of us in pediatrics, the place where irregularity raises its ugly head is with teenagers and weekends. Although the numbers are far from clear, the question remains of how effective is catch-up sleep after a week of too-early mornings and too-late bedtimes for the chronically under-slept adolescent.

In some studies in which patients had the demonstrable effects of sleep deprivation (e.g., metabolic and cardiovascular) there was some improvement when weekend sleep was extended by 1 or 2 hours, but none beyond 2 hours.

The panel’s findings, while certainly significant, merely add weight and nuance to the existing evidence of importance of sleep and the damage done by sleep deprivation. As one of the panel members has said, “Sleep is the third pillar of health, equally important as diet and exercise, if not more.” However, this message is not getting out, or at least it is not being heeded. Like obesity, our efforts as advisers to our patients isn’t working. Unfortunately, this is because our advice is often whispered and given halfheartedly.

There was some evidence of improvement as a result of the pandemic, when those fortunate enough to be able to work from home were taking advantage of the flexibility in their schedules and getting more sleep. But health care providers certainly can’t take responsibility for what was an accident of nature.

Those of you who have been reading Letters from Maine for the last 3 decades may tire of my beating the tired horse of sleep deprivation. But I will not be deterred. I see very little evidence among health care professionals in taking the importance of sleep seriously. Sure, they may include it buried in the list of potential contributors to their patient’s complaint, but I see very little effort to move it higher on their list of priorities and almost no movement toward making substantive recommendations and then reinforcing them with follow-up.

Like obesity, sleep deprivation is a societal problem. We can lay some of the blame on Thomas Edison, but until we as health care professionals take sleep deprivation seriously, we will be undertreating and mistreating our patients who would benefit from a serious discussion of their sleep habits. Until that time you will continue to read columns like this one when I encounter significant studies on the importance of sleep.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

Click to view more from Pulmonology Data Trends 2023.

Click to view more from Pulmonology Data Trends 2023.

Click to view more from Pulmonology Data Trends 2023.

Use of continuous positive-airway pressure devices for at least 4 hours a day was associated with a reduced risk of major adverse cardiac and cerebrovascular events in adults with cardiovascular disease and obstructive sleep apnea, based on data from more than 4,000 individuals.

Obstructive sleep apnea (OSA) is associated with an increased risk of cardiovascular diseases, but the association between management of OSA with a continuous positive-airway pressure device (CPAP) and major adverse cardiac or cerebrovascular events (MACCEs) remains unclear, wrote Manuel Sánchez-de-la-Torre, PhD, of the University of Lleida, Spain, and colleagues.

In a meta-analysis published in JAMA, the researchers reviewed data from 4,186 individuals with a mean age of 61.2 years; 82.1% were men. The study population included 2,097 patients who used CPAP and 2,089 who did not. The mean apnea-hypopnea index (AHI) was 31.2 events per hour, and OSA was defined as an oxygen desaturation index of 12 events or more per hour or an AHI of 15 events or more per hour. The composite primary outcome included the first MACCE, or death from cardiovascular causes, myocardial infarction, stroke, revascularization procedure, hospital admission for heart failure, hospital admission for unstable angina, or hospital admission for transient ischemic attack. Each of these components was a secondary endpoint.

Overall, the primary outcome of MACCE was similar for CPAP and non-CPAP using patients (hazard ratio, 1.01) with a total of 349 MACCE events in the CPAP group and 342 in the non-CPAP group. The mean adherence to CPAP was 3.1 hours per day. A total of 38.5% of patients in the CPAP group met the criteria for good adherence, defined as a mean of 4 or more hours per day.

However, as defined, good adherence to CPAP significantly reduced the risk of MACCE, compared with no CPAP use (HR, 0.69), and a sensitivity analysis showed a significant risk reduction, compared with patients who did not meet the criteria for good adherence (HR, 0.55; P = .005).

“Adherence to treatment is complex to determine and there are other potential factors that could affect patient adherence, such as health education, motivation, attitude, self-efficacy, psychosocial factors, and other health care system–related features,” the researchers wrote in their discussion.

The findings were limited by several factors including the evaluation only of CPAP as a treatment for OSA, and the inability to assess separate components of the composite endpoint, the researchers noted. Other limitations included the relatively small number of female patients, reliance mainly on at-home sleep apnea tests, and the potential for selection bias, they said.

However, the results suggest that CPAP adherence is important to prevention of secondary cardiovascular outcomes in OSA patients, and that implementation of specific and personalized strategies to improve adherence to treatment should be a clinical priority, they concluded.

The study was funded by the Instituto de Salud Carlos III, the European Union and FEDER, IRBLleida–Fundació Dr Pifarré, SEPAR, ResMed Ltd. (Australia), Associació Lleidatana de Respiratori, and CIBERES. Dr Sánchez-de-la-Torre also disclosed financial support from a Ramón y Cajal grant.

Use of continuous positive-airway pressure devices for at least 4 hours a day was associated with a reduced risk of major adverse cardiac and cerebrovascular events in adults with cardiovascular disease and obstructive sleep apnea, based on data from more than 4,000 individuals.

Obstructive sleep apnea (OSA) is associated with an increased risk of cardiovascular diseases, but the association between management of OSA with a continuous positive-airway pressure device (CPAP) and major adverse cardiac or cerebrovascular events (MACCEs) remains unclear, wrote Manuel Sánchez-de-la-Torre, PhD, of the University of Lleida, Spain, and colleagues.

In a meta-analysis published in JAMA, the researchers reviewed data from 4,186 individuals with a mean age of 61.2 years; 82.1% were men. The study population included 2,097 patients who used CPAP and 2,089 who did not. The mean apnea-hypopnea index (AHI) was 31.2 events per hour, and OSA was defined as an oxygen desaturation index of 12 events or more per hour or an AHI of 15 events or more per hour. The composite primary outcome included the first MACCE, or death from cardiovascular causes, myocardial infarction, stroke, revascularization procedure, hospital admission for heart failure, hospital admission for unstable angina, or hospital admission for transient ischemic attack. Each of these components was a secondary endpoint.

Overall, the primary outcome of MACCE was similar for CPAP and non-CPAP using patients (hazard ratio, 1.01) with a total of 349 MACCE events in the CPAP group and 342 in the non-CPAP group. The mean adherence to CPAP was 3.1 hours per day. A total of 38.5% of patients in the CPAP group met the criteria for good adherence, defined as a mean of 4 or more hours per day.

However, as defined, good adherence to CPAP significantly reduced the risk of MACCE, compared with no CPAP use (HR, 0.69), and a sensitivity analysis showed a significant risk reduction, compared with patients who did not meet the criteria for good adherence (HR, 0.55; P = .005).

“Adherence to treatment is complex to determine and there are other potential factors that could affect patient adherence, such as health education, motivation, attitude, self-efficacy, psychosocial factors, and other health care system–related features,” the researchers wrote in their discussion.

The findings were limited by several factors including the evaluation only of CPAP as a treatment for OSA, and the inability to assess separate components of the composite endpoint, the researchers noted. Other limitations included the relatively small number of female patients, reliance mainly on at-home sleep apnea tests, and the potential for selection bias, they said.

However, the results suggest that CPAP adherence is important to prevention of secondary cardiovascular outcomes in OSA patients, and that implementation of specific and personalized strategies to improve adherence to treatment should be a clinical priority, they concluded.

The study was funded by the Instituto de Salud Carlos III, the European Union and FEDER, IRBLleida–Fundació Dr Pifarré, SEPAR, ResMed Ltd. (Australia), Associació Lleidatana de Respiratori, and CIBERES. Dr Sánchez-de-la-Torre also disclosed financial support from a Ramón y Cajal grant.

Use of continuous positive-airway pressure devices for at least 4 hours a day was associated with a reduced risk of major adverse cardiac and cerebrovascular events in adults with cardiovascular disease and obstructive sleep apnea, based on data from more than 4,000 individuals.

Obstructive sleep apnea (OSA) is associated with an increased risk of cardiovascular diseases, but the association between management of OSA with a continuous positive-airway pressure device (CPAP) and major adverse cardiac or cerebrovascular events (MACCEs) remains unclear, wrote Manuel Sánchez-de-la-Torre, PhD, of the University of Lleida, Spain, and colleagues.

In a meta-analysis published in JAMA, the researchers reviewed data from 4,186 individuals with a mean age of 61.2 years; 82.1% were men. The study population included 2,097 patients who used CPAP and 2,089 who did not. The mean apnea-hypopnea index (AHI) was 31.2 events per hour, and OSA was defined as an oxygen desaturation index of 12 events or more per hour or an AHI of 15 events or more per hour. The composite primary outcome included the first MACCE, or death from cardiovascular causes, myocardial infarction, stroke, revascularization procedure, hospital admission for heart failure, hospital admission for unstable angina, or hospital admission for transient ischemic attack. Each of these components was a secondary endpoint.

Overall, the primary outcome of MACCE was similar for CPAP and non-CPAP using patients (hazard ratio, 1.01) with a total of 349 MACCE events in the CPAP group and 342 in the non-CPAP group. The mean adherence to CPAP was 3.1 hours per day. A total of 38.5% of patients in the CPAP group met the criteria for good adherence, defined as a mean of 4 or more hours per day.

However, as defined, good adherence to CPAP significantly reduced the risk of MACCE, compared with no CPAP use (HR, 0.69), and a sensitivity analysis showed a significant risk reduction, compared with patients who did not meet the criteria for good adherence (HR, 0.55; P = .005).

“Adherence to treatment is complex to determine and there are other potential factors that could affect patient adherence, such as health education, motivation, attitude, self-efficacy, psychosocial factors, and other health care system–related features,” the researchers wrote in their discussion.

The findings were limited by several factors including the evaluation only of CPAP as a treatment for OSA, and the inability to assess separate components of the composite endpoint, the researchers noted. Other limitations included the relatively small number of female patients, reliance mainly on at-home sleep apnea tests, and the potential for selection bias, they said.

However, the results suggest that CPAP adherence is important to prevention of secondary cardiovascular outcomes in OSA patients, and that implementation of specific and personalized strategies to improve adherence to treatment should be a clinical priority, they concluded.

The study was funded by the Instituto de Salud Carlos III, the European Union and FEDER, IRBLleida–Fundació Dr Pifarré, SEPAR, ResMed Ltd. (Australia), Associació Lleidatana de Respiratori, and CIBERES. Dr Sánchez-de-la-Torre also disclosed financial support from a Ramón y Cajal grant.

Nearly half of patients undergoing drug-induced sleep endoscopy (DISE) experienced a sentinel central event after an average of 6 minutes in a study of 103 individuals with obstructive sleep apnea (OSA).

DISE has become the top choice for surgical selection in patients with OSA, but it has a variable effect on surgical outcomes, Julianna G. Rodin, MD, of the University of Pennsylvania, Philadelphia, and colleagues explained.

The University of Pennsylvania sleep surgery team developed a comprehensive DISE platform that includes simultaneous collection of respiratory airflow and effort measurements, airway collapsibility, and videoendoscopy.

“This home sleep study-style setup has allowed us to better characterize the upper airway during DISE, and even helped our team diagnose a patient with Cheyne-Stokes breathing/central sleep apnea,” Dr. Rodin said in an interview.

“With it, we also began to notice relatively frequent central and/or mixed sleep disordered breathing events during DISE after propofol dosing initiation,” she said.

In a study presented at the annual meeting of the American Academy of Otolaryngology–Head and Neck Surgery, Dr. Rodin and colleagues measured both the frequency and timing of sentinel central and/or mixed events (SCent) in adults undergoing DISE to assess the prevalence and impact on DISE.

The researchers also assessed differences in VOTE classification (velum, oropharynx, tongue base, and epiglottis) in sentinel central events, compared with obstructive events. VOTE scores were calculated using a grade of 0 for no obstruction, 1 for partial obstruction, and 2 for total obstruction.

The study population included 103 adults with OSA who underwent DISE with propofol sedation at a single tertiary academic medical center between June 2020 and November 2022. The mean age of the participants was 53.5 years, the mean body mass index (BMI) was 29.7 kg/m², and 67% were male. The average apnea-hypopnea index (AHI) was 30.7 events per hour. The researchers used a polysomnography platform to capture data on nasal airflow, thoraco-abdominal effort belt signals, and videoendoscopy.

A total of 47 patients (46%) had at least one SCent. The average time to the first SCent was just under 6 minutes, and average transition to obstructive pathology in these patients occurred between 7 and 8 minutes. Using the one-sided prediction interval, at least 95% of patients were expected to transition to obstructive pathology within 12-13 minutes, Dr. Rodin said.

In addition, 29 of the 46 patients with SCent (63%) showed significant variability between central/mixed VOTE scores and obstructive VOTE scores.

No statistically significant differences were noted between patients with and without SCent in terms of demographics or AHI.
 

Surprising prevalence of SCents

“We anecdotally noted that SCents seemed to be somewhat common during the initial period of DISE, but were surprised that we saw at least one SCent in almost 50% of our DISE population,” Dr. Rodin said. “We also saw that the majority of these SCents eventually transitioned to obstructive events after approximately 12 minutes, which is often past the average duration of normal DISE exams.”

The high frequency of differing VOTE scores between SCents and obstructive events also was unexpected, she added. Within the changes in VOTE scores as defined in the study, “there was a higher tendency for SCents to have more complete tongue base collapse compared to no or partial collapse in obstructive events, and to transition from anterior-posterior velum to concentric velum collapse during the obstructive event.”

This outcome could potentially affect a patient’s candidacy for hypoglossal nerve stimulator therapy, she explained.

The takeaway from the current study is an increased awareness of the prevalence and timing of SCents in OSA patients, said Dr. Rodin. Clinicians who offer DISE and PAP alternatives also should be mindful of clinical signs of effort, by monitoring the chest and abdomen during DISE in the absence of respiratory effort belts.

The study findings also suggest that clinicians consider extending the minimum DISE duration to 10 minutes to ensure that the majority of SCents have passed, and delay VOTE scoring until patients transition to obstructive events, she added.

As for additional research, Dr. Rodin said: “If we could repeat the study with a standardized protocol of target-controlled infusion (TCI) of propofol, that would further bolster the data.” However, TCI is not approved in the United States.

“Our propofol dosing technique was not standardized across all patients, which in theory could account for more SCents if patients were more sedated,” Dr. Rodin noted. “However, we did not see a difference in average bispectral index levels across all patients.”

Other limitations of the current study included an inability to visualize the entire upper airway to achieve a complete VOTE score for every patient, which could have led to underestimation of the VOTE difference frequency, she added.
 

Data inform team approaches to DISE

As DISE procedures become more widespread, “it is paramount that we understand the risks associated with these procedures to increase safety, improve shared decision-making, and encourage a team-based approach in the operating room with our anesthesia colleagues,” said Daniel M. Zeitler, MD, from the University of Washington and Virgina Mason Medical Center, both in Seattle, who served as a moderator for the session in which the study was presented.

“I was surprised by these data for two reasons,” Dr. Zeitler said in an interview. “We typically don’t wait more than a few minutes between induction of anesthesia and the initiation of the airway procedure. This study calls that practice into question, and the duration of time before the onset of a sentinel event was much longer than I would have expected,” he said.

Second, “I was quite surprised that there were no differences in the demographics or AHI between the two groups; this reminds us that AHI and BMI alone may not be themselves predictive of risk and all patients should be assessed similarly.”

“Otolaryngologists performing DISE need to be aware of these data, communicate them to the involved teams, including anesthesia, nursing, and postanesthesia care units, and remember to delay the manipulation of the airway long enough to minimize the risk of a sentinel event,” Dr. Zeitler said. “Perhaps this also means we need improved intraoperative monitoring for these patients, including respiratory airflow and effort monitoring.”

For further research, “we need to increase the number of patients, perform a multicenter study, and expand the study to a wider range of ages, BMI, and AHI,” he added. A recommended algorithm for these cases in order to standardize the practice would be useful.

The study received no outside funding. Dr. Rodin and Dr. Zeitler reported no relevant financial relationships. Several coauthors disclosed funding and relationships with multiple companies unrelated to the current study.

A version of this article appeared on Medscape.com.

Nearly half of patients undergoing drug-induced sleep endoscopy (DISE) experienced a sentinel central event after an average of 6 minutes in a study of 103 individuals with obstructive sleep apnea (OSA).

DISE has become the top choice for surgical selection in patients with OSA, but it has a variable effect on surgical outcomes, Julianna G. Rodin, MD, of the University of Pennsylvania, Philadelphia, and colleagues explained.

The University of Pennsylvania sleep surgery team developed a comprehensive DISE platform that includes simultaneous collection of respiratory airflow and effort measurements, airway collapsibility, and videoendoscopy.

“This home sleep study-style setup has allowed us to better characterize the upper airway during DISE, and even helped our team diagnose a patient with Cheyne-Stokes breathing/central sleep apnea,” Dr. Rodin said in an interview.

“With it, we also began to notice relatively frequent central and/or mixed sleep disordered breathing events during DISE after propofol dosing initiation,” she said.

In a study presented at the annual meeting of the American Academy of Otolaryngology–Head and Neck Surgery, Dr. Rodin and colleagues measured both the frequency and timing of sentinel central and/or mixed events (SCent) in adults undergoing DISE to assess the prevalence and impact on DISE.

The researchers also assessed differences in VOTE classification (velum, oropharynx, tongue base, and epiglottis) in sentinel central events, compared with obstructive events. VOTE scores were calculated using a grade of 0 for no obstruction, 1 for partial obstruction, and 2 for total obstruction.

The study population included 103 adults with OSA who underwent DISE with propofol sedation at a single tertiary academic medical center between June 2020 and November 2022. The mean age of the participants was 53.5 years, the mean body mass index (BMI) was 29.7 kg/m², and 67% were male. The average apnea-hypopnea index (AHI) was 30.7 events per hour. The researchers used a polysomnography platform to capture data on nasal airflow, thoraco-abdominal effort belt signals, and videoendoscopy.

A total of 47 patients (46%) had at least one SCent. The average time to the first SCent was just under 6 minutes, and average transition to obstructive pathology in these patients occurred between 7 and 8 minutes. Using the one-sided prediction interval, at least 95% of patients were expected to transition to obstructive pathology within 12-13 minutes, Dr. Rodin said.

In addition, 29 of the 46 patients with SCent (63%) showed significant variability between central/mixed VOTE scores and obstructive VOTE scores.

No statistically significant differences were noted between patients with and without SCent in terms of demographics or AHI.
 

Surprising prevalence of SCents

“We anecdotally noted that SCents seemed to be somewhat common during the initial period of DISE, but were surprised that we saw at least one SCent in almost 50% of our DISE population,” Dr. Rodin said. “We also saw that the majority of these SCents eventually transitioned to obstructive events after approximately 12 minutes, which is often past the average duration of normal DISE exams.”

The high frequency of differing VOTE scores between SCents and obstructive events also was unexpected, she added. Within the changes in VOTE scores as defined in the study, “there was a higher tendency for SCents to have more complete tongue base collapse compared to no or partial collapse in obstructive events, and to transition from anterior-posterior velum to concentric velum collapse during the obstructive event.”

This outcome could potentially affect a patient’s candidacy for hypoglossal nerve stimulator therapy, she explained.

The takeaway from the current study is an increased awareness of the prevalence and timing of SCents in OSA patients, said Dr. Rodin. Clinicians who offer DISE and PAP alternatives also should be mindful of clinical signs of effort, by monitoring the chest and abdomen during DISE in the absence of respiratory effort belts.

The study findings also suggest that clinicians consider extending the minimum DISE duration to 10 minutes to ensure that the majority of SCents have passed, and delay VOTE scoring until patients transition to obstructive events, she added.

As for additional research, Dr. Rodin said: “If we could repeat the study with a standardized protocol of target-controlled infusion (TCI) of propofol, that would further bolster the data.” However, TCI is not approved in the United States.

“Our propofol dosing technique was not standardized across all patients, which in theory could account for more SCents if patients were more sedated,” Dr. Rodin noted. “However, we did not see a difference in average bispectral index levels across all patients.”

Other limitations of the current study included an inability to visualize the entire upper airway to achieve a complete VOTE score for every patient, which could have led to underestimation of the VOTE difference frequency, she added.
 

Data inform team approaches to DISE

As DISE procedures become more widespread, “it is paramount that we understand the risks associated with these procedures to increase safety, improve shared decision-making, and encourage a team-based approach in the operating room with our anesthesia colleagues,” said Daniel M. Zeitler, MD, from the University of Washington and Virgina Mason Medical Center, both in Seattle, who served as a moderator for the session in which the study was presented.

“I was surprised by these data for two reasons,” Dr. Zeitler said in an interview. “We typically don’t wait more than a few minutes between induction of anesthesia and the initiation of the airway procedure. This study calls that practice into question, and the duration of time before the onset of a sentinel event was much longer than I would have expected,” he said.

Second, “I was quite surprised that there were no differences in the demographics or AHI between the two groups; this reminds us that AHI and BMI alone may not be themselves predictive of risk and all patients should be assessed similarly.”

“Otolaryngologists performing DISE need to be aware of these data, communicate them to the involved teams, including anesthesia, nursing, and postanesthesia care units, and remember to delay the manipulation of the airway long enough to minimize the risk of a sentinel event,” Dr. Zeitler said. “Perhaps this also means we need improved intraoperative monitoring for these patients, including respiratory airflow and effort monitoring.”

For further research, “we need to increase the number of patients, perform a multicenter study, and expand the study to a wider range of ages, BMI, and AHI,” he added. A recommended algorithm for these cases in order to standardize the practice would be useful.

The study received no outside funding. Dr. Rodin and Dr. Zeitler reported no relevant financial relationships. Several coauthors disclosed funding and relationships with multiple companies unrelated to the current study.

A version of this article appeared on Medscape.com.

Nearly half of patients undergoing drug-induced sleep endoscopy (DISE) experienced a sentinel central event after an average of 6 minutes in a study of 103 individuals with obstructive sleep apnea (OSA).

DISE has become the top choice for surgical selection in patients with OSA, but it has a variable effect on surgical outcomes, Julianna G. Rodin, MD, of the University of Pennsylvania, Philadelphia, and colleagues explained.

The University of Pennsylvania sleep surgery team developed a comprehensive DISE platform that includes simultaneous collection of respiratory airflow and effort measurements, airway collapsibility, and videoendoscopy.

“This home sleep study-style setup has allowed us to better characterize the upper airway during DISE, and even helped our team diagnose a patient with Cheyne-Stokes breathing/central sleep apnea,” Dr. Rodin said in an interview.

“With it, we also began to notice relatively frequent central and/or mixed sleep disordered breathing events during DISE after propofol dosing initiation,” she said.

In a study presented at the annual meeting of the American Academy of Otolaryngology–Head and Neck Surgery, Dr. Rodin and colleagues measured both the frequency and timing of sentinel central and/or mixed events (SCent) in adults undergoing DISE to assess the prevalence and impact on DISE.

The researchers also assessed differences in VOTE classification (velum, oropharynx, tongue base, and epiglottis) in sentinel central events, compared with obstructive events. VOTE scores were calculated using a grade of 0 for no obstruction, 1 for partial obstruction, and 2 for total obstruction.

The study population included 103 adults with OSA who underwent DISE with propofol sedation at a single tertiary academic medical center between June 2020 and November 2022. The mean age of the participants was 53.5 years, the mean body mass index (BMI) was 29.7 kg/m², and 67% were male. The average apnea-hypopnea index (AHI) was 30.7 events per hour. The researchers used a polysomnography platform to capture data on nasal airflow, thoraco-abdominal effort belt signals, and videoendoscopy.

A total of 47 patients (46%) had at least one SCent. The average time to the first SCent was just under 6 minutes, and average transition to obstructive pathology in these patients occurred between 7 and 8 minutes. Using the one-sided prediction interval, at least 95% of patients were expected to transition to obstructive pathology within 12-13 minutes, Dr. Rodin said.

In addition, 29 of the 46 patients with SCent (63%) showed significant variability between central/mixed VOTE scores and obstructive VOTE scores.

No statistically significant differences were noted between patients with and without SCent in terms of demographics or AHI.
 

Surprising prevalence of SCents

“We anecdotally noted that SCents seemed to be somewhat common during the initial period of DISE, but were surprised that we saw at least one SCent in almost 50% of our DISE population,” Dr. Rodin said. “We also saw that the majority of these SCents eventually transitioned to obstructive events after approximately 12 minutes, which is often past the average duration of normal DISE exams.”

The high frequency of differing VOTE scores between SCents and obstructive events also was unexpected, she added. Within the changes in VOTE scores as defined in the study, “there was a higher tendency for SCents to have more complete tongue base collapse compared to no or partial collapse in obstructive events, and to transition from anterior-posterior velum to concentric velum collapse during the obstructive event.”

This outcome could potentially affect a patient’s candidacy for hypoglossal nerve stimulator therapy, she explained.

The takeaway from the current study is an increased awareness of the prevalence and timing of SCents in OSA patients, said Dr. Rodin. Clinicians who offer DISE and PAP alternatives also should be mindful of clinical signs of effort, by monitoring the chest and abdomen during DISE in the absence of respiratory effort belts.

The study findings also suggest that clinicians consider extending the minimum DISE duration to 10 minutes to ensure that the majority of SCents have passed, and delay VOTE scoring until patients transition to obstructive events, she added.

As for additional research, Dr. Rodin said: “If we could repeat the study with a standardized protocol of target-controlled infusion (TCI) of propofol, that would further bolster the data.” However, TCI is not approved in the United States.

“Our propofol dosing technique was not standardized across all patients, which in theory could account for more SCents if patients were more sedated,” Dr. Rodin noted. “However, we did not see a difference in average bispectral index levels across all patients.”

Other limitations of the current study included an inability to visualize the entire upper airway to achieve a complete VOTE score for every patient, which could have led to underestimation of the VOTE difference frequency, she added.
 

Data inform team approaches to DISE

As DISE procedures become more widespread, “it is paramount that we understand the risks associated with these procedures to increase safety, improve shared decision-making, and encourage a team-based approach in the operating room with our anesthesia colleagues,” said Daniel M. Zeitler, MD, from the University of Washington and Virgina Mason Medical Center, both in Seattle, who served as a moderator for the session in which the study was presented.

“I was surprised by these data for two reasons,” Dr. Zeitler said in an interview. “We typically don’t wait more than a few minutes between induction of anesthesia and the initiation of the airway procedure. This study calls that practice into question, and the duration of time before the onset of a sentinel event was much longer than I would have expected,” he said.

Second, “I was quite surprised that there were no differences in the demographics or AHI between the two groups; this reminds us that AHI and BMI alone may not be themselves predictive of risk and all patients should be assessed similarly.”

“Otolaryngologists performing DISE need to be aware of these data, communicate them to the involved teams, including anesthesia, nursing, and postanesthesia care units, and remember to delay the manipulation of the airway long enough to minimize the risk of a sentinel event,” Dr. Zeitler said. “Perhaps this also means we need improved intraoperative monitoring for these patients, including respiratory airflow and effort monitoring.”

For further research, “we need to increase the number of patients, perform a multicenter study, and expand the study to a wider range of ages, BMI, and AHI,” he added. A recommended algorithm for these cases in order to standardize the practice would be useful.

The study received no outside funding. Dr. Rodin and Dr. Zeitler reported no relevant financial relationships. Several coauthors disclosed funding and relationships with multiple companies unrelated to the current study.

A version of this article appeared on Medscape.com.

Patients with chronic insomnia that does not improve with nonpharmacologic techniques often develop tolerance to sedative medications (benzodiazepines) prescribed for nightly use. When nonbenzodiazepine medications are used, tachyphylaxis can develop and these medications no longer initiate or maintain sleep. Strategies that alternate between these 2 types of agents are simple to follow and may allow patients to maintain sensitivity to both types of medications. In this article, I review the types, causes, evaluation, and treatment of insomnia; describe an alternating medication strategy to help patients avoid developing tolerance/tachyphylaxis; and present 3 fictional case vignettes to illustrate this approach.

A common, troubling condition

Insomnia is a common problem among psychiatric patients. Approximately 30% to 50% of adults experience occasional, short-term (<3 months) insomnia, and 5% to 10% experience chronic (≥3 months) insomnia,¹ with associated negative impacts on health and quality of life. Insomnia is sometimes primary and may have a hereditary component, but more often is associated with medical, neurologic, or psychiatric disorders.

Patterns of insomnia include difficulty falling asleep (initial or sleep-onset insomnia), remaining asleep (middle or sleep-maintenance insomnia), or falling back asleep after early awakening (late or sleep-offset insomnia). Sleep-onset insomnia correlates with high levels of anxiety and worrying, but once asleep, patients usually stay asleep. Sleep-maintenance problems involve multiple awakenings after falling asleep and taking hours to fall back to sleep. These patients experience inadequate sleep when they must wake up early for school or work. Early-awakening patients report feeling wide awake by 4 to 5 am and being unable to get back to sleep.

Caffeine is an important consideration for patients with sleep difficulties. Its use is widespread in much of the world, whether ingested as coffee, tea, in soft drinks, or in “energy” drinks that may contain as much as 200 mg of caffeine (twice the amount in a typical cup of brewed coffee). Caffeine may also be ingested as an ingredient of medications for headache or migraine. While some individuals maintain that they can fall asleep easily after drinking caffeinated coffee, many may not recognize the amount of caffeine they consume and its negative impact on sleep.² Author Michael Pollan stopped use of all caffeine and reported on the surprising positive effect on his sleep.³

Patients with mood, anxiety, or psychotic disorders are likely to experience insomnia intermittently or chronically, and insomnia predisposes some individuals to develop mood and anxiety symptoms.⁴ Patients with insomnia often experience anxiety focused on a fear of not getting adequate sleep, which creates a vicious cycle in which hyperarousal associated with fear of not sleeping complicates other causes of insomnia. A patient’s chronotype (preference for the time of day in which they carry out activities vs sleeping) also may play a role in sleep difficulties (Box⁵).

Box

Certain medications may contribute to insomnia, particularly stimulants. It is important to understand and explain to patients the time frame during which immediate-release or extended-release (ER) stimulants are active, which varies in individuals depending on liver enzyme activity. Other commonly used psychotropic medications—including bupropion, modafinil, armodafinil, atomoxetine, amphetamine salts, and methylphenidate—may interfere with sleep if used later in the day.⁶

Patients typically do not mention their use of alcohol and/or marijuana unless asked. Those who are binge drinkers or alcohol-dependent may expect alcohol to help them fall asleep, but usually find their sleep is disrupted and difficult to maintain. Patients may use marijuana to help them sleep, particularly marijuana high in tetrahydrocannabinol (THC). While it may help with sleep initiation, THC can disrupt sleep maintenance. Cannabidiol does not have intrinsic sedating effects and may even interfere with sleep.^7,8

Continue to: Women may be more likely...

Women may be more likely than men to experience insomnia.⁹ The onset of menopause can bring hot flashes that interfere with sleep.

Women with a history of mood disorders are more likely to have a history of premenstrual dysphoric disorder, postpartum depression, and unusual responses to oral contraceptives.¹⁰ These women are more likely to report problems with mood, energy, and sleep at perimenopause. Treatment with estrogen replacement may be an option for women without risk factors, such as clotting disorders, smoking history, or a personal or family history of breast or uterine cancer. For many who are not candidates for or who refuse estrogen replacement, use of a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor at low doses may help with vasomotor symptoms but not with insomnia.

Insomnia symptoms typically increase with age.¹¹ When sleep is adequate early in life but becomes a problem in midlife, an individual’s eating habits, obesity, and lack of exercise may be contributing factors. The typical American diet includes highly refined carbohydrates with excess salt; such foods are often readily available to the exclusion of healthy options. Overweight and obese patients may insist they eat a healthy diet with 3 meals per day, but a careful history often uncovers nighttime binge eating. Nighttime binge eating is rarely reported. This not only maintains obesity, but also interferes with sleep, since patients stay up late to avoid discovery by family members.¹² This lack of sleep can lead to an endless loop because insufficient sleep is a risk factor for obesity.¹³

Evaluating sleep difficulties

New patient evaluations should include a careful history beginning with childhood, including personal early childhood history and family psychiatric history. Patients often report the onset of sleep difficulty and anxiety during childhood, which should raise further questions about aspects of mood regulation from early life such as concentration, energy, motivation, appetite, and academic performance. While many children and adolescents are diagnosed with attention-deficit/hyperactivity disorder due to concentration problems that cause difficulties at school, be aware this might be part of a syndrome related to mood regulation.¹⁴ Unexpected responses to an SSRI—such as agitation, euphoria, or an immediate response with the first dose—should also raise suspicion of a mood disorder. Once the underlying mood disorder is stabilized, many patients report improved sleep.¹⁵

If a patient reports having difficulty falling and remaining asleep but is not sure if there is a pattern, keeping a sleep diary can help. Further questioning may uncover the cause. Does the patient have spontaneous jerks of lower extremities (restless leg syndrome) that interfere with falling asleep or wake them up? Have they noticed problems with dreams/nightmares that wake them, which could be associated with posttraumatic stress, anxiety, or depression? Have they been told by a partner that they act out dreams or are seemingly awake but not responsive, which could point to REM sleep behavior disorder or early Parkinson’s disease? Referral to a sleep laboratory and a neurologist can help establish the correct diagnosis and point to appropriate treatment.^16-18

Treatment options

Several cognitive-behavioral techniques, including cognitive-behavioral therapy for insomnia (CBT-I), yogic breathing, progressive relaxation, mindfulness meditation, and sleep hygiene techniques may help considerably,^19,20 but insomnia often remains difficult to treat. Pharmacotherapy is not necessarily more effective than nonpharmacologic approaches. Both options require the patient to take initiative to either find nonpharmacologic approaches or discuss the problem with a physician and agree to take medication.²¹ A trial comparing CBT-I to sedatives or the combination of CBT-I plus sedatives found higher rates of sleep with CBT-I for 3 months, after which improvement fluctuated; the combination showed sustained improvement for the entire 6-month trial.²² CBT-I has also been shown to be as effective with patients who do not have psychiatric illness as for those who are depressed, anxious, or stressed.²³ However, behavioral techniques that require regular practice may be difficult for individuals to maintain, particularly when they are depressed or anxious.

Continue to: Clinicians should understand...

Clinicians should understand the distinctions among the various types of pharmacotherapy for insomnia. Sedative-hypnotics include medications with varying half-lives and metabolic pathways. Short-acting benzodiazepines such as triazolam or alprazolam and the “z-drugs” zolpidem or zaleplon may help initiate sleep in patients with sleep-onset insomnia. Longer-acting benzodiazepines such as diazepam, clonazepam, or temazepam and the z-drug eszopiclone may also help with sleep maintenance.²³ Based on my clinical experience, individual patients may respond better to 1 type of medication over another, or even to different agents within the same class of sedative-hypnotics.

Some clinicians prescribe nonbenzodiazepine medications for sleep, such as doxepin (which is FDA-approved for treating insomnia) or off-label trazodone, mirtazapine, or quetiapine. Their antihistaminic properties confer sedating effects. Virtually all over-the-counter (OTC) medications for insomnia are antihistaminic. These OTC medications are not designed to treat insomnia, and the optimal dosage to maintain sleep without daytime sedation must be determined by trial and error. Sedating nonbenzodiazepine medications may be slowly absorbed if taken at bedtime (depending on whether they are taken with or without food) and cause daytime sedation and cognitive slowness in patients with sleep-onset and maintenance insomnia who must wake up early. Starting trazodone at 50 to 75 mg may cause slow metabolizers to wake up with considerable sedation, while fast metabolizers might never feel soundly asleep.²⁴

Patients with mood and anxiety disorders that complicate insomnia are often prescribed second-generation antipsychotics such as quetiapine, lurasidone, or olanzapine, which are sedating as well as mood-stabilizing. These approaches require careful attention to titrating doses and timing their use.

Problems with pharmacotherapy

When either benzodiazepines or nonbenzodiazepine medications are used on a long-standing, nightly basis, they often stop working well. It is not unusual that after days to weeks of taking a benzodiazepine, patients find they no longer stay asleep but can’t fall asleep if they don’t take them. Once tolerance develops, the individual experiences pharmacologic withdrawal with an inability to fall asleep or stay asleep. The medication becomes necessary but ineffective, and many patients increase their use to higher doses to fall asleep, and sometimes in early morning to maintain sleep. This leads to negative effects on cognition, coordination/balance, and mood during the day, especially in older patients.

Nonbenzodiazepine sedating medications do not lead to pharmacologic tolerance but do lead to tachyphylaxis as the CNS attempts to downregulate sedation to keep the organism safe. For some patients, this happens quickly, within a matter of days.²⁵ Others increase doses to stay asleep. For example, a patient with a starting dose of trazodone 75 mg/d might increase the dosage to 300 mg/d. While trazodone is approved in doses of 300 to 600 mg as an antidepressant, it is preferable to keep doses lower when used only for sedation.

Continue to: An alternating medication strategy

Alternating between medications from different classes can help patients avoid developing tolerance with benzodiazepines or tachyphylaxis as occurs with antihistaminic medications. It can be effective for patients with primary insomnia as well as for those whose sleep problems are associated with mood or anxiety disorders. Patients typically maintain sensitivity to any form of pharmacologic sedation for several nights without loss of effect but need to take a break to maintain the sedation effect. For example, in 1 case study, a 30-year-old female who rapidly developed tachyphylaxis to the sedative action of mirtazapine experienced a return of the medication’s sedative effects after taking a 3-day break.²⁵

To initiate an alternating strategy, the clinician must first help the patient establish a sedating dose of 2 medications from different classes, such as trazodone and zolpidem, and then instruct the patient to use each for 2 to 3 consecutive nights on an alternating basis. Patients can use calendars or pillboxes to avoid confusion about which medication to take on a given night. In many cases, this approach can work indefinitely.

The following 3 case vignettes illustrate how this alternating medication strategy can work.

CASE 1

Mr. B, age 58, is a married salesman whose territory includes 3 states. He drives from client to client from Monday through Thursday each week, staying overnight in hotels. He is comfortable talking to clients, has a close and supportive relationship with his wife, and enjoys socializing with friends. Mr. B has a high level of trait anxiety and perfectionism and is proud of his sales record throughout his career, but this leads to insomnia during his nights on the road, and often on Sunday night as he starts anticipating the week ahead. Mr. B denies having a depressed mood or cognitive problems. When on vacation with his wife he has no trouble sleeping. He has no psychiatric family history or any substantial medical problems. He simply wishes that he could sleep on work nights.

We set up an alternating medication approach. Mr. B takes trazodone 100 mg on the first night and 150 mg on the second and third nights. He then takes triazolam 0.25 mg for 2 nights; previously, he had found that zolpidem did not work as well for maintaining sleep. He can sleep adequately for the 2 weekend nights, then restarts the alternating pattern. Mr. B has done well with this regimen for >10 years.

Continue to: CASE 2

Ms. C, age 60, is widowed and has a successful career as a corporate attorney. She has been anxious since early childhood and has had trouble falling asleep for much of her life. Once she falls asleep on her sofa—often between 1 and 2 am—Ms. C can sleep soundly for 7 to 8 hours, but early morning work meetings require her to set an alarm for 6 am daily. Ms. C feels irritable and anxious on awakening but arrives at her office by 7:30 am, where she maintains a full schedule, with frequent 12-hour workdays. Ms. C did not experience significant insomnia or hot flashes with menopause at age 52 and does not use hormone replacement therapy.

Ms. C denies having depression, but experienced appropriate grief related to her husband’s illness and death from metastatic cancer 3 years ago. At the time, her internist prescribed escitalopram and zolpidem; escitalopram caused greater agitation and distress, so she stopped it after 10 days. Zolpidem 10 mg/d allowed her to sleep but she worried about taking it because her mother had long-standing sedative dependence. Ms. C lives alone, but her adult children live nearby, and she has a strong support system that includes colleagues at her firm, friends at her book club, and a support group for partners of cancer patients.

Ms. C tries trazodone, starting with 50 mg, but reports feeling agitated rather than sleepy and has cognitive fogginess in the morning. She is switched to quetiapine 50 mg, which she tolerates well and allows her to sleep soundly. To avoid developing tachyphylaxis with quetiapine, she takes eszopiclone 3 mg for 2 nights, alternating with quetiapine for 3 nights. This strategy allows her to reliably fall asleep by 11 pm, wake up at 6 am, and feel rested throughout the day.

CASE 3

Ms. D, age 55, is married with a long-standing diagnosis of generalized anxiety disorder (GAD), panic disorder, and depression so severe she is unable to work as a preschool teacher. She notes that past clinicians have prescribed a wide array of antidepressants and benzodiazepines but she remains anxious, agitated, and unable to sleep. She worries constantly about running out of benzodiazepines, which are “the only medication that helps me.” At the time of evaluation, her medications are venlafaxine ER 150 mg/d, lorazepam 1 mg 3 times daily and 2 mg at bedtime, and buspirone 15 mg 3 times daily, which she admits to not taking. She is overweight and does not exercise. She spends her days snacking and watching television. She can’t settle down enough to read and feels overwhelmed most of the time. Her adult children won’t allow her to babysit their young children because she dozes during the day.

Ms. D has a strong family history of psychiatric illness, including a father with bipolar I disorder and alcohol use disorder and a sister with schizoaffective disorder. Ms. D has never felt overtly manic, but has spent most of her life feeling depressed, anxious, and hopeless, and at times she has wished she was dead. She has had poor responses to many antidepressants, with transient euphoria followed by more anxiety.

Continue to: Rather than major depressive disorder...

Rather than major depressive disorder or GAD, Ms. D’s symptoms better meet the criteria for bipolar II disorder. She agrees to a slow taper of venlafaxine and a slow increase of divalproex, starting with 125 mg each evening. While taking venlafaxine 75 mg/d and divalproex 375 mg/d, she experiences distinct improvement in anxiety and agitation, which further improve after venlafaxine is stopped and divalproex is increased to 750 mg in the evening. She finds that she forgets daytime doses of lorazepam but depends on it to fall asleep. While taking quetiapine 50 mg and lorazepam 1 mg at bedtime, Ms. D reports sleeping soundly and feeling alert in the morning. Over several weeks, she tapers lorazepam slowly by 0.5 mg every 2 weeks. She finds she needs a higher dose of quetiapine to stay asleep, eventually requiring 400 mg each night. Ms. D says overall she feels better but is distressed because she has gained 25 lbs since starting divalproex and quetiapine.

To avoid further increases in quetiapine and maintain its sedating effect, Ms. D is switched to an alternating schedule of clonazepam 1.5 mg for 2 nights and quetiapine 300 mg for 3 nights. She agrees to begin exercising by walking in her neighborhood daily, and gradually increases this to 1 hour per day. After starting to exercise regularly, she finds she is oversedated by quetiapine at night, so she is gradually decreased to a dose of 150 mg, while still alternating with clonazepam 1.5 mg. Ms. D loses most of the weight she had gained and begins volunteering as a reading coach in the elementary school in her neighborhood.

Bottom Line

Patients with chronic insomnia can often maintain adequate sedation without developing tolerance to benzodiazepines or tachyphylaxis with nonsedating agents by using 2 sleep medications that have different mechanisms of action on an alternating schedule.

Related Resources

• Sateia MJ, Buysse DJ, Krystal AD, et al. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2): 307-349. doi:10.5664/jcsm.6470
• Muppavarapu K, Muthukanagaraj M, Saeed SA. Cognitive-behavioral therapy for insomnia: a review of 8 studies. Current Psychiatry. 2020;19(9):40-46. doi:10.12788/cp.0040

Drug Brand Names

Alprazolam • Xanax
Armodafinil • Nuvigil
Atomoxetine • Strattera
Bupropion • Wellbutrin
Clonazepam • Klonopin
Diazepam • Valium
Divalproex • Depakote
Doxepin • Sinequan
Escitalopram • Lexapro
Eszopiclone • Lunesta
Lorazepam • Ativan
Lurasidone • Latuda
Methylphenidate • Concerta
Mirtazapine • Remeron
Modafinil • Provigil
Olanzapine • Zyprexa
Quetiapine • Seroquel
Temazepam • Restoril
Trazodone • Desyrel
Triazolam • Halcion
Venlafaxine • Effexor
Zaleplon • Sonata
Zolpidem • Ambien

Patients with chronic insomnia that does not improve with nonpharmacologic techniques often develop tolerance to sedative medications (benzodiazepines) prescribed for nightly use. When nonbenzodiazepine medications are used, tachyphylaxis can develop and these medications no longer initiate or maintain sleep. Strategies that alternate between these 2 types of agents are simple to follow and may allow patients to maintain sensitivity to both types of medications. In this article, I review the types, causes, evaluation, and treatment of insomnia; describe an alternating medication strategy to help patients avoid developing tolerance/tachyphylaxis; and present 3 fictional case vignettes to illustrate this approach.

A common, troubling condition

Insomnia is a common problem among psychiatric patients. Approximately 30% to 50% of adults experience occasional, short-term (<3 months) insomnia, and 5% to 10% experience chronic (≥3 months) insomnia,¹ with associated negative impacts on health and quality of life. Insomnia is sometimes primary and may have a hereditary component, but more often is associated with medical, neurologic, or psychiatric disorders.

Patterns of insomnia include difficulty falling asleep (initial or sleep-onset insomnia), remaining asleep (middle or sleep-maintenance insomnia), or falling back asleep after early awakening (late or sleep-offset insomnia). Sleep-onset insomnia correlates with high levels of anxiety and worrying, but once asleep, patients usually stay asleep. Sleep-maintenance problems involve multiple awakenings after falling asleep and taking hours to fall back to sleep. These patients experience inadequate sleep when they must wake up early for school or work. Early-awakening patients report feeling wide awake by 4 to 5 am and being unable to get back to sleep.

Caffeine is an important consideration for patients with sleep difficulties. Its use is widespread in much of the world, whether ingested as coffee, tea, in soft drinks, or in “energy” drinks that may contain as much as 200 mg of caffeine (twice the amount in a typical cup of brewed coffee). Caffeine may also be ingested as an ingredient of medications for headache or migraine. While some individuals maintain that they can fall asleep easily after drinking caffeinated coffee, many may not recognize the amount of caffeine they consume and its negative impact on sleep.² Author Michael Pollan stopped use of all caffeine and reported on the surprising positive effect on his sleep.³

Patients with mood, anxiety, or psychotic disorders are likely to experience insomnia intermittently or chronically, and insomnia predisposes some individuals to develop mood and anxiety symptoms.⁴ Patients with insomnia often experience anxiety focused on a fear of not getting adequate sleep, which creates a vicious cycle in which hyperarousal associated with fear of not sleeping complicates other causes of insomnia. A patient’s chronotype (preference for the time of day in which they carry out activities vs sleeping) also may play a role in sleep difficulties (Box⁵).

Box

Certain medications may contribute to insomnia, particularly stimulants. It is important to understand and explain to patients the time frame during which immediate-release or extended-release (ER) stimulants are active, which varies in individuals depending on liver enzyme activity. Other commonly used psychotropic medications—including bupropion, modafinil, armodafinil, atomoxetine, amphetamine salts, and methylphenidate—may interfere with sleep if used later in the day.⁶

Patients typically do not mention their use of alcohol and/or marijuana unless asked. Those who are binge drinkers or alcohol-dependent may expect alcohol to help them fall asleep, but usually find their sleep is disrupted and difficult to maintain. Patients may use marijuana to help them sleep, particularly marijuana high in tetrahydrocannabinol (THC). While it may help with sleep initiation, THC can disrupt sleep maintenance. Cannabidiol does not have intrinsic sedating effects and may even interfere with sleep.^7,8

Continue to: Women may be more likely...

Women may be more likely than men to experience insomnia.⁹ The onset of menopause can bring hot flashes that interfere with sleep.

Women with a history of mood disorders are more likely to have a history of premenstrual dysphoric disorder, postpartum depression, and unusual responses to oral contraceptives.¹⁰ These women are more likely to report problems with mood, energy, and sleep at perimenopause. Treatment with estrogen replacement may be an option for women without risk factors, such as clotting disorders, smoking history, or a personal or family history of breast or uterine cancer. For many who are not candidates for or who refuse estrogen replacement, use of a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor at low doses may help with vasomotor symptoms but not with insomnia.

Insomnia symptoms typically increase with age.¹¹ When sleep is adequate early in life but becomes a problem in midlife, an individual’s eating habits, obesity, and lack of exercise may be contributing factors. The typical American diet includes highly refined carbohydrates with excess salt; such foods are often readily available to the exclusion of healthy options. Overweight and obese patients may insist they eat a healthy diet with 3 meals per day, but a careful history often uncovers nighttime binge eating. Nighttime binge eating is rarely reported. This not only maintains obesity, but also interferes with sleep, since patients stay up late to avoid discovery by family members.¹² This lack of sleep can lead to an endless loop because insufficient sleep is a risk factor for obesity.¹³

Evaluating sleep difficulties

New patient evaluations should include a careful history beginning with childhood, including personal early childhood history and family psychiatric history. Patients often report the onset of sleep difficulty and anxiety during childhood, which should raise further questions about aspects of mood regulation from early life such as concentration, energy, motivation, appetite, and academic performance. While many children and adolescents are diagnosed with attention-deficit/hyperactivity disorder due to concentration problems that cause difficulties at school, be aware this might be part of a syndrome related to mood regulation.¹⁴ Unexpected responses to an SSRI—such as agitation, euphoria, or an immediate response with the first dose—should also raise suspicion of a mood disorder. Once the underlying mood disorder is stabilized, many patients report improved sleep.¹⁵

If a patient reports having difficulty falling and remaining asleep but is not sure if there is a pattern, keeping a sleep diary can help. Further questioning may uncover the cause. Does the patient have spontaneous jerks of lower extremities (restless leg syndrome) that interfere with falling asleep or wake them up? Have they noticed problems with dreams/nightmares that wake them, which could be associated with posttraumatic stress, anxiety, or depression? Have they been told by a partner that they act out dreams or are seemingly awake but not responsive, which could point to REM sleep behavior disorder or early Parkinson’s disease? Referral to a sleep laboratory and a neurologist can help establish the correct diagnosis and point to appropriate treatment.^16-18

Treatment options

Several cognitive-behavioral techniques, including cognitive-behavioral therapy for insomnia (CBT-I), yogic breathing, progressive relaxation, mindfulness meditation, and sleep hygiene techniques may help considerably,^19,20 but insomnia often remains difficult to treat. Pharmacotherapy is not necessarily more effective than nonpharmacologic approaches. Both options require the patient to take initiative to either find nonpharmacologic approaches or discuss the problem with a physician and agree to take medication.²¹ A trial comparing CBT-I to sedatives or the combination of CBT-I plus sedatives found higher rates of sleep with CBT-I for 3 months, after which improvement fluctuated; the combination showed sustained improvement for the entire 6-month trial.²² CBT-I has also been shown to be as effective with patients who do not have psychiatric illness as for those who are depressed, anxious, or stressed.²³ However, behavioral techniques that require regular practice may be difficult for individuals to maintain, particularly when they are depressed or anxious.

Continue to: Clinicians should understand...

Clinicians should understand the distinctions among the various types of pharmacotherapy for insomnia. Sedative-hypnotics include medications with varying half-lives and metabolic pathways. Short-acting benzodiazepines such as triazolam or alprazolam and the “z-drugs” zolpidem or zaleplon may help initiate sleep in patients with sleep-onset insomnia. Longer-acting benzodiazepines such as diazepam, clonazepam, or temazepam and the z-drug eszopiclone may also help with sleep maintenance.²³ Based on my clinical experience, individual patients may respond better to 1 type of medication over another, or even to different agents within the same class of sedative-hypnotics.

Some clinicians prescribe nonbenzodiazepine medications for sleep, such as doxepin (which is FDA-approved for treating insomnia) or off-label trazodone, mirtazapine, or quetiapine. Their antihistaminic properties confer sedating effects. Virtually all over-the-counter (OTC) medications for insomnia are antihistaminic. These OTC medications are not designed to treat insomnia, and the optimal dosage to maintain sleep without daytime sedation must be determined by trial and error. Sedating nonbenzodiazepine medications may be slowly absorbed if taken at bedtime (depending on whether they are taken with or without food) and cause daytime sedation and cognitive slowness in patients with sleep-onset and maintenance insomnia who must wake up early. Starting trazodone at 50 to 75 mg may cause slow metabolizers to wake up with considerable sedation, while fast metabolizers might never feel soundly asleep.²⁴

Patients with mood and anxiety disorders that complicate insomnia are often prescribed second-generation antipsychotics such as quetiapine, lurasidone, or olanzapine, which are sedating as well as mood-stabilizing. These approaches require careful attention to titrating doses and timing their use.

Problems with pharmacotherapy

When either benzodiazepines or nonbenzodiazepine medications are used on a long-standing, nightly basis, they often stop working well. It is not unusual that after days to weeks of taking a benzodiazepine, patients find they no longer stay asleep but can’t fall asleep if they don’t take them. Once tolerance develops, the individual experiences pharmacologic withdrawal with an inability to fall asleep or stay asleep. The medication becomes necessary but ineffective, and many patients increase their use to higher doses to fall asleep, and sometimes in early morning to maintain sleep. This leads to negative effects on cognition, coordination/balance, and mood during the day, especially in older patients.

Nonbenzodiazepine sedating medications do not lead to pharmacologic tolerance but do lead to tachyphylaxis as the CNS attempts to downregulate sedation to keep the organism safe. For some patients, this happens quickly, within a matter of days.²⁵ Others increase doses to stay asleep. For example, a patient with a starting dose of trazodone 75 mg/d might increase the dosage to 300 mg/d. While trazodone is approved in doses of 300 to 600 mg as an antidepressant, it is preferable to keep doses lower when used only for sedation.

Continue to: An alternating medication strategy

Alternating between medications from different classes can help patients avoid developing tolerance with benzodiazepines or tachyphylaxis as occurs with antihistaminic medications. It can be effective for patients with primary insomnia as well as for those whose sleep problems are associated with mood or anxiety disorders. Patients typically maintain sensitivity to any form of pharmacologic sedation for several nights without loss of effect but need to take a break to maintain the sedation effect. For example, in 1 case study, a 30-year-old female who rapidly developed tachyphylaxis to the sedative action of mirtazapine experienced a return of the medication’s sedative effects after taking a 3-day break.²⁵

To initiate an alternating strategy, the clinician must first help the patient establish a sedating dose of 2 medications from different classes, such as trazodone and zolpidem, and then instruct the patient to use each for 2 to 3 consecutive nights on an alternating basis. Patients can use calendars or pillboxes to avoid confusion about which medication to take on a given night. In many cases, this approach can work indefinitely.

The following 3 case vignettes illustrate how this alternating medication strategy can work.

CASE 1

Mr. B, age 58, is a married salesman whose territory includes 3 states. He drives from client to client from Monday through Thursday each week, staying overnight in hotels. He is comfortable talking to clients, has a close and supportive relationship with his wife, and enjoys socializing with friends. Mr. B has a high level of trait anxiety and perfectionism and is proud of his sales record throughout his career, but this leads to insomnia during his nights on the road, and often on Sunday night as he starts anticipating the week ahead. Mr. B denies having a depressed mood or cognitive problems. When on vacation with his wife he has no trouble sleeping. He has no psychiatric family history or any substantial medical problems. He simply wishes that he could sleep on work nights.

We set up an alternating medication approach. Mr. B takes trazodone 100 mg on the first night and 150 mg on the second and third nights. He then takes triazolam 0.25 mg for 2 nights; previously, he had found that zolpidem did not work as well for maintaining sleep. He can sleep adequately for the 2 weekend nights, then restarts the alternating pattern. Mr. B has done well with this regimen for >10 years.

Continue to: CASE 2

Ms. C, age 60, is widowed and has a successful career as a corporate attorney. She has been anxious since early childhood and has had trouble falling asleep for much of her life. Once she falls asleep on her sofa—often between 1 and 2 am—Ms. C can sleep soundly for 7 to 8 hours, but early morning work meetings require her to set an alarm for 6 am daily. Ms. C feels irritable and anxious on awakening but arrives at her office by 7:30 am, where she maintains a full schedule, with frequent 12-hour workdays. Ms. C did not experience significant insomnia or hot flashes with menopause at age 52 and does not use hormone replacement therapy.

Ms. C denies having depression, but experienced appropriate grief related to her husband’s illness and death from metastatic cancer 3 years ago. At the time, her internist prescribed escitalopram and zolpidem; escitalopram caused greater agitation and distress, so she stopped it after 10 days. Zolpidem 10 mg/d allowed her to sleep but she worried about taking it because her mother had long-standing sedative dependence. Ms. C lives alone, but her adult children live nearby, and she has a strong support system that includes colleagues at her firm, friends at her book club, and a support group for partners of cancer patients.

Ms. C tries trazodone, starting with 50 mg, but reports feeling agitated rather than sleepy and has cognitive fogginess in the morning. She is switched to quetiapine 50 mg, which she tolerates well and allows her to sleep soundly. To avoid developing tachyphylaxis with quetiapine, she takes eszopiclone 3 mg for 2 nights, alternating with quetiapine for 3 nights. This strategy allows her to reliably fall asleep by 11 pm, wake up at 6 am, and feel rested throughout the day.

CASE 3

Ms. D, age 55, is married with a long-standing diagnosis of generalized anxiety disorder (GAD), panic disorder, and depression so severe she is unable to work as a preschool teacher. She notes that past clinicians have prescribed a wide array of antidepressants and benzodiazepines but she remains anxious, agitated, and unable to sleep. She worries constantly about running out of benzodiazepines, which are “the only medication that helps me.” At the time of evaluation, her medications are venlafaxine ER 150 mg/d, lorazepam 1 mg 3 times daily and 2 mg at bedtime, and buspirone 15 mg 3 times daily, which she admits to not taking. She is overweight and does not exercise. She spends her days snacking and watching television. She can’t settle down enough to read and feels overwhelmed most of the time. Her adult children won’t allow her to babysit their young children because she dozes during the day.

Ms. D has a strong family history of psychiatric illness, including a father with bipolar I disorder and alcohol use disorder and a sister with schizoaffective disorder. Ms. D has never felt overtly manic, but has spent most of her life feeling depressed, anxious, and hopeless, and at times she has wished she was dead. She has had poor responses to many antidepressants, with transient euphoria followed by more anxiety.

Continue to: Rather than major depressive disorder...

Rather than major depressive disorder or GAD, Ms. D’s symptoms better meet the criteria for bipolar II disorder. She agrees to a slow taper of venlafaxine and a slow increase of divalproex, starting with 125 mg each evening. While taking venlafaxine 75 mg/d and divalproex 375 mg/d, she experiences distinct improvement in anxiety and agitation, which further improve after venlafaxine is stopped and divalproex is increased to 750 mg in the evening. She finds that she forgets daytime doses of lorazepam but depends on it to fall asleep. While taking quetiapine 50 mg and lorazepam 1 mg at bedtime, Ms. D reports sleeping soundly and feeling alert in the morning. Over several weeks, she tapers lorazepam slowly by 0.5 mg every 2 weeks. She finds she needs a higher dose of quetiapine to stay asleep, eventually requiring 400 mg each night. Ms. D says overall she feels better but is distressed because she has gained 25 lbs since starting divalproex and quetiapine.

To avoid further increases in quetiapine and maintain its sedating effect, Ms. D is switched to an alternating schedule of clonazepam 1.5 mg for 2 nights and quetiapine 300 mg for 3 nights. She agrees to begin exercising by walking in her neighborhood daily, and gradually increases this to 1 hour per day. After starting to exercise regularly, she finds she is oversedated by quetiapine at night, so she is gradually decreased to a dose of 150 mg, while still alternating with clonazepam 1.5 mg. Ms. D loses most of the weight she had gained and begins volunteering as a reading coach in the elementary school in her neighborhood.

Bottom Line

Patients with chronic insomnia can often maintain adequate sedation without developing tolerance to benzodiazepines or tachyphylaxis with nonsedating agents by using 2 sleep medications that have different mechanisms of action on an alternating schedule.

Related Resources

• Sateia MJ, Buysse DJ, Krystal AD, et al. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2): 307-349. doi:10.5664/jcsm.6470
• Muppavarapu K, Muthukanagaraj M, Saeed SA. Cognitive-behavioral therapy for insomnia: a review of 8 studies. Current Psychiatry. 2020;19(9):40-46. doi:10.12788/cp.0040

Drug Brand Names

Alprazolam • Xanax
Armodafinil • Nuvigil
Atomoxetine • Strattera
Bupropion • Wellbutrin
Clonazepam • Klonopin
Diazepam • Valium
Divalproex • Depakote
Doxepin • Sinequan
Escitalopram • Lexapro
Eszopiclone • Lunesta
Lorazepam • Ativan
Lurasidone • Latuda
Methylphenidate • Concerta
Mirtazapine • Remeron
Modafinil • Provigil
Olanzapine • Zyprexa
Quetiapine • Seroquel
Temazepam • Restoril
Trazodone • Desyrel
Triazolam • Halcion
Venlafaxine • Effexor
Zaleplon • Sonata
Zolpidem • Ambien

Patients with chronic insomnia that does not improve with nonpharmacologic techniques often develop tolerance to sedative medications (benzodiazepines) prescribed for nightly use. When nonbenzodiazepine medications are used, tachyphylaxis can develop and these medications no longer initiate or maintain sleep. Strategies that alternate between these 2 types of agents are simple to follow and may allow patients to maintain sensitivity to both types of medications. In this article, I review the types, causes, evaluation, and treatment of insomnia; describe an alternating medication strategy to help patients avoid developing tolerance/tachyphylaxis; and present 3 fictional case vignettes to illustrate this approach.

A common, troubling condition

Insomnia is a common problem among psychiatric patients. Approximately 30% to 50% of adults experience occasional, short-term (<3 months) insomnia, and 5% to 10% experience chronic (≥3 months) insomnia,¹ with associated negative impacts on health and quality of life. Insomnia is sometimes primary and may have a hereditary component, but more often is associated with medical, neurologic, or psychiatric disorders.

Patterns of insomnia include difficulty falling asleep (initial or sleep-onset insomnia), remaining asleep (middle or sleep-maintenance insomnia), or falling back asleep after early awakening (late or sleep-offset insomnia). Sleep-onset insomnia correlates with high levels of anxiety and worrying, but once asleep, patients usually stay asleep. Sleep-maintenance problems involve multiple awakenings after falling asleep and taking hours to fall back to sleep. These patients experience inadequate sleep when they must wake up early for school or work. Early-awakening patients report feeling wide awake by 4 to 5 am and being unable to get back to sleep.

Caffeine is an important consideration for patients with sleep difficulties. Its use is widespread in much of the world, whether ingested as coffee, tea, in soft drinks, or in “energy” drinks that may contain as much as 200 mg of caffeine (twice the amount in a typical cup of brewed coffee). Caffeine may also be ingested as an ingredient of medications for headache or migraine. While some individuals maintain that they can fall asleep easily after drinking caffeinated coffee, many may not recognize the amount of caffeine they consume and its negative impact on sleep.² Author Michael Pollan stopped use of all caffeine and reported on the surprising positive effect on his sleep.³

Patients with mood, anxiety, or psychotic disorders are likely to experience insomnia intermittently or chronically, and insomnia predisposes some individuals to develop mood and anxiety symptoms.⁴ Patients with insomnia often experience anxiety focused on a fear of not getting adequate sleep, which creates a vicious cycle in which hyperarousal associated with fear of not sleeping complicates other causes of insomnia. A patient’s chronotype (preference for the time of day in which they carry out activities vs sleeping) also may play a role in sleep difficulties (Box⁵).

Box

Certain medications may contribute to insomnia, particularly stimulants. It is important to understand and explain to patients the time frame during which immediate-release or extended-release (ER) stimulants are active, which varies in individuals depending on liver enzyme activity. Other commonly used psychotropic medications—including bupropion, modafinil, armodafinil, atomoxetine, amphetamine salts, and methylphenidate—may interfere with sleep if used later in the day.⁶

Patients typically do not mention their use of alcohol and/or marijuana unless asked. Those who are binge drinkers or alcohol-dependent may expect alcohol to help them fall asleep, but usually find their sleep is disrupted and difficult to maintain. Patients may use marijuana to help them sleep, particularly marijuana high in tetrahydrocannabinol (THC). While it may help with sleep initiation, THC can disrupt sleep maintenance. Cannabidiol does not have intrinsic sedating effects and may even interfere with sleep.^7,8

Continue to: Women may be more likely...

Women may be more likely than men to experience insomnia.⁹ The onset of menopause can bring hot flashes that interfere with sleep.

Women with a history of mood disorders are more likely to have a history of premenstrual dysphoric disorder, postpartum depression, and unusual responses to oral contraceptives.¹⁰ These women are more likely to report problems with mood, energy, and sleep at perimenopause. Treatment with estrogen replacement may be an option for women without risk factors, such as clotting disorders, smoking history, or a personal or family history of breast or uterine cancer. For many who are not candidates for or who refuse estrogen replacement, use of a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor at low doses may help with vasomotor symptoms but not with insomnia.

Insomnia symptoms typically increase with age.¹¹ When sleep is adequate early in life but becomes a problem in midlife, an individual’s eating habits, obesity, and lack of exercise may be contributing factors. The typical American diet includes highly refined carbohydrates with excess salt; such foods are often readily available to the exclusion of healthy options. Overweight and obese patients may insist they eat a healthy diet with 3 meals per day, but a careful history often uncovers nighttime binge eating. Nighttime binge eating is rarely reported. This not only maintains obesity, but also interferes with sleep, since patients stay up late to avoid discovery by family members.¹² This lack of sleep can lead to an endless loop because insufficient sleep is a risk factor for obesity.¹³

Evaluating sleep difficulties

New patient evaluations should include a careful history beginning with childhood, including personal early childhood history and family psychiatric history. Patients often report the onset of sleep difficulty and anxiety during childhood, which should raise further questions about aspects of mood regulation from early life such as concentration, energy, motivation, appetite, and academic performance. While many children and adolescents are diagnosed with attention-deficit/hyperactivity disorder due to concentration problems that cause difficulties at school, be aware this might be part of a syndrome related to mood regulation.¹⁴ Unexpected responses to an SSRI—such as agitation, euphoria, or an immediate response with the first dose—should also raise suspicion of a mood disorder. Once the underlying mood disorder is stabilized, many patients report improved sleep.¹⁵

If a patient reports having difficulty falling and remaining asleep but is not sure if there is a pattern, keeping a sleep diary can help. Further questioning may uncover the cause. Does the patient have spontaneous jerks of lower extremities (restless leg syndrome) that interfere with falling asleep or wake them up? Have they noticed problems with dreams/nightmares that wake them, which could be associated with posttraumatic stress, anxiety, or depression? Have they been told by a partner that they act out dreams or are seemingly awake but not responsive, which could point to REM sleep behavior disorder or early Parkinson’s disease? Referral to a sleep laboratory and a neurologist can help establish the correct diagnosis and point to appropriate treatment.^16-18

Treatment options

Several cognitive-behavioral techniques, including cognitive-behavioral therapy for insomnia (CBT-I), yogic breathing, progressive relaxation, mindfulness meditation, and sleep hygiene techniques may help considerably,^19,20 but insomnia often remains difficult to treat. Pharmacotherapy is not necessarily more effective than nonpharmacologic approaches. Both options require the patient to take initiative to either find nonpharmacologic approaches or discuss the problem with a physician and agree to take medication.²¹ A trial comparing CBT-I to sedatives or the combination of CBT-I plus sedatives found higher rates of sleep with CBT-I for 3 months, after which improvement fluctuated; the combination showed sustained improvement for the entire 6-month trial.²² CBT-I has also been shown to be as effective with patients who do not have psychiatric illness as for those who are depressed, anxious, or stressed.²³ However, behavioral techniques that require regular practice may be difficult for individuals to maintain, particularly when they are depressed or anxious.

Continue to: Clinicians should understand...

Clinicians should understand the distinctions among the various types of pharmacotherapy for insomnia. Sedative-hypnotics include medications with varying half-lives and metabolic pathways. Short-acting benzodiazepines such as triazolam or alprazolam and the “z-drugs” zolpidem or zaleplon may help initiate sleep in patients with sleep-onset insomnia. Longer-acting benzodiazepines such as diazepam, clonazepam, or temazepam and the z-drug eszopiclone may also help with sleep maintenance.²³ Based on my clinical experience, individual patients may respond better to 1 type of medication over another, or even to different agents within the same class of sedative-hypnotics.

Some clinicians prescribe nonbenzodiazepine medications for sleep, such as doxepin (which is FDA-approved for treating insomnia) or off-label trazodone, mirtazapine, or quetiapine. Their antihistaminic properties confer sedating effects. Virtually all over-the-counter (OTC) medications for insomnia are antihistaminic. These OTC medications are not designed to treat insomnia, and the optimal dosage to maintain sleep without daytime sedation must be determined by trial and error. Sedating nonbenzodiazepine medications may be slowly absorbed if taken at bedtime (depending on whether they are taken with or without food) and cause daytime sedation and cognitive slowness in patients with sleep-onset and maintenance insomnia who must wake up early. Starting trazodone at 50 to 75 mg may cause slow metabolizers to wake up with considerable sedation, while fast metabolizers might never feel soundly asleep.²⁴

Patients with mood and anxiety disorders that complicate insomnia are often prescribed second-generation antipsychotics such as quetiapine, lurasidone, or olanzapine, which are sedating as well as mood-stabilizing. These approaches require careful attention to titrating doses and timing their use.

Problems with pharmacotherapy

When either benzodiazepines or nonbenzodiazepine medications are used on a long-standing, nightly basis, they often stop working well. It is not unusual that after days to weeks of taking a benzodiazepine, patients find they no longer stay asleep but can’t fall asleep if they don’t take them. Once tolerance develops, the individual experiences pharmacologic withdrawal with an inability to fall asleep or stay asleep. The medication becomes necessary but ineffective, and many patients increase their use to higher doses to fall asleep, and sometimes in early morning to maintain sleep. This leads to negative effects on cognition, coordination/balance, and mood during the day, especially in older patients.

Nonbenzodiazepine sedating medications do not lead to pharmacologic tolerance but do lead to tachyphylaxis as the CNS attempts to downregulate sedation to keep the organism safe. For some patients, this happens quickly, within a matter of days.²⁵ Others increase doses to stay asleep. For example, a patient with a starting dose of trazodone 75 mg/d might increase the dosage to 300 mg/d. While trazodone is approved in doses of 300 to 600 mg as an antidepressant, it is preferable to keep doses lower when used only for sedation.

Continue to: An alternating medication strategy

Alternating between medications from different classes can help patients avoid developing tolerance with benzodiazepines or tachyphylaxis as occurs with antihistaminic medications. It can be effective for patients with primary insomnia as well as for those whose sleep problems are associated with mood or anxiety disorders. Patients typically maintain sensitivity to any form of pharmacologic sedation for several nights without loss of effect but need to take a break to maintain the sedation effect. For example, in 1 case study, a 30-year-old female who rapidly developed tachyphylaxis to the sedative action of mirtazapine experienced a return of the medication’s sedative effects after taking a 3-day break.²⁵

To initiate an alternating strategy, the clinician must first help the patient establish a sedating dose of 2 medications from different classes, such as trazodone and zolpidem, and then instruct the patient to use each for 2 to 3 consecutive nights on an alternating basis. Patients can use calendars or pillboxes to avoid confusion about which medication to take on a given night. In many cases, this approach can work indefinitely.

The following 3 case vignettes illustrate how this alternating medication strategy can work.

CASE 1

Mr. B, age 58, is a married salesman whose territory includes 3 states. He drives from client to client from Monday through Thursday each week, staying overnight in hotels. He is comfortable talking to clients, has a close and supportive relationship with his wife, and enjoys socializing with friends. Mr. B has a high level of trait anxiety and perfectionism and is proud of his sales record throughout his career, but this leads to insomnia during his nights on the road, and often on Sunday night as he starts anticipating the week ahead. Mr. B denies having a depressed mood or cognitive problems. When on vacation with his wife he has no trouble sleeping. He has no psychiatric family history or any substantial medical problems. He simply wishes that he could sleep on work nights.

We set up an alternating medication approach. Mr. B takes trazodone 100 mg on the first night and 150 mg on the second and third nights. He then takes triazolam 0.25 mg for 2 nights; previously, he had found that zolpidem did not work as well for maintaining sleep. He can sleep adequately for the 2 weekend nights, then restarts the alternating pattern. Mr. B has done well with this regimen for >10 years.

Continue to: CASE 2

Ms. C, age 60, is widowed and has a successful career as a corporate attorney. She has been anxious since early childhood and has had trouble falling asleep for much of her life. Once she falls asleep on her sofa—often between 1 and 2 am—Ms. C can sleep soundly for 7 to 8 hours, but early morning work meetings require her to set an alarm for 6 am daily. Ms. C feels irritable and anxious on awakening but arrives at her office by 7:30 am, where she maintains a full schedule, with frequent 12-hour workdays. Ms. C did not experience significant insomnia or hot flashes with menopause at age 52 and does not use hormone replacement therapy.

Ms. C denies having depression, but experienced appropriate grief related to her husband’s illness and death from metastatic cancer 3 years ago. At the time, her internist prescribed escitalopram and zolpidem; escitalopram caused greater agitation and distress, so she stopped it after 10 days. Zolpidem 10 mg/d allowed her to sleep but she worried about taking it because her mother had long-standing sedative dependence. Ms. C lives alone, but her adult children live nearby, and she has a strong support system that includes colleagues at her firm, friends at her book club, and a support group for partners of cancer patients.

Ms. C tries trazodone, starting with 50 mg, but reports feeling agitated rather than sleepy and has cognitive fogginess in the morning. She is switched to quetiapine 50 mg, which she tolerates well and allows her to sleep soundly. To avoid developing tachyphylaxis with quetiapine, she takes eszopiclone 3 mg for 2 nights, alternating with quetiapine for 3 nights. This strategy allows her to reliably fall asleep by 11 pm, wake up at 6 am, and feel rested throughout the day.

CASE 3

Ms. D, age 55, is married with a long-standing diagnosis of generalized anxiety disorder (GAD), panic disorder, and depression so severe she is unable to work as a preschool teacher. She notes that past clinicians have prescribed a wide array of antidepressants and benzodiazepines but she remains anxious, agitated, and unable to sleep. She worries constantly about running out of benzodiazepines, which are “the only medication that helps me.” At the time of evaluation, her medications are venlafaxine ER 150 mg/d, lorazepam 1 mg 3 times daily and 2 mg at bedtime, and buspirone 15 mg 3 times daily, which she admits to not taking. She is overweight and does not exercise. She spends her days snacking and watching television. She can’t settle down enough to read and feels overwhelmed most of the time. Her adult children won’t allow her to babysit their young children because she dozes during the day.

Ms. D has a strong family history of psychiatric illness, including a father with bipolar I disorder and alcohol use disorder and a sister with schizoaffective disorder. Ms. D has never felt overtly manic, but has spent most of her life feeling depressed, anxious, and hopeless, and at times she has wished she was dead. She has had poor responses to many antidepressants, with transient euphoria followed by more anxiety.

Continue to: Rather than major depressive disorder...

Rather than major depressive disorder or GAD, Ms. D’s symptoms better meet the criteria for bipolar II disorder. She agrees to a slow taper of venlafaxine and a slow increase of divalproex, starting with 125 mg each evening. While taking venlafaxine 75 mg/d and divalproex 375 mg/d, she experiences distinct improvement in anxiety and agitation, which further improve after venlafaxine is stopped and divalproex is increased to 750 mg in the evening. She finds that she forgets daytime doses of lorazepam but depends on it to fall asleep. While taking quetiapine 50 mg and lorazepam 1 mg at bedtime, Ms. D reports sleeping soundly and feeling alert in the morning. Over several weeks, she tapers lorazepam slowly by 0.5 mg every 2 weeks. She finds she needs a higher dose of quetiapine to stay asleep, eventually requiring 400 mg each night. Ms. D says overall she feels better but is distressed because she has gained 25 lbs since starting divalproex and quetiapine.

To avoid further increases in quetiapine and maintain its sedating effect, Ms. D is switched to an alternating schedule of clonazepam 1.5 mg for 2 nights and quetiapine 300 mg for 3 nights. She agrees to begin exercising by walking in her neighborhood daily, and gradually increases this to 1 hour per day. After starting to exercise regularly, she finds she is oversedated by quetiapine at night, so she is gradually decreased to a dose of 150 mg, while still alternating with clonazepam 1.5 mg. Ms. D loses most of the weight she had gained and begins volunteering as a reading coach in the elementary school in her neighborhood.

Bottom Line

Patients with chronic insomnia can often maintain adequate sedation without developing tolerance to benzodiazepines or tachyphylaxis with nonsedating agents by using 2 sleep medications that have different mechanisms of action on an alternating schedule.

Related Resources

• Sateia MJ, Buysse DJ, Krystal AD, et al. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2): 307-349. doi:10.5664/jcsm.6470
• Muppavarapu K, Muthukanagaraj M, Saeed SA. Cognitive-behavioral therapy for insomnia: a review of 8 studies. Current Psychiatry. 2020;19(9):40-46. doi:10.12788/cp.0040

Drug Brand Names

Alprazolam • Xanax
Armodafinil • Nuvigil
Atomoxetine • Strattera
Bupropion • Wellbutrin
Clonazepam • Klonopin
Diazepam • Valium
Divalproex • Depakote
Doxepin • Sinequan
Escitalopram • Lexapro
Eszopiclone • Lunesta
Lorazepam • Ativan
Lurasidone • Latuda
Methylphenidate • Concerta
Mirtazapine • Remeron
Modafinil • Provigil
Olanzapine • Zyprexa
Quetiapine • Seroquel
Temazepam • Restoril
Trazodone • Desyrel
Triazolam • Halcion
Venlafaxine • Effexor
Zaleplon • Sonata
Zolpidem • Ambien

Obstructive sleep apnea (OSA) remains a significantly underdiagnosed condition, despite its high prevalence. Primary care physicians play a pivotal role in identifying patients afflicted by this condition. To effectively diagnose OSA in primary care, increasing awareness and enhancing communication are imperative. Fortunately, several straightforward diagnostic tools are readily available, and even more sophisticated ones, driven by artificial intelligence, are on the horizon.

Recognize the problem

At the annual congress of the European Respiratory Society, Cláudia Sofia De Almeida Vicente Ferreira, MD, a family physician from Coimbra, Portugal, and coordinator of the Respiratory Diseases Interest Group of the Portuguese Association of General and Family Medicine, highlighted the challenges of diagnosing OSA.

“Sleep apnea is underdiagnosed because the most common symptoms, like excessive daytime sleepiness or snoring, are undervalued by patients. People do not come to the doctor and complain about it. Sometimes you catch it in the middle of other things,” she said in an interview.

Moreover, physicians’ busy schedules and limited appointment times often lead to a focus on the symptoms reported by patients, and insufficient attention is paid to the quality of sleep. This may be compounded by a tendency among medical professionals to underestimate the risks associated with OSA, as it is not directly linked to mortality, despite its clear connection to cardiovascular risks.

Identifying and recognizing risk factors can facilitate OSA suspicion during patient evaluations. These factors encompass both structural (for example, craniofacial and upper airway anomalies) and nonstructural elements (for example, smoking, alcohol use, or sedative consumption). While men are at higher risk, postmenopausal women who are not receiving hormone replacement therapy face similar risks. Certain medical conditions, such as hypothyroidism, acromegaly, amyloidosis, Cushing syndrome, and Down syndrome, have also been associated with OSA. A comprehensive physical examination can provide additional clues. Factors might include obesity, neck circumference, Mallampati score, and nasal and pharyngeal problems.
 

Inquire actively

Once the possibility of OSA is considered, the next step is to ask patients about their symptoms. Questionnaires are simple yet valuable tools for this purpose. The STOP questionnaire comprises four key questions:

• Do you SNORE loudly (louder than talking or loud enough to be heard through closed doors)?
• Do you often feel TIRED, fatigued, or sleepy during daytime?
• Has anyone OBSERVED you stop breathing during your sleep?
• Do you have or are you being treated for high blood PRESSURE?

The STOP-BANG questionnaire adds four clinical attributes: obesity (body mass index > 35 kg/m²), age (> 50 years), neck size (> 40 cm, or 16 inches), and sex.

Patients are classified as being at low, intermediate, or high risk for OSA.

The Epworth Sleepiness Scale, which is self-administered, is also useful: patients rate the likelihood of falling asleep in various daytime contexts. These questionnaires can be seamlessly integrated into routine patient appointments.
 

Comorbidities and occupation

Primary care physicians should carefully assess comorbidities, especially those linked to cardiovascular risk. Patients with resistant hypertension, pulmonary hypertension, and recurrent atrial fibrillation following cardioversion/ablation should be prioritized for diagnostic testing for OSA. Patients with other conditions, such as coronary artery disease or cerebrovascular disease, should also be referred to a sleep center if OSA is suspected on the basis of comprehensive sleep assessment. OSA has also been associated with type 2 diabetes, metabolic syndrome, and asthma.

Gaining access to sleep study services and subsequent therapy, such as continuous positive airway pressure (CPAP), can be challenging. Primary care physicians should prioritize patients on the basis of their risk levels. Occupation plays a significant role in this prioritization, as sleep fragmentation and daytime sleepiness can lead to workplace and vehicular accidents.

“You should include the occupation in the patient’s profile. What is he doing? Is he sitting at a desk, or is he working at height, driving, or operating machines? These workers are high-risk patients,” continued Dr. De Almeida Vicente Ferreira.

“I think that the family physician has a key role in the follow-up. Nobody else will look for CPAP compliance and will verify if CPAP is working or not. If the patient is not using it or if it is not effective, still there is someone paying for the machine (the national health care system or an insurance company). More importantly, if CPAP is not working, we are not improving our patient’s life in terms of reducing cardiovascular risk and ameliorating the quality of life.”
 

Is home testing a viable option?

Diagnosing OSA typically relies on overnight polysomnography in specialized sleep clinics, which is often associated with long waiting lists. Researchers are actively working on innovative sensors and digital solutions for home-based sleep testing, but according to Dr. De Almeida Vicente Ferreira, they are not yet ready for prime time: “Home-based studies with fewer evaluation parameters (such as pulse and oxygen levels) are not so secure or sensitive to establish a correct and complete diagnosis. Actually, the architecture of sleep is very complex. The test must be performed and read by a specialized team.”

Still, according to Renaud Tamisier, MD, PhD, professor of clinical physiology at the Université Grenoble Alpes in La Tronche, France, simplified sleep testing could be very useful. “There are many patients that still are not diagnosed despite having severe sleep apnea, with symptoms and comorbidities. These patients usually are not aware of their disease but complain about changes in their quality of life with excessive tiredness and sleepiness. Also, they are not connected to the healthcare system, for different reasons, including no time for consulting a sleep physician and performing a polysomnography, health cost, negligence. Therefore, providing through primary care a simple diagnostic approach deserves efforts and research,” he said in an interview.

New technologies could enable diagnostic sleep tests to be conducted at home, with the added benefit of multiple-night recordings to overcome the challenges of night-to-night variability in the apnea-hypopnea index. These novel testing methods should be cost effective, easy to install, and user friendly. Dr. Tamisier continued: “The issue about sleep diagnosis is that up to now, there was no such devices available. Many physicians use type III sleep recording that are dedicated to highly trained sleep scorers, but they use automatic analysis which in many cases is unsuccessful. For a trained sleep physician, it is easy to see that the result is inaccurate. New devices are being built for automatic analysis using artificial intelligence algorithms. Because by design they are automatic, the rate of success is very high, and if used with the right purpose, they could be highly effective and quick.”

In conclusion, the diagnosis of sleep apnea in primary care is becoming more feasible with advancements in diagnostic tools and technology. However, it is crucial for primary care physicians to exercise caution in cases in which the clinical presentation is not straightforward or when OSA is associated with comorbidities. Care management and clear boundaries are vital to ensure effective treatment and improve patient outcomes.

Dr. De Almeida Vicente Ferreira and Dr. Tamisier disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Obstructive sleep apnea (OSA) remains a significantly underdiagnosed condition, despite its high prevalence. Primary care physicians play a pivotal role in identifying patients afflicted by this condition. To effectively diagnose OSA in primary care, increasing awareness and enhancing communication are imperative. Fortunately, several straightforward diagnostic tools are readily available, and even more sophisticated ones, driven by artificial intelligence, are on the horizon.

Recognize the problem

At the annual congress of the European Respiratory Society, Cláudia Sofia De Almeida Vicente Ferreira, MD, a family physician from Coimbra, Portugal, and coordinator of the Respiratory Diseases Interest Group of the Portuguese Association of General and Family Medicine, highlighted the challenges of diagnosing OSA.

“Sleep apnea is underdiagnosed because the most common symptoms, like excessive daytime sleepiness or snoring, are undervalued by patients. People do not come to the doctor and complain about it. Sometimes you catch it in the middle of other things,” she said in an interview.

Moreover, physicians’ busy schedules and limited appointment times often lead to a focus on the symptoms reported by patients, and insufficient attention is paid to the quality of sleep. This may be compounded by a tendency among medical professionals to underestimate the risks associated with OSA, as it is not directly linked to mortality, despite its clear connection to cardiovascular risks.

Identifying and recognizing risk factors can facilitate OSA suspicion during patient evaluations. These factors encompass both structural (for example, craniofacial and upper airway anomalies) and nonstructural elements (for example, smoking, alcohol use, or sedative consumption). While men are at higher risk, postmenopausal women who are not receiving hormone replacement therapy face similar risks. Certain medical conditions, such as hypothyroidism, acromegaly, amyloidosis, Cushing syndrome, and Down syndrome, have also been associated with OSA. A comprehensive physical examination can provide additional clues. Factors might include obesity, neck circumference, Mallampati score, and nasal and pharyngeal problems.
 

Inquire actively

Once the possibility of OSA is considered, the next step is to ask patients about their symptoms. Questionnaires are simple yet valuable tools for this purpose. The STOP questionnaire comprises four key questions:

• Do you SNORE loudly (louder than talking or loud enough to be heard through closed doors)?
• Do you often feel TIRED, fatigued, or sleepy during daytime?
• Has anyone OBSERVED you stop breathing during your sleep?
• Do you have or are you being treated for high blood PRESSURE?

The STOP-BANG questionnaire adds four clinical attributes: obesity (body mass index > 35 kg/m²), age (> 50 years), neck size (> 40 cm, or 16 inches), and sex.

Patients are classified as being at low, intermediate, or high risk for OSA.

The Epworth Sleepiness Scale, which is self-administered, is also useful: patients rate the likelihood of falling asleep in various daytime contexts. These questionnaires can be seamlessly integrated into routine patient appointments.
 

Comorbidities and occupation

Primary care physicians should carefully assess comorbidities, especially those linked to cardiovascular risk. Patients with resistant hypertension, pulmonary hypertension, and recurrent atrial fibrillation following cardioversion/ablation should be prioritized for diagnostic testing for OSA. Patients with other conditions, such as coronary artery disease or cerebrovascular disease, should also be referred to a sleep center if OSA is suspected on the basis of comprehensive sleep assessment. OSA has also been associated with type 2 diabetes, metabolic syndrome, and asthma.

Gaining access to sleep study services and subsequent therapy, such as continuous positive airway pressure (CPAP), can be challenging. Primary care physicians should prioritize patients on the basis of their risk levels. Occupation plays a significant role in this prioritization, as sleep fragmentation and daytime sleepiness can lead to workplace and vehicular accidents.

“You should include the occupation in the patient’s profile. What is he doing? Is he sitting at a desk, or is he working at height, driving, or operating machines? These workers are high-risk patients,” continued Dr. De Almeida Vicente Ferreira.

“I think that the family physician has a key role in the follow-up. Nobody else will look for CPAP compliance and will verify if CPAP is working or not. If the patient is not using it or if it is not effective, still there is someone paying for the machine (the national health care system or an insurance company). More importantly, if CPAP is not working, we are not improving our patient’s life in terms of reducing cardiovascular risk and ameliorating the quality of life.”
 

Is home testing a viable option?

Diagnosing OSA typically relies on overnight polysomnography in specialized sleep clinics, which is often associated with long waiting lists. Researchers are actively working on innovative sensors and digital solutions for home-based sleep testing, but according to Dr. De Almeida Vicente Ferreira, they are not yet ready for prime time: “Home-based studies with fewer evaluation parameters (such as pulse and oxygen levels) are not so secure or sensitive to establish a correct and complete diagnosis. Actually, the architecture of sleep is very complex. The test must be performed and read by a specialized team.”

Still, according to Renaud Tamisier, MD, PhD, professor of clinical physiology at the Université Grenoble Alpes in La Tronche, France, simplified sleep testing could be very useful. “There are many patients that still are not diagnosed despite having severe sleep apnea, with symptoms and comorbidities. These patients usually are not aware of their disease but complain about changes in their quality of life with excessive tiredness and sleepiness. Also, they are not connected to the healthcare system, for different reasons, including no time for consulting a sleep physician and performing a polysomnography, health cost, negligence. Therefore, providing through primary care a simple diagnostic approach deserves efforts and research,” he said in an interview.

New technologies could enable diagnostic sleep tests to be conducted at home, with the added benefit of multiple-night recordings to overcome the challenges of night-to-night variability in the apnea-hypopnea index. These novel testing methods should be cost effective, easy to install, and user friendly. Dr. Tamisier continued: “The issue about sleep diagnosis is that up to now, there was no such devices available. Many physicians use type III sleep recording that are dedicated to highly trained sleep scorers, but they use automatic analysis which in many cases is unsuccessful. For a trained sleep physician, it is easy to see that the result is inaccurate. New devices are being built for automatic analysis using artificial intelligence algorithms. Because by design they are automatic, the rate of success is very high, and if used with the right purpose, they could be highly effective and quick.”

In conclusion, the diagnosis of sleep apnea in primary care is becoming more feasible with advancements in diagnostic tools and technology. However, it is crucial for primary care physicians to exercise caution in cases in which the clinical presentation is not straightforward or when OSA is associated with comorbidities. Care management and clear boundaries are vital to ensure effective treatment and improve patient outcomes.

Dr. De Almeida Vicente Ferreira and Dr. Tamisier disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Obstructive sleep apnea (OSA) remains a significantly underdiagnosed condition, despite its high prevalence. Primary care physicians play a pivotal role in identifying patients afflicted by this condition. To effectively diagnose OSA in primary care, increasing awareness and enhancing communication are imperative. Fortunately, several straightforward diagnostic tools are readily available, and even more sophisticated ones, driven by artificial intelligence, are on the horizon.

Recognize the problem

At the annual congress of the European Respiratory Society, Cláudia Sofia De Almeida Vicente Ferreira, MD, a family physician from Coimbra, Portugal, and coordinator of the Respiratory Diseases Interest Group of the Portuguese Association of General and Family Medicine, highlighted the challenges of diagnosing OSA.

“Sleep apnea is underdiagnosed because the most common symptoms, like excessive daytime sleepiness or snoring, are undervalued by patients. People do not come to the doctor and complain about it. Sometimes you catch it in the middle of other things,” she said in an interview.

Moreover, physicians’ busy schedules and limited appointment times often lead to a focus on the symptoms reported by patients, and insufficient attention is paid to the quality of sleep. This may be compounded by a tendency among medical professionals to underestimate the risks associated with OSA, as it is not directly linked to mortality, despite its clear connection to cardiovascular risks.

Identifying and recognizing risk factors can facilitate OSA suspicion during patient evaluations. These factors encompass both structural (for example, craniofacial and upper airway anomalies) and nonstructural elements (for example, smoking, alcohol use, or sedative consumption). While men are at higher risk, postmenopausal women who are not receiving hormone replacement therapy face similar risks. Certain medical conditions, such as hypothyroidism, acromegaly, amyloidosis, Cushing syndrome, and Down syndrome, have also been associated with OSA. A comprehensive physical examination can provide additional clues. Factors might include obesity, neck circumference, Mallampati score, and nasal and pharyngeal problems.
 

Inquire actively

Once the possibility of OSA is considered, the next step is to ask patients about their symptoms. Questionnaires are simple yet valuable tools for this purpose. The STOP questionnaire comprises four key questions:

• Do you SNORE loudly (louder than talking or loud enough to be heard through closed doors)?
• Do you often feel TIRED, fatigued, or sleepy during daytime?
• Has anyone OBSERVED you stop breathing during your sleep?
• Do you have or are you being treated for high blood PRESSURE?

The STOP-BANG questionnaire adds four clinical attributes: obesity (body mass index > 35 kg/m²), age (> 50 years), neck size (> 40 cm, or 16 inches), and sex.

Patients are classified as being at low, intermediate, or high risk for OSA.

The Epworth Sleepiness Scale, which is self-administered, is also useful: patients rate the likelihood of falling asleep in various daytime contexts. These questionnaires can be seamlessly integrated into routine patient appointments.
 

Comorbidities and occupation

Primary care physicians should carefully assess comorbidities, especially those linked to cardiovascular risk. Patients with resistant hypertension, pulmonary hypertension, and recurrent atrial fibrillation following cardioversion/ablation should be prioritized for diagnostic testing for OSA. Patients with other conditions, such as coronary artery disease or cerebrovascular disease, should also be referred to a sleep center if OSA is suspected on the basis of comprehensive sleep assessment. OSA has also been associated with type 2 diabetes, metabolic syndrome, and asthma.

Gaining access to sleep study services and subsequent therapy, such as continuous positive airway pressure (CPAP), can be challenging. Primary care physicians should prioritize patients on the basis of their risk levels. Occupation plays a significant role in this prioritization, as sleep fragmentation and daytime sleepiness can lead to workplace and vehicular accidents.

“You should include the occupation in the patient’s profile. What is he doing? Is he sitting at a desk, or is he working at height, driving, or operating machines? These workers are high-risk patients,” continued Dr. De Almeida Vicente Ferreira.

“I think that the family physician has a key role in the follow-up. Nobody else will look for CPAP compliance and will verify if CPAP is working or not. If the patient is not using it or if it is not effective, still there is someone paying for the machine (the national health care system or an insurance company). More importantly, if CPAP is not working, we are not improving our patient’s life in terms of reducing cardiovascular risk and ameliorating the quality of life.”
 

Is home testing a viable option?

Diagnosing OSA typically relies on overnight polysomnography in specialized sleep clinics, which is often associated with long waiting lists. Researchers are actively working on innovative sensors and digital solutions for home-based sleep testing, but according to Dr. De Almeida Vicente Ferreira, they are not yet ready for prime time: “Home-based studies with fewer evaluation parameters (such as pulse and oxygen levels) are not so secure or sensitive to establish a correct and complete diagnosis. Actually, the architecture of sleep is very complex. The test must be performed and read by a specialized team.”

Still, according to Renaud Tamisier, MD, PhD, professor of clinical physiology at the Université Grenoble Alpes in La Tronche, France, simplified sleep testing could be very useful. “There are many patients that still are not diagnosed despite having severe sleep apnea, with symptoms and comorbidities. These patients usually are not aware of their disease but complain about changes in their quality of life with excessive tiredness and sleepiness. Also, they are not connected to the healthcare system, for different reasons, including no time for consulting a sleep physician and performing a polysomnography, health cost, negligence. Therefore, providing through primary care a simple diagnostic approach deserves efforts and research,” he said in an interview.

New technologies could enable diagnostic sleep tests to be conducted at home, with the added benefit of multiple-night recordings to overcome the challenges of night-to-night variability in the apnea-hypopnea index. These novel testing methods should be cost effective, easy to install, and user friendly. Dr. Tamisier continued: “The issue about sleep diagnosis is that up to now, there was no such devices available. Many physicians use type III sleep recording that are dedicated to highly trained sleep scorers, but they use automatic analysis which in many cases is unsuccessful. For a trained sleep physician, it is easy to see that the result is inaccurate. New devices are being built for automatic analysis using artificial intelligence algorithms. Because by design they are automatic, the rate of success is very high, and if used with the right purpose, they could be highly effective and quick.”

In conclusion, the diagnosis of sleep apnea in primary care is becoming more feasible with advancements in diagnostic tools and technology. However, it is crucial for primary care physicians to exercise caution in cases in which the clinical presentation is not straightforward or when OSA is associated with comorbidities. Care management and clear boundaries are vital to ensure effective treatment and improve patient outcomes.

Dr. De Almeida Vicente Ferreira and Dr. Tamisier disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

TOPLINE:

Eight psychosocial factors, grouped into two distinct clusters, are significantly associated with risk for atrial fibrillation in postmenopausal women, with insomnia and stressful life events (SLEs) being the most strongly associated with AFib, a large new study has found.

METHODOLOGY:

• In addition to traditional risk factors such as obesity, advanced age, ethnicity, smoking, alcohol, hypertension, diabetes, coronary artery disease, heart failure, and emotional and psychological distress may also affect AFib.
• The study included 83,736 postmenopausal women in the Women’s Health Initiative (mean age, 63.9 years; 88.1% White) who did not have AFib at baseline.
• From questionnaires, researchers collected information on psychosocial stressors and used hierarchical cluster analysis to identify patterns of psychosocial predictors.
• They separated these clusters into quartiles, identified associations between psychosocial exposure variables, and adjusted for traditional risk factors.
• Over an average follow-up of 10.5 years, 23,954 participants (28.6%) developed incident AFib.
•  

TAKEAWAY:

• The analysis generated two clusters of distinct psychosocial variables that were significantly associated with AFib: the Stress Cluster, including SLEs, depressive symptoms, and insomnia; and the Strain Cluster, including three personality traits: optimism, cynical hostility, and emotional expressiveness; and two social measures: social support, and social strain.
• Those in the highest quartiles of both the Stress Cluster and the Strain Cluster had greater rates of AFib, compared with those in the lowest quartiles.
• In a final model, the association between SLEs (hazard ratio, 1.02; 95% confidence interval, 1.01-1.04) and insomnia (HR, 1.04; 95% CI, 1.03-1.06) were most strongly linked to increased incidence of AFib, and a sensitivity analysis using snoring as a surrogate marker for sleep apnea didn’t change this outcome, supporting the independent effect of insomnia on AFib.
• In subgroup analyses, the Stress Cluster had a stronger association with AFib incidence in younger (50-69 years) versus older women (70-79 years), and in non-Hispanic White and Asian women versus Hispanic and non-Hispanic Black women.
•  

IN PRACTICE:

The results support the hypothesis that psychosocial predictors account for additional risk for AFib “above and beyond” traditional risk factors, the authors wrote. Identifying and addressing sex-specific, modifiable risk factors, including insomnia, “may help reduce the burden of AF[ib] in aging women.”

SOURCE:

The study was conducted by Susan X. Zhao, MD, division of cardiology, department of medicine, Santa Clara Valley Medical Center, San Jose, Calif., and colleagues. It was published online in the Journal of the American Heart Association.

LIMITATIONS:

The psychometric questionnaires were administered only at study entry, but psychosocial variables may change over time. Data on sleep apnea and other sleep disorders, which may confound the relationship between insomnia and AFib, were not available, and although the study included a sensitivity analysis controlling for snoring, this is an imperfect surrogate for sleep apnea. Generalizability to other demographic, racial, and ethnic groups is limited.

DISCLOSURES:

The Women’s Health Initiative program is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and the Department of Health & Human Services. The authors have no relevant conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Eight psychosocial factors, grouped into two distinct clusters, are significantly associated with risk for atrial fibrillation in postmenopausal women, with insomnia and stressful life events (SLEs) being the most strongly associated with AFib, a large new study has found.

METHODOLOGY:

• In addition to traditional risk factors such as obesity, advanced age, ethnicity, smoking, alcohol, hypertension, diabetes, coronary artery disease, heart failure, and emotional and psychological distress may also affect AFib.
• The study included 83,736 postmenopausal women in the Women’s Health Initiative (mean age, 63.9 years; 88.1% White) who did not have AFib at baseline.
• From questionnaires, researchers collected information on psychosocial stressors and used hierarchical cluster analysis to identify patterns of psychosocial predictors.
• They separated these clusters into quartiles, identified associations between psychosocial exposure variables, and adjusted for traditional risk factors.
• Over an average follow-up of 10.5 years, 23,954 participants (28.6%) developed incident AFib.
•  

TAKEAWAY:

• The analysis generated two clusters of distinct psychosocial variables that were significantly associated with AFib: the Stress Cluster, including SLEs, depressive symptoms, and insomnia; and the Strain Cluster, including three personality traits: optimism, cynical hostility, and emotional expressiveness; and two social measures: social support, and social strain.
• Those in the highest quartiles of both the Stress Cluster and the Strain Cluster had greater rates of AFib, compared with those in the lowest quartiles.
• In a final model, the association between SLEs (hazard ratio, 1.02; 95% confidence interval, 1.01-1.04) and insomnia (HR, 1.04; 95% CI, 1.03-1.06) were most strongly linked to increased incidence of AFib, and a sensitivity analysis using snoring as a surrogate marker for sleep apnea didn’t change this outcome, supporting the independent effect of insomnia on AFib.
• In subgroup analyses, the Stress Cluster had a stronger association with AFib incidence in younger (50-69 years) versus older women (70-79 years), and in non-Hispanic White and Asian women versus Hispanic and non-Hispanic Black women.
•  

IN PRACTICE:

The results support the hypothesis that psychosocial predictors account for additional risk for AFib “above and beyond” traditional risk factors, the authors wrote. Identifying and addressing sex-specific, modifiable risk factors, including insomnia, “may help reduce the burden of AF[ib] in aging women.”

SOURCE:

The study was conducted by Susan X. Zhao, MD, division of cardiology, department of medicine, Santa Clara Valley Medical Center, San Jose, Calif., and colleagues. It was published online in the Journal of the American Heart Association.

LIMITATIONS:

The psychometric questionnaires were administered only at study entry, but psychosocial variables may change over time. Data on sleep apnea and other sleep disorders, which may confound the relationship between insomnia and AFib, were not available, and although the study included a sensitivity analysis controlling for snoring, this is an imperfect surrogate for sleep apnea. Generalizability to other demographic, racial, and ethnic groups is limited.

DISCLOSURES:

The Women’s Health Initiative program is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and the Department of Health & Human Services. The authors have no relevant conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Eight psychosocial factors, grouped into two distinct clusters, are significantly associated with risk for atrial fibrillation in postmenopausal women, with insomnia and stressful life events (SLEs) being the most strongly associated with AFib, a large new study has found.

METHODOLOGY:

• In addition to traditional risk factors such as obesity, advanced age, ethnicity, smoking, alcohol, hypertension, diabetes, coronary artery disease, heart failure, and emotional and psychological distress may also affect AFib.
• The study included 83,736 postmenopausal women in the Women’s Health Initiative (mean age, 63.9 years; 88.1% White) who did not have AFib at baseline.
• From questionnaires, researchers collected information on psychosocial stressors and used hierarchical cluster analysis to identify patterns of psychosocial predictors.
• They separated these clusters into quartiles, identified associations between psychosocial exposure variables, and adjusted for traditional risk factors.
• Over an average follow-up of 10.5 years, 23,954 participants (28.6%) developed incident AFib.
•  

TAKEAWAY:

• The analysis generated two clusters of distinct psychosocial variables that were significantly associated with AFib: the Stress Cluster, including SLEs, depressive symptoms, and insomnia; and the Strain Cluster, including three personality traits: optimism, cynical hostility, and emotional expressiveness; and two social measures: social support, and social strain.
• Those in the highest quartiles of both the Stress Cluster and the Strain Cluster had greater rates of AFib, compared with those in the lowest quartiles.
• In a final model, the association between SLEs (hazard ratio, 1.02; 95% confidence interval, 1.01-1.04) and insomnia (HR, 1.04; 95% CI, 1.03-1.06) were most strongly linked to increased incidence of AFib, and a sensitivity analysis using snoring as a surrogate marker for sleep apnea didn’t change this outcome, supporting the independent effect of insomnia on AFib.
• In subgroup analyses, the Stress Cluster had a stronger association with AFib incidence in younger (50-69 years) versus older women (70-79 years), and in non-Hispanic White and Asian women versus Hispanic and non-Hispanic Black women.
•  

IN PRACTICE:

The results support the hypothesis that psychosocial predictors account for additional risk for AFib “above and beyond” traditional risk factors, the authors wrote. Identifying and addressing sex-specific, modifiable risk factors, including insomnia, “may help reduce the burden of AF[ib] in aging women.”

SOURCE:

The study was conducted by Susan X. Zhao, MD, division of cardiology, department of medicine, Santa Clara Valley Medical Center, San Jose, Calif., and colleagues. It was published online in the Journal of the American Heart Association.

LIMITATIONS:

The psychometric questionnaires were administered only at study entry, but psychosocial variables may change over time. Data on sleep apnea and other sleep disorders, which may confound the relationship between insomnia and AFib, were not available, and although the study included a sensitivity analysis controlling for snoring, this is an imperfect surrogate for sleep apnea. Generalizability to other demographic, racial, and ethnic groups is limited.

DISCLOSURES:

The Women’s Health Initiative program is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and the Department of Health & Human Services. The authors have no relevant conflicts of interest.

A version of this article appeared on Medscape.com.

“Night owls” have an increased risk for developing type 2 diabetes and are more likely to smoke more, exercise less, and have poor sleep habits, compared with their “early bird” counterparts, according to a new study, published in Annals of Internal Medicine.

The work focused on participants’ self-assessed chronotype – an individuals’ circadian preference, or natural preference to sleep and wake up earlier or later, commonly known as being an early bird or a night owl.

Analyzing the self-reported lifestyle behaviors and sleeping habits of more than 60,000 middle-aged female nurses, researchers from Brigham and Women’s Hospital and Harvard Medical School, both in Boston, found that those with a preference for waking up later had a 72% higher risk for diabetes and were 54% more likely to have unhealthy lifestyle behaviors, compared with participants who tended to wake up earlier.

After adjustment for six lifestyle factors – diet, alcohol use, body mass index (BMI), physical activity, smoking status, and sleep duration – the association between diabetes risk and evening chronotype weakened to a 19% higher risk of developing type 2 diabetes.

In a subgroup analysis, this association was stronger among women who either had had no night shifts over the previous 2 years or had worked night shifts for less than 10 years in their careers. For nurses who had worked night shifts recently, the study found no association between evening chronotype and diabetes risk.

The participants, drawn from the Nurses’ Health Study II, were between 45 and 62 years age, with no history of cancer, cardiovascular disease, or diabetes. Researchers followed the group from 2009 until 2017.
 

Is there a mismatch between natural circadian rhythm and work schedule?

The authors, led by Sina Kianersi, DVM, PhD, of Harvard Medical School, Boston, suggest that their results may be linked to a mismatch between a person’s circadian rhythm and their physical and social environment – for example, if someone lives on a schedule opposite to their circadian preference.

In one 2015 study, female nurses who had worked daytime shifts for more than 10 years but had an evening chronotype had the highest diabetes risk, compared with early chronotypes (51% more likely to develop type 2 diabetes).

In a 2022 study, an evening chronotype was associated with a 30% elevated risk for type 2 diabetes. The authors speculated that circadian misalignment could be to blame – for example, being a night owl but working early morning – which can disrupt glycemic and lipid metabolism.

Previous studies have found that shorter or irregular sleep habits are associated with a higher risk of type 2 diabetes. Other studies have also found that people with an evening chronotype are more likely than early birds to have unhealthy eating habits, have lower levels of physical activity, and smoke and drink.

This new study did not find that an evening chronotype was associated with unhealthy drinking, which the authors defined as having one or more drinks per day.

In an accompanying editorial, two physicians from the Harvard T.H. Chan School of Public Health in Boston caution that the statistical design of the study limits its ability to establish causation.

“Chronotype could change later, which might correlate with lifestyle changes,” write Kehuan Lin, MS, Mingyang Song, MBBS, and Edward Giovannucci, MD. “Experimental trials are required to determine whether chronotype is a marker of unhealthy lifestyle or an independent determinant.”

They also suggest that psychological factors and the type of work being performed by the participants could be potential confounders.

The authors of the study note that their findings might not be generalizable to groups other than middle-aged White female nurses. The study population also had a relatively high level of education and were socioeconomically advantaged.

Self-reporting chronotypes with a single question could also result in misclassification and measurement error, the authors acknowledge.

The findings underscore the value of assessing an individuals’ chronotype for scheduling shift work – for example, assigning night owls to night shifts may improve their metabolic health and sleeping habits, according to the authors of the study.

“Given the importance of lifestyle modification in diabetes prevention, future research is warranted to investigate whether improving lifestyle behaviors could effectively reduce diabetes risk in persons with an evening chronotype,” the authors conclude.

The study was supported by grants from the National Institutes of Health and the European Research Council.

A version of this article first appeared on Medscape.com.

“Night owls” have an increased risk for developing type 2 diabetes and are more likely to smoke more, exercise less, and have poor sleep habits, compared with their “early bird” counterparts, according to a new study, published in Annals of Internal Medicine.

The work focused on participants’ self-assessed chronotype – an individuals’ circadian preference, or natural preference to sleep and wake up earlier or later, commonly known as being an early bird or a night owl.

Analyzing the self-reported lifestyle behaviors and sleeping habits of more than 60,000 middle-aged female nurses, researchers from Brigham and Women’s Hospital and Harvard Medical School, both in Boston, found that those with a preference for waking up later had a 72% higher risk for diabetes and were 54% more likely to have unhealthy lifestyle behaviors, compared with participants who tended to wake up earlier.

After adjustment for six lifestyle factors – diet, alcohol use, body mass index (BMI), physical activity, smoking status, and sleep duration – the association between diabetes risk and evening chronotype weakened to a 19% higher risk of developing type 2 diabetes.

In a subgroup analysis, this association was stronger among women who either had had no night shifts over the previous 2 years or had worked night shifts for less than 10 years in their careers. For nurses who had worked night shifts recently, the study found no association between evening chronotype and diabetes risk.

The participants, drawn from the Nurses’ Health Study II, were between 45 and 62 years age, with no history of cancer, cardiovascular disease, or diabetes. Researchers followed the group from 2009 until 2017.
 

Is there a mismatch between natural circadian rhythm and work schedule?

The authors, led by Sina Kianersi, DVM, PhD, of Harvard Medical School, Boston, suggest that their results may be linked to a mismatch between a person’s circadian rhythm and their physical and social environment – for example, if someone lives on a schedule opposite to their circadian preference.

In one 2015 study, female nurses who had worked daytime shifts for more than 10 years but had an evening chronotype had the highest diabetes risk, compared with early chronotypes (51% more likely to develop type 2 diabetes).

In a 2022 study, an evening chronotype was associated with a 30% elevated risk for type 2 diabetes. The authors speculated that circadian misalignment could be to blame – for example, being a night owl but working early morning – which can disrupt glycemic and lipid metabolism.

Previous studies have found that shorter or irregular sleep habits are associated with a higher risk of type 2 diabetes. Other studies have also found that people with an evening chronotype are more likely than early birds to have unhealthy eating habits, have lower levels of physical activity, and smoke and drink.

This new study did not find that an evening chronotype was associated with unhealthy drinking, which the authors defined as having one or more drinks per day.

In an accompanying editorial, two physicians from the Harvard T.H. Chan School of Public Health in Boston caution that the statistical design of the study limits its ability to establish causation.

“Chronotype could change later, which might correlate with lifestyle changes,” write Kehuan Lin, MS, Mingyang Song, MBBS, and Edward Giovannucci, MD. “Experimental trials are required to determine whether chronotype is a marker of unhealthy lifestyle or an independent determinant.”

They also suggest that psychological factors and the type of work being performed by the participants could be potential confounders.

The authors of the study note that their findings might not be generalizable to groups other than middle-aged White female nurses. The study population also had a relatively high level of education and were socioeconomically advantaged.

Self-reporting chronotypes with a single question could also result in misclassification and measurement error, the authors acknowledge.

The findings underscore the value of assessing an individuals’ chronotype for scheduling shift work – for example, assigning night owls to night shifts may improve their metabolic health and sleeping habits, according to the authors of the study.

“Given the importance of lifestyle modification in diabetes prevention, future research is warranted to investigate whether improving lifestyle behaviors could effectively reduce diabetes risk in persons with an evening chronotype,” the authors conclude.

The study was supported by grants from the National Institutes of Health and the European Research Council.

A version of this article first appeared on Medscape.com.

“Night owls” have an increased risk for developing type 2 diabetes and are more likely to smoke more, exercise less, and have poor sleep habits, compared with their “early bird” counterparts, according to a new study, published in Annals of Internal Medicine.

The work focused on participants’ self-assessed chronotype – an individuals’ circadian preference, or natural preference to sleep and wake up earlier or later, commonly known as being an early bird or a night owl.

Analyzing the self-reported lifestyle behaviors and sleeping habits of more than 60,000 middle-aged female nurses, researchers from Brigham and Women’s Hospital and Harvard Medical School, both in Boston, found that those with a preference for waking up later had a 72% higher risk for diabetes and were 54% more likely to have unhealthy lifestyle behaviors, compared with participants who tended to wake up earlier.

After adjustment for six lifestyle factors – diet, alcohol use, body mass index (BMI), physical activity, smoking status, and sleep duration – the association between diabetes risk and evening chronotype weakened to a 19% higher risk of developing type 2 diabetes.

In a subgroup analysis, this association was stronger among women who either had had no night shifts over the previous 2 years or had worked night shifts for less than 10 years in their careers. For nurses who had worked night shifts recently, the study found no association between evening chronotype and diabetes risk.

The participants, drawn from the Nurses’ Health Study II, were between 45 and 62 years age, with no history of cancer, cardiovascular disease, or diabetes. Researchers followed the group from 2009 until 2017.
 

Is there a mismatch between natural circadian rhythm and work schedule?

The authors, led by Sina Kianersi, DVM, PhD, of Harvard Medical School, Boston, suggest that their results may be linked to a mismatch between a person’s circadian rhythm and their physical and social environment – for example, if someone lives on a schedule opposite to their circadian preference.

In one 2015 study, female nurses who had worked daytime shifts for more than 10 years but had an evening chronotype had the highest diabetes risk, compared with early chronotypes (51% more likely to develop type 2 diabetes).

In a 2022 study, an evening chronotype was associated with a 30% elevated risk for type 2 diabetes. The authors speculated that circadian misalignment could be to blame – for example, being a night owl but working early morning – which can disrupt glycemic and lipid metabolism.

Previous studies have found that shorter or irregular sleep habits are associated with a higher risk of type 2 diabetes. Other studies have also found that people with an evening chronotype are more likely than early birds to have unhealthy eating habits, have lower levels of physical activity, and smoke and drink.

This new study did not find that an evening chronotype was associated with unhealthy drinking, which the authors defined as having one or more drinks per day.

In an accompanying editorial, two physicians from the Harvard T.H. Chan School of Public Health in Boston caution that the statistical design of the study limits its ability to establish causation.

“Chronotype could change later, which might correlate with lifestyle changes,” write Kehuan Lin, MS, Mingyang Song, MBBS, and Edward Giovannucci, MD. “Experimental trials are required to determine whether chronotype is a marker of unhealthy lifestyle or an independent determinant.”

They also suggest that psychological factors and the type of work being performed by the participants could be potential confounders.

The authors of the study note that their findings might not be generalizable to groups other than middle-aged White female nurses. The study population also had a relatively high level of education and were socioeconomically advantaged.

Self-reporting chronotypes with a single question could also result in misclassification and measurement error, the authors acknowledge.

The findings underscore the value of assessing an individuals’ chronotype for scheduling shift work – for example, assigning night owls to night shifts may improve their metabolic health and sleeping habits, according to the authors of the study.

“Given the importance of lifestyle modification in diabetes prevention, future research is warranted to investigate whether improving lifestyle behaviors could effectively reduce diabetes risk in persons with an evening chronotype,” the authors conclude.

The study was supported by grants from the National Institutes of Health and the European Research Council.

A version of this article first appeared on Medscape.com.

It is estimated that almost one billion people globally are affected by obstructive sleep apnea (OSA) (Benjafield A, et al. Lancet Respir Med. 2019;7[8]:687-98). Despite such high prevalence, the treatment options for OSA are somewhat limited. Continuous positive airway pressure (CPAP), the gold standard therapy, is not viable for many due to difficulties tolerating the device or mask, and thus may not be a realistic long-term solution. As per certain estimates, nearly 50% of CPAP users discontinue treatment by the fifth year (Schoch O, et al. Respiration. 2014;87[2]:121-8). Furthermore, alternative options such as mandibular advancement devices, positional therapy, weight loss, and maxillofacial or palate surgery, also have unique challenges and limitations.

CHEST

First described in 2001, hypoglossal nerve stimulation (HGNS) is a relatively new and emerging technology for the treatment of OSA (Schwartz A, et al. Arch Otolaryngol Head Neck Surg. 2001 Oct;127[10]:1216-23). HGNS therapy was approved by the Food and Drug Administration in 2014 for the treatment of moderate to severe OSA. The therapy involves surgical implantation of the HGNS device, optimization of device settings, and evaluation for treatment response. A physician-led multidisciplinary Hypoglossal Nerve Stimulation Clinic involves collaboration from essential stakeholders, most importantly sleep medicine providers, clinic staff, sleep technologists, and ENT sleep surgeons. Goals of the multidisciplinary program are to ensure timely follow-up, optimization of device settings, and maximizing treatment efficacy. This review describes steps involved in developing a successful multidisciplinary HGNS program within a sleep medicine practice.
 

Patient selection and evaluation

There is growing interest in HGNS relative to conventional CPAP therapy, with many patients presenting to clinic to inquire about this therapy. However, not all patients are candidates for HGNS therapy. Prioritizing appropriate patient selection and education are key first steps. The initial assessments usually occur with a sleep medicine specialist. It begins with confirmation of the diagnosis of OSA in all patients and a concerted effort to troubleshoot and address any barriers to CPAP use before consideration of surgery. Patients who are unwilling to use or unable to tolerate CPAP therapy undergo further evaluation for HGNS therapy. It is important to ensure that patients are also screened for other sleep disorders, such as insomnia or restless leg syndrome, to rule out its contribution to daytime (or nighttime) symptoms.

Other salient inclusion criteria include an apnea-hypopnea index (AHI) between 15-100 events per hour (previously 65), at least 18 years of age, and a body mass index (BMI) less than 40 kg/m² (previously 32). Qualifying patients undergo an updated polysomnography if a recent study is not available. If the polysomnography reveals central and mixed apneas comprising less than 25 percent of the total AHI, patients are referred to ENT Sleep Surgery, and drug-induced sleep endoscopy is offered to examine upper airway anatomy. When a complete concentric collapse of the soft palate is seen on drug-induced sleep endoscopy, surgery is contraindicated. Prior palate surgery or maxillomandibular advancement (MMA) are not contraindications to HGNS therapy.

The patients receive comprehensive information on the nature of the surgery, expected recovery course, and device activation timeline. Perhaps most importantly, the patients receive structured education on HGNS therapy and potential outcomes to set realistic expectations. In the STAR trial, patients experienced a reduction in the AHI of approximately 70% (Strollo P, et al. N Engl J Med. 2014;370[2]:139-49). It is important to note that a response to therapy was defined as a reduction in the AHI by at least 50% and a value less than 20 events/hour (Strollo P, et al. Sleep. 2015;38[10]:1593-8). Therefore, patients who are expecting complete resolution of snoring and/or OSA may not be ideal candidates for surgery. Furthermore, patients who continue to experience fatigue and sleepiness on CPAP despite control of OSA may not experience amelioration of these symptoms with HGNS therapy.
 

Surgery and device management

The surgery, performed under general anesthesia, lasts approximately 3 hours, and may be followed by an overnight hospital stay depending on patient’s comorbidities. The device implantation involves placement of an implantable pulse generator (IPG) in the chest wall and leads to the hypoglossal nerve. The IPG is similar to a pacemaker and functions to stimulate the ipsilateral hypoglossal nerve innervating the tongue during sleep. The most common postoperative complications noted in the STAR trial data include incision site pain and swelling as well as temporary tongue weakness or paresthesia. Postoperative restrictions are minimal and include no heavy lifting for one month after surgery.

One week postsurgery, patients return to the ENT Sleep Surgery Clinic for follow-up, at which time the incisions as well as tongue strength and sensation are evaluated. In a subsequent visit between 4 and 6 weeks postsurgery, patients are evaluated in a joint Sleep Medicine and ENT clinic. They undergo device education and activation of the IPG using a dedicated programmer obtained from the device manufacturer. Device comfort features such as start delay and pause time are also programmed. Furthermore, appropriate tongue movement, lead placement, and voltage range settings are assessed during the visit. The ENT surgery team reevaluates the incision sites and assesses for tongue function and sensation. Patients are instructed to increase the voltage incrementally every week as tolerated with the goal of using the device nightly for the entirety of sleep. If patients tolerate the therapy well during the 2- to 3-month follow-up, a sleep study is scheduled to evaluate treatment effectiveness at the peak tolerable voltage. For those struggling with the therapy, adjustments to electrode configurations should be considered for pulse width, and rate. Occasionally, patients may require awake endoscopy and/or an advanced HGNS titration while asleep to determine the most appropriate settings to optimally control sleep apnea.

Until recently, patients implanted with an early version of the HGNS were limited to magnetic resonance imaging (MRI) scans of the head, neck, and extremities only. However, patients with the latest model IPGs can now undergo full-body MRI scans. It is important to note that the MRI’s Tesla cannot exceed 1.5T, necessitating specific imaging centers. Other constraints include the inability to adjust device settings remotely, which could mean long travel for minor setting adjustments such as altering start delay or pause times. Furthermore, provider education on operating and managing the device can be time consuming and may also be a barrier to implementation in a clinic. Also challenging may be the availability of an ENT surgery, which plays a critical role in the implantation of the devices and follow-up.

Currently, Inspire Medical Systems is the only FDA-approved hypoglossal nerve stimulation device available in the United States, and globally, more than 45,000 patients have been implanted. However, the field of neurostimulation is rapidly growing. Companies like LivaNova have secured Investigational Device Exemption for their HGNS device. The Genio system by Nyxoah is evaluating the use of bilateral hypoglossal nerve stimulation in patients with OSA and complete concentric collapse of the palate. A multidisciplinary Hypoglossal Nerve Stimulation Clinic is an important component of a comprehensive sleep medicine clinic for patient care and medical education. In the appropriate patient, this emerging technology may provide improvement in OSA severity and symptoms.
 

Dr. Gill is Clinical Associate Professor, Division of Sleep Medicine, Stanford (Calif.) University.

It is estimated that almost one billion people globally are affected by obstructive sleep apnea (OSA) (Benjafield A, et al. Lancet Respir Med. 2019;7[8]:687-98). Despite such high prevalence, the treatment options for OSA are somewhat limited. Continuous positive airway pressure (CPAP), the gold standard therapy, is not viable for many due to difficulties tolerating the device or mask, and thus may not be a realistic long-term solution. As per certain estimates, nearly 50% of CPAP users discontinue treatment by the fifth year (Schoch O, et al. Respiration. 2014;87[2]:121-8). Furthermore, alternative options such as mandibular advancement devices, positional therapy, weight loss, and maxillofacial or palate surgery, also have unique challenges and limitations.

CHEST

First described in 2001, hypoglossal nerve stimulation (HGNS) is a relatively new and emerging technology for the treatment of OSA (Schwartz A, et al. Arch Otolaryngol Head Neck Surg. 2001 Oct;127[10]:1216-23). HGNS therapy was approved by the Food and Drug Administration in 2014 for the treatment of moderate to severe OSA. The therapy involves surgical implantation of the HGNS device, optimization of device settings, and evaluation for treatment response. A physician-led multidisciplinary Hypoglossal Nerve Stimulation Clinic involves collaboration from essential stakeholders, most importantly sleep medicine providers, clinic staff, sleep technologists, and ENT sleep surgeons. Goals of the multidisciplinary program are to ensure timely follow-up, optimization of device settings, and maximizing treatment efficacy. This review describes steps involved in developing a successful multidisciplinary HGNS program within a sleep medicine practice.
 

Patient selection and evaluation

There is growing interest in HGNS relative to conventional CPAP therapy, with many patients presenting to clinic to inquire about this therapy. However, not all patients are candidates for HGNS therapy. Prioritizing appropriate patient selection and education are key first steps. The initial assessments usually occur with a sleep medicine specialist. It begins with confirmation of the diagnosis of OSA in all patients and a concerted effort to troubleshoot and address any barriers to CPAP use before consideration of surgery. Patients who are unwilling to use or unable to tolerate CPAP therapy undergo further evaluation for HGNS therapy. It is important to ensure that patients are also screened for other sleep disorders, such as insomnia or restless leg syndrome, to rule out its contribution to daytime (or nighttime) symptoms.

Other salient inclusion criteria include an apnea-hypopnea index (AHI) between 15-100 events per hour (previously 65), at least 18 years of age, and a body mass index (BMI) less than 40 kg/m² (previously 32). Qualifying patients undergo an updated polysomnography if a recent study is not available. If the polysomnography reveals central and mixed apneas comprising less than 25 percent of the total AHI, patients are referred to ENT Sleep Surgery, and drug-induced sleep endoscopy is offered to examine upper airway anatomy. When a complete concentric collapse of the soft palate is seen on drug-induced sleep endoscopy, surgery is contraindicated. Prior palate surgery or maxillomandibular advancement (MMA) are not contraindications to HGNS therapy.

The patients receive comprehensive information on the nature of the surgery, expected recovery course, and device activation timeline. Perhaps most importantly, the patients receive structured education on HGNS therapy and potential outcomes to set realistic expectations. In the STAR trial, patients experienced a reduction in the AHI of approximately 70% (Strollo P, et al. N Engl J Med. 2014;370[2]:139-49). It is important to note that a response to therapy was defined as a reduction in the AHI by at least 50% and a value less than 20 events/hour (Strollo P, et al. Sleep. 2015;38[10]:1593-8). Therefore, patients who are expecting complete resolution of snoring and/or OSA may not be ideal candidates for surgery. Furthermore, patients who continue to experience fatigue and sleepiness on CPAP despite control of OSA may not experience amelioration of these symptoms with HGNS therapy.
 

Surgery and device management

The surgery, performed under general anesthesia, lasts approximately 3 hours, and may be followed by an overnight hospital stay depending on patient’s comorbidities. The device implantation involves placement of an implantable pulse generator (IPG) in the chest wall and leads to the hypoglossal nerve. The IPG is similar to a pacemaker and functions to stimulate the ipsilateral hypoglossal nerve innervating the tongue during sleep. The most common postoperative complications noted in the STAR trial data include incision site pain and swelling as well as temporary tongue weakness or paresthesia. Postoperative restrictions are minimal and include no heavy lifting for one month after surgery.

One week postsurgery, patients return to the ENT Sleep Surgery Clinic for follow-up, at which time the incisions as well as tongue strength and sensation are evaluated. In a subsequent visit between 4 and 6 weeks postsurgery, patients are evaluated in a joint Sleep Medicine and ENT clinic. They undergo device education and activation of the IPG using a dedicated programmer obtained from the device manufacturer. Device comfort features such as start delay and pause time are also programmed. Furthermore, appropriate tongue movement, lead placement, and voltage range settings are assessed during the visit. The ENT surgery team reevaluates the incision sites and assesses for tongue function and sensation. Patients are instructed to increase the voltage incrementally every week as tolerated with the goal of using the device nightly for the entirety of sleep. If patients tolerate the therapy well during the 2- to 3-month follow-up, a sleep study is scheduled to evaluate treatment effectiveness at the peak tolerable voltage. For those struggling with the therapy, adjustments to electrode configurations should be considered for pulse width, and rate. Occasionally, patients may require awake endoscopy and/or an advanced HGNS titration while asleep to determine the most appropriate settings to optimally control sleep apnea.

Until recently, patients implanted with an early version of the HGNS were limited to magnetic resonance imaging (MRI) scans of the head, neck, and extremities only. However, patients with the latest model IPGs can now undergo full-body MRI scans. It is important to note that the MRI’s Tesla cannot exceed 1.5T, necessitating specific imaging centers. Other constraints include the inability to adjust device settings remotely, which could mean long travel for minor setting adjustments such as altering start delay or pause times. Furthermore, provider education on operating and managing the device can be time consuming and may also be a barrier to implementation in a clinic. Also challenging may be the availability of an ENT surgery, which plays a critical role in the implantation of the devices and follow-up.

Currently, Inspire Medical Systems is the only FDA-approved hypoglossal nerve stimulation device available in the United States, and globally, more than 45,000 patients have been implanted. However, the field of neurostimulation is rapidly growing. Companies like LivaNova have secured Investigational Device Exemption for their HGNS device. The Genio system by Nyxoah is evaluating the use of bilateral hypoglossal nerve stimulation in patients with OSA and complete concentric collapse of the palate. A multidisciplinary Hypoglossal Nerve Stimulation Clinic is an important component of a comprehensive sleep medicine clinic for patient care and medical education. In the appropriate patient, this emerging technology may provide improvement in OSA severity and symptoms.
 

Dr. Gill is Clinical Associate Professor, Division of Sleep Medicine, Stanford (Calif.) University.

It is estimated that almost one billion people globally are affected by obstructive sleep apnea (OSA) (Benjafield A, et al. Lancet Respir Med. 2019;7[8]:687-98). Despite such high prevalence, the treatment options for OSA are somewhat limited. Continuous positive airway pressure (CPAP), the gold standard therapy, is not viable for many due to difficulties tolerating the device or mask, and thus may not be a realistic long-term solution. As per certain estimates, nearly 50% of CPAP users discontinue treatment by the fifth year (Schoch O, et al. Respiration. 2014;87[2]:121-8). Furthermore, alternative options such as mandibular advancement devices, positional therapy, weight loss, and maxillofacial or palate surgery, also have unique challenges and limitations.

CHEST

First described in 2001, hypoglossal nerve stimulation (HGNS) is a relatively new and emerging technology for the treatment of OSA (Schwartz A, et al. Arch Otolaryngol Head Neck Surg. 2001 Oct;127[10]:1216-23). HGNS therapy was approved by the Food and Drug Administration in 2014 for the treatment of moderate to severe OSA. The therapy involves surgical implantation of the HGNS device, optimization of device settings, and evaluation for treatment response. A physician-led multidisciplinary Hypoglossal Nerve Stimulation Clinic involves collaboration from essential stakeholders, most importantly sleep medicine providers, clinic staff, sleep technologists, and ENT sleep surgeons. Goals of the multidisciplinary program are to ensure timely follow-up, optimization of device settings, and maximizing treatment efficacy. This review describes steps involved in developing a successful multidisciplinary HGNS program within a sleep medicine practice.
 

Patient selection and evaluation

There is growing interest in HGNS relative to conventional CPAP therapy, with many patients presenting to clinic to inquire about this therapy. However, not all patients are candidates for HGNS therapy. Prioritizing appropriate patient selection and education are key first steps. The initial assessments usually occur with a sleep medicine specialist. It begins with confirmation of the diagnosis of OSA in all patients and a concerted effort to troubleshoot and address any barriers to CPAP use before consideration of surgery. Patients who are unwilling to use or unable to tolerate CPAP therapy undergo further evaluation for HGNS therapy. It is important to ensure that patients are also screened for other sleep disorders, such as insomnia or restless leg syndrome, to rule out its contribution to daytime (or nighttime) symptoms.

Other salient inclusion criteria include an apnea-hypopnea index (AHI) between 15-100 events per hour (previously 65), at least 18 years of age, and a body mass index (BMI) less than 40 kg/m² (previously 32). Qualifying patients undergo an updated polysomnography if a recent study is not available. If the polysomnography reveals central and mixed apneas comprising less than 25 percent of the total AHI, patients are referred to ENT Sleep Surgery, and drug-induced sleep endoscopy is offered to examine upper airway anatomy. When a complete concentric collapse of the soft palate is seen on drug-induced sleep endoscopy, surgery is contraindicated. Prior palate surgery or maxillomandibular advancement (MMA) are not contraindications to HGNS therapy.

The patients receive comprehensive information on the nature of the surgery, expected recovery course, and device activation timeline. Perhaps most importantly, the patients receive structured education on HGNS therapy and potential outcomes to set realistic expectations. In the STAR trial, patients experienced a reduction in the AHI of approximately 70% (Strollo P, et al. N Engl J Med. 2014;370[2]:139-49). It is important to note that a response to therapy was defined as a reduction in the AHI by at least 50% and a value less than 20 events/hour (Strollo P, et al. Sleep. 2015;38[10]:1593-8). Therefore, patients who are expecting complete resolution of snoring and/or OSA may not be ideal candidates for surgery. Furthermore, patients who continue to experience fatigue and sleepiness on CPAP despite control of OSA may not experience amelioration of these symptoms with HGNS therapy.
 

Surgery and device management

The surgery, performed under general anesthesia, lasts approximately 3 hours, and may be followed by an overnight hospital stay depending on patient’s comorbidities. The device implantation involves placement of an implantable pulse generator (IPG) in the chest wall and leads to the hypoglossal nerve. The IPG is similar to a pacemaker and functions to stimulate the ipsilateral hypoglossal nerve innervating the tongue during sleep. The most common postoperative complications noted in the STAR trial data include incision site pain and swelling as well as temporary tongue weakness or paresthesia. Postoperative restrictions are minimal and include no heavy lifting for one month after surgery.

One week postsurgery, patients return to the ENT Sleep Surgery Clinic for follow-up, at which time the incisions as well as tongue strength and sensation are evaluated. In a subsequent visit between 4 and 6 weeks postsurgery, patients are evaluated in a joint Sleep Medicine and ENT clinic. They undergo device education and activation of the IPG using a dedicated programmer obtained from the device manufacturer. Device comfort features such as start delay and pause time are also programmed. Furthermore, appropriate tongue movement, lead placement, and voltage range settings are assessed during the visit. The ENT surgery team reevaluates the incision sites and assesses for tongue function and sensation. Patients are instructed to increase the voltage incrementally every week as tolerated with the goal of using the device nightly for the entirety of sleep. If patients tolerate the therapy well during the 2- to 3-month follow-up, a sleep study is scheduled to evaluate treatment effectiveness at the peak tolerable voltage. For those struggling with the therapy, adjustments to electrode configurations should be considered for pulse width, and rate. Occasionally, patients may require awake endoscopy and/or an advanced HGNS titration while asleep to determine the most appropriate settings to optimally control sleep apnea.

Until recently, patients implanted with an early version of the HGNS were limited to magnetic resonance imaging (MRI) scans of the head, neck, and extremities only. However, patients with the latest model IPGs can now undergo full-body MRI scans. It is important to note that the MRI’s Tesla cannot exceed 1.5T, necessitating specific imaging centers. Other constraints include the inability to adjust device settings remotely, which could mean long travel for minor setting adjustments such as altering start delay or pause times. Furthermore, provider education on operating and managing the device can be time consuming and may also be a barrier to implementation in a clinic. Also challenging may be the availability of an ENT surgery, which plays a critical role in the implantation of the devices and follow-up.

Currently, Inspire Medical Systems is the only FDA-approved hypoglossal nerve stimulation device available in the United States, and globally, more than 45,000 patients have been implanted. However, the field of neurostimulation is rapidly growing. Companies like LivaNova have secured Investigational Device Exemption for their HGNS device. The Genio system by Nyxoah is evaluating the use of bilateral hypoglossal nerve stimulation in patients with OSA and complete concentric collapse of the palate. A multidisciplinary Hypoglossal Nerve Stimulation Clinic is an important component of a comprehensive sleep medicine clinic for patient care and medical education. In the appropriate patient, this emerging technology may provide improvement in OSA severity and symptoms.
 

Dr. Gill is Clinical Associate Professor, Division of Sleep Medicine, Stanford (Calif.) University.

Adults with asthma who were newly prescribed mepolizumab showed significant improvement in symptoms after 1 year regardless of comorbidities, based on data from 822 individuals.

Comorbidities including chronic rhinosinusitis with polyps (CRSwNP), gastroesophageal reflux disease GERD), anxiety and depression, and chronic obstructive pulmonary disorder (COPD) are common in patients with severe asthma and add to the disease burden, wrote Mark C. Liu, MD, of Johns Hopkins University, Baltimore, and colleagues.

“Some comorbidities, such as CRSwNP, share pathophysiological mechanisms with severe asthma, with interleukin-5 (IL-5),” and treatments targeting IL-5 could improve outcomes, they said.

In the real-world REALITI-A study, mepolizumab, a humanized monoclonal antibody that targets IL-5, significantly reduced asthma exacerbation and oral corticosteroid use in severe asthma patients, they said.

To assess the impact of mepolizumab on patients with comorbidities, the researchers conducted a post hoc analysis of 822 adults with severe asthma, including 321 with CRSwNP, 309 with GERD, 203 with depression/anxiety, and 81 with COPD. The findings were published in the Journal of Allergy and Clinical Immunology: In Practice.

The main outcomes were the rate of clinically significant asthma exacerbations (CSEs) between the 12 months before and after mepolizumab initiation, and the changes from baseline in the daily maintenance use of oral corticosteroids (OCS).

Across all comorbidities, the rate of CSEs decreased significantly from the pretreatment period to the follow-up period, from 4.28 events per year to 1.23 events per year.

“A numerically greater reduction in the rate of CSEs was reported for patients with versus without CRSwNP, whereas the reverse was reported for patients with versus without COPD and depression/anxiety, although the confidence intervals were large for the with COPD subgroup,” the researchers wrote.

The median maintenance dose of oral corticosteroids decreased by at least 50% across all comorbidities after mepolizumab treatment; patients with CRSwNP had the greatest reduction (83%).

In addition, scores on the Asthma Control Questionnaire–5 decreased by at least 0.63 points, and least squared (LS) mean changes in forced expiratory volume per second (FEV₁) increased from baseline across all comorbidities after mepolizumab treatment by at least 74 mL.

Although patients with versus without CRSwNP had greater improvements, patients without GERD, depression/anxiety, and COPD had greater improvements than did those without the respective conditions with the exception of greater FEV₁ improvement in patients with vs. without COPD.

“Patients with severe asthma and comorbid CRSwNP are recognized as having a high disease burden, as demonstrated by more frequent exacerbations,” the researchers wrote in their discussion. “Mepolizumab may serve to reduce the disease burden of this high-risk group by targeting the common pathophysiological pathway of IL-5 and eosinophilic-driven inflammation because it has proven clinical benefits in treating asthma and CRSwNP separately and together,” and the current study findings support the use of mepolizumab for this population in particular, they said.

The findings were limited by several factors including the incomplete data for voluntary assessments, the post hoc design and relatively small numbers of patients in various subgroups, notably COPD, and the potential inaccurate diagnosis of COPD, the researchers noted.

“Nevertheless, because the amount of improvement in each outcome following mepolizumab treatment differed depending on the comorbidity in question, our findings highlight the impact that comorbidities and their prevalence and severity have on outcomes,” and the overall success of mepolizumab across clinical characteristics and comorbidities supports the generalizability of the findings to the larger population of adults with severe asthma, they concluded.

The study was supported by GlaxoSmithKline. Dr. Liu disclosed research funding from GSK, Boehringer Ingelheim, and Gossamer Bio, and participation on advisory boards for AstraZeneca, GSK, and Gossamer Bio.

Adults with asthma who were newly prescribed mepolizumab showed significant improvement in symptoms after 1 year regardless of comorbidities, based on data from 822 individuals.

Comorbidities including chronic rhinosinusitis with polyps (CRSwNP), gastroesophageal reflux disease GERD), anxiety and depression, and chronic obstructive pulmonary disorder (COPD) are common in patients with severe asthma and add to the disease burden, wrote Mark C. Liu, MD, of Johns Hopkins University, Baltimore, and colleagues.

“Some comorbidities, such as CRSwNP, share pathophysiological mechanisms with severe asthma, with interleukin-5 (IL-5),” and treatments targeting IL-5 could improve outcomes, they said.

In the real-world REALITI-A study, mepolizumab, a humanized monoclonal antibody that targets IL-5, significantly reduced asthma exacerbation and oral corticosteroid use in severe asthma patients, they said.

To assess the impact of mepolizumab on patients with comorbidities, the researchers conducted a post hoc analysis of 822 adults with severe asthma, including 321 with CRSwNP, 309 with GERD, 203 with depression/anxiety, and 81 with COPD. The findings were published in the Journal of Allergy and Clinical Immunology: In Practice.

The main outcomes were the rate of clinically significant asthma exacerbations (CSEs) between the 12 months before and after mepolizumab initiation, and the changes from baseline in the daily maintenance use of oral corticosteroids (OCS).

Across all comorbidities, the rate of CSEs decreased significantly from the pretreatment period to the follow-up period, from 4.28 events per year to 1.23 events per year.

“A numerically greater reduction in the rate of CSEs was reported for patients with versus without CRSwNP, whereas the reverse was reported for patients with versus without COPD and depression/anxiety, although the confidence intervals were large for the with COPD subgroup,” the researchers wrote.

The median maintenance dose of oral corticosteroids decreased by at least 50% across all comorbidities after mepolizumab treatment; patients with CRSwNP had the greatest reduction (83%).

In addition, scores on the Asthma Control Questionnaire–5 decreased by at least 0.63 points, and least squared (LS) mean changes in forced expiratory volume per second (FEV₁) increased from baseline across all comorbidities after mepolizumab treatment by at least 74 mL.

Although patients with versus without CRSwNP had greater improvements, patients without GERD, depression/anxiety, and COPD had greater improvements than did those without the respective conditions with the exception of greater FEV₁ improvement in patients with vs. without COPD.

“Patients with severe asthma and comorbid CRSwNP are recognized as having a high disease burden, as demonstrated by more frequent exacerbations,” the researchers wrote in their discussion. “Mepolizumab may serve to reduce the disease burden of this high-risk group by targeting the common pathophysiological pathway of IL-5 and eosinophilic-driven inflammation because it has proven clinical benefits in treating asthma and CRSwNP separately and together,” and the current study findings support the use of mepolizumab for this population in particular, they said.

The findings were limited by several factors including the incomplete data for voluntary assessments, the post hoc design and relatively small numbers of patients in various subgroups, notably COPD, and the potential inaccurate diagnosis of COPD, the researchers noted.

“Nevertheless, because the amount of improvement in each outcome following mepolizumab treatment differed depending on the comorbidity in question, our findings highlight the impact that comorbidities and their prevalence and severity have on outcomes,” and the overall success of mepolizumab across clinical characteristics and comorbidities supports the generalizability of the findings to the larger population of adults with severe asthma, they concluded.

The study was supported by GlaxoSmithKline. Dr. Liu disclosed research funding from GSK, Boehringer Ingelheim, and Gossamer Bio, and participation on advisory boards for AstraZeneca, GSK, and Gossamer Bio.

Adults with asthma who were newly prescribed mepolizumab showed significant improvement in symptoms after 1 year regardless of comorbidities, based on data from 822 individuals.

Comorbidities including chronic rhinosinusitis with polyps (CRSwNP), gastroesophageal reflux disease GERD), anxiety and depression, and chronic obstructive pulmonary disorder (COPD) are common in patients with severe asthma and add to the disease burden, wrote Mark C. Liu, MD, of Johns Hopkins University, Baltimore, and colleagues.

“Some comorbidities, such as CRSwNP, share pathophysiological mechanisms with severe asthma, with interleukin-5 (IL-5),” and treatments targeting IL-5 could improve outcomes, they said.

In the real-world REALITI-A study, mepolizumab, a humanized monoclonal antibody that targets IL-5, significantly reduced asthma exacerbation and oral corticosteroid use in severe asthma patients, they said.

To assess the impact of mepolizumab on patients with comorbidities, the researchers conducted a post hoc analysis of 822 adults with severe asthma, including 321 with CRSwNP, 309 with GERD, 203 with depression/anxiety, and 81 with COPD. The findings were published in the Journal of Allergy and Clinical Immunology: In Practice.

The main outcomes were the rate of clinically significant asthma exacerbations (CSEs) between the 12 months before and after mepolizumab initiation, and the changes from baseline in the daily maintenance use of oral corticosteroids (OCS).

Across all comorbidities, the rate of CSEs decreased significantly from the pretreatment period to the follow-up period, from 4.28 events per year to 1.23 events per year.

“A numerically greater reduction in the rate of CSEs was reported for patients with versus without CRSwNP, whereas the reverse was reported for patients with versus without COPD and depression/anxiety, although the confidence intervals were large for the with COPD subgroup,” the researchers wrote.

The median maintenance dose of oral corticosteroids decreased by at least 50% across all comorbidities after mepolizumab treatment; patients with CRSwNP had the greatest reduction (83%).

In addition, scores on the Asthma Control Questionnaire–5 decreased by at least 0.63 points, and least squared (LS) mean changes in forced expiratory volume per second (FEV₁) increased from baseline across all comorbidities after mepolizumab treatment by at least 74 mL.

Although patients with versus without CRSwNP had greater improvements, patients without GERD, depression/anxiety, and COPD had greater improvements than did those without the respective conditions with the exception of greater FEV₁ improvement in patients with vs. without COPD.

“Patients with severe asthma and comorbid CRSwNP are recognized as having a high disease burden, as demonstrated by more frequent exacerbations,” the researchers wrote in their discussion. “Mepolizumab may serve to reduce the disease burden of this high-risk group by targeting the common pathophysiological pathway of IL-5 and eosinophilic-driven inflammation because it has proven clinical benefits in treating asthma and CRSwNP separately and together,” and the current study findings support the use of mepolizumab for this population in particular, they said.

The findings were limited by several factors including the incomplete data for voluntary assessments, the post hoc design and relatively small numbers of patients in various subgroups, notably COPD, and the potential inaccurate diagnosis of COPD, the researchers noted.

“Nevertheless, because the amount of improvement in each outcome following mepolizumab treatment differed depending on the comorbidity in question, our findings highlight the impact that comorbidities and their prevalence and severity have on outcomes,” and the overall success of mepolizumab across clinical characteristics and comorbidities supports the generalizability of the findings to the larger population of adults with severe asthma, they concluded.

The study was supported by GlaxoSmithKline. Dr. Liu disclosed research funding from GSK, Boehringer Ingelheim, and Gossamer Bio, and participation on advisory boards for AstraZeneca, GSK, and Gossamer Bio.