CHARLOTTE, N.C. – Erratic sleep patterns over years or even decades, along with a patient’s age and history of depression, may be harbingers of cognitive impairment later in life, an analysis of decades of data from a large sleep study has found.

“What we were a little surprised to find in this model was that sleep duration, whether short, long or average, was not significant, but the sleep variability – the change in sleep across those time measurements—was significantly impacting the incidence of cognitive impairment,” Samantha Keil, PhD, a postdoctoral fellow at the University of Washington, Seattle, reported at the at the annual meeting of the Associated Professional Sleep Societies.

The researchers analyzed sleep and cognition data collected over decades on 1,104 adults who participated in the Seattle Longitudinal Study. Study participants ranged from age 55 to over 100, with almost 80% of the study cohort aged 65 and older.

The Seattle Longitudinal Study first started gathering data in the 1950s. Participants in the study cohort underwent an extensive cognitive battery, which was added to the study in 1984 and gathered every 5-7 years, and completed a health behavioral questionnaire (HBQ), which was added in 1993 and administered every 3-5 years, Dr. Keil said. The HBQ included a question on average nightly sleep duration.

The study used a multivariable Cox proportional hazard regression model to evaluate the overall effect of average sleep duration and changes in sleep duration over time on cognitive impairment. Covariates used in the model included apolipoprotein E4 (APOE4) genotype, gender, years of education, ethnicity, and depression.

Dr. Keil said the model found, as expected, that the  demographic variables of education, APOE status, and depression were significantly associated with cognitive impairment (hazard ratios of 1.11; 95% confidence interval [CI], 1.02-1.21; P = .01; and 2.08; 95% CI, 1.31-3.31; P < .005; and 1.08; 95% CI, 1.04-1.13; P < .005, respectively). Importantly, when evaluating the duration, change and variability of sleep, the researchers found that increased sleep variability was significantly associated with cognitive impairment (HR, 3.15; 95% CI, 1.69-5.87; P < .005).  

Under this analysis, “sleep variability over time and not median sleep duration was associated with cognitive impairment,” she said. When sleep variability was added into the model, it improved the concordance score – a value that reflects the ability of a model to predict an outcome better than random chance – from .63 to .73 (a value of .5 indicates the model is no better at predicting an outcome than a random chance model; a value of .7 or greater indicates a good model).

Identification of sleep variability as a sleep pattern of interest in longitudinal studies is important, Dr. Keil said, because simply evaluating mean or median sleep duration across time might not account for a subject’s variable sleep phenotype. Most importantly, further evaluation of sleep variability with a linear regression prediction analysis (F statistic 8.796, P < .0001, adjusted R-squared .235) found that increased age, depression, and sleep variability significantly predicted cognitive impairment 10 years downstream. “Longitudinal sleep variability is perhaps for the first time being reported as significantly associated with the development of downstream cognitive impairment,” Dr. Keil said.

What makes this study unique, Dr. Keil said in an interview, is that it used self-reported longitudinal data gathered at 3- to 5-year intervals for up to 25 years, allowing for the assessment of variation of sleep duration across this entire time frame. “If you could use that shift in sleep duration as a point of therapeutic intervention, that would be really exciting,” she said.

Future research will evaluate how sleep variability and cognitive function are impacted by other variables gathered in the Seattle Longitudinal Study over the years, including factors such as diabetes and hypertension status, diet, alcohol and tobacco use, and marital and family status. Follow-up studies will be investigating the impact of sleep variability on neuropathologic disease progression and lymphatic system impairment, Dr. Keil said.
 

A newer approach

By linking sleep variability and daytime functioning, the study employs a “newer approach,” said Joseph M. Dzierzewski, PhD, director of behavioral medicine concentration in the department of psychology at Virginia Commonwealth University in Richmond. “While some previous work has examined night-to-night fluctuation in various sleep characteristics and cognitive functioning, what differentiates the present study from these previous works is the duration of the investigation,” he said. The “richness of data” in the Seattle Longitudinal Study and how it tracks sleep and cognition over years make it “quite unique and novel.”

Future studies, he said, should be deliberate in how they evaluate sleep and neurocognitive function across years. “Disentangling short-term moment-to-moment and day-to-day fluctuation, which may be more reversible in nature, from long-term, enduring month-to-month or year-to-year fluctuation, which may be more permanent, will be important for continuing to advance our understanding of these complex phenomena,” Dr. Dzierzewski said. “An additional important area of future investigation would be to continue the hunt for a common biological factor underpinning both sleep variability and Alzheimer’s disease.” That, he said, may help identify potential intervention targets.

Dr. Keil and Dr. Dzierzewski have no relevant disclosures.

CHARLOTTE, N.C. – Erratic sleep patterns over years or even decades, along with a patient’s age and history of depression, may be harbingers of cognitive impairment later in life, an analysis of decades of data from a large sleep study has found.

“What we were a little surprised to find in this model was that sleep duration, whether short, long or average, was not significant, but the sleep variability – the change in sleep across those time measurements—was significantly impacting the incidence of cognitive impairment,” Samantha Keil, PhD, a postdoctoral fellow at the University of Washington, Seattle, reported at the at the annual meeting of the Associated Professional Sleep Societies.

The researchers analyzed sleep and cognition data collected over decades on 1,104 adults who participated in the Seattle Longitudinal Study. Study participants ranged from age 55 to over 100, with almost 80% of the study cohort aged 65 and older.

The Seattle Longitudinal Study first started gathering data in the 1950s. Participants in the study cohort underwent an extensive cognitive battery, which was added to the study in 1984 and gathered every 5-7 years, and completed a health behavioral questionnaire (HBQ), which was added in 1993 and administered every 3-5 years, Dr. Keil said. The HBQ included a question on average nightly sleep duration.

The study used a multivariable Cox proportional hazard regression model to evaluate the overall effect of average sleep duration and changes in sleep duration over time on cognitive impairment. Covariates used in the model included apolipoprotein E4 (APOE4) genotype, gender, years of education, ethnicity, and depression.

Dr. Keil said the model found, as expected, that the  demographic variables of education, APOE status, and depression were significantly associated with cognitive impairment (hazard ratios of 1.11; 95% confidence interval [CI], 1.02-1.21; P = .01; and 2.08; 95% CI, 1.31-3.31; P < .005; and 1.08; 95% CI, 1.04-1.13; P < .005, respectively). Importantly, when evaluating the duration, change and variability of sleep, the researchers found that increased sleep variability was significantly associated with cognitive impairment (HR, 3.15; 95% CI, 1.69-5.87; P < .005).  

Under this analysis, “sleep variability over time and not median sleep duration was associated with cognitive impairment,” she said. When sleep variability was added into the model, it improved the concordance score – a value that reflects the ability of a model to predict an outcome better than random chance – from .63 to .73 (a value of .5 indicates the model is no better at predicting an outcome than a random chance model; a value of .7 or greater indicates a good model).

Identification of sleep variability as a sleep pattern of interest in longitudinal studies is important, Dr. Keil said, because simply evaluating mean or median sleep duration across time might not account for a subject’s variable sleep phenotype. Most importantly, further evaluation of sleep variability with a linear regression prediction analysis (F statistic 8.796, P < .0001, adjusted R-squared .235) found that increased age, depression, and sleep variability significantly predicted cognitive impairment 10 years downstream. “Longitudinal sleep variability is perhaps for the first time being reported as significantly associated with the development of downstream cognitive impairment,” Dr. Keil said.

What makes this study unique, Dr. Keil said in an interview, is that it used self-reported longitudinal data gathered at 3- to 5-year intervals for up to 25 years, allowing for the assessment of variation of sleep duration across this entire time frame. “If you could use that shift in sleep duration as a point of therapeutic intervention, that would be really exciting,” she said.

Future research will evaluate how sleep variability and cognitive function are impacted by other variables gathered in the Seattle Longitudinal Study over the years, including factors such as diabetes and hypertension status, diet, alcohol and tobacco use, and marital and family status. Follow-up studies will be investigating the impact of sleep variability on neuropathologic disease progression and lymphatic system impairment, Dr. Keil said.
 

A newer approach

By linking sleep variability and daytime functioning, the study employs a “newer approach,” said Joseph M. Dzierzewski, PhD, director of behavioral medicine concentration in the department of psychology at Virginia Commonwealth University in Richmond. “While some previous work has examined night-to-night fluctuation in various sleep characteristics and cognitive functioning, what differentiates the present study from these previous works is the duration of the investigation,” he said. The “richness of data” in the Seattle Longitudinal Study and how it tracks sleep and cognition over years make it “quite unique and novel.”

Future studies, he said, should be deliberate in how they evaluate sleep and neurocognitive function across years. “Disentangling short-term moment-to-moment and day-to-day fluctuation, which may be more reversible in nature, from long-term, enduring month-to-month or year-to-year fluctuation, which may be more permanent, will be important for continuing to advance our understanding of these complex phenomena,” Dr. Dzierzewski said. “An additional important area of future investigation would be to continue the hunt for a common biological factor underpinning both sleep variability and Alzheimer’s disease.” That, he said, may help identify potential intervention targets.

Dr. Keil and Dr. Dzierzewski have no relevant disclosures.

CHARLOTTE, N.C. – Erratic sleep patterns over years or even decades, along with a patient’s age and history of depression, may be harbingers of cognitive impairment later in life, an analysis of decades of data from a large sleep study has found.

“What we were a little surprised to find in this model was that sleep duration, whether short, long or average, was not significant, but the sleep variability – the change in sleep across those time measurements—was significantly impacting the incidence of cognitive impairment,” Samantha Keil, PhD, a postdoctoral fellow at the University of Washington, Seattle, reported at the at the annual meeting of the Associated Professional Sleep Societies.

The researchers analyzed sleep and cognition data collected over decades on 1,104 adults who participated in the Seattle Longitudinal Study. Study participants ranged from age 55 to over 100, with almost 80% of the study cohort aged 65 and older.

The Seattle Longitudinal Study first started gathering data in the 1950s. Participants in the study cohort underwent an extensive cognitive battery, which was added to the study in 1984 and gathered every 5-7 years, and completed a health behavioral questionnaire (HBQ), which was added in 1993 and administered every 3-5 years, Dr. Keil said. The HBQ included a question on average nightly sleep duration.

The study used a multivariable Cox proportional hazard regression model to evaluate the overall effect of average sleep duration and changes in sleep duration over time on cognitive impairment. Covariates used in the model included apolipoprotein E4 (APOE4) genotype, gender, years of education, ethnicity, and depression.

Dr. Keil said the model found, as expected, that the  demographic variables of education, APOE status, and depression were significantly associated with cognitive impairment (hazard ratios of 1.11; 95% confidence interval [CI], 1.02-1.21; P = .01; and 2.08; 95% CI, 1.31-3.31; P < .005; and 1.08; 95% CI, 1.04-1.13; P < .005, respectively). Importantly, when evaluating the duration, change and variability of sleep, the researchers found that increased sleep variability was significantly associated with cognitive impairment (HR, 3.15; 95% CI, 1.69-5.87; P < .005).  

Under this analysis, “sleep variability over time and not median sleep duration was associated with cognitive impairment,” she said. When sleep variability was added into the model, it improved the concordance score – a value that reflects the ability of a model to predict an outcome better than random chance – from .63 to .73 (a value of .5 indicates the model is no better at predicting an outcome than a random chance model; a value of .7 or greater indicates a good model).

Identification of sleep variability as a sleep pattern of interest in longitudinal studies is important, Dr. Keil said, because simply evaluating mean or median sleep duration across time might not account for a subject’s variable sleep phenotype. Most importantly, further evaluation of sleep variability with a linear regression prediction analysis (F statistic 8.796, P < .0001, adjusted R-squared .235) found that increased age, depression, and sleep variability significantly predicted cognitive impairment 10 years downstream. “Longitudinal sleep variability is perhaps for the first time being reported as significantly associated with the development of downstream cognitive impairment,” Dr. Keil said.

What makes this study unique, Dr. Keil said in an interview, is that it used self-reported longitudinal data gathered at 3- to 5-year intervals for up to 25 years, allowing for the assessment of variation of sleep duration across this entire time frame. “If you could use that shift in sleep duration as a point of therapeutic intervention, that would be really exciting,” she said.

Future research will evaluate how sleep variability and cognitive function are impacted by other variables gathered in the Seattle Longitudinal Study over the years, including factors such as diabetes and hypertension status, diet, alcohol and tobacco use, and marital and family status. Follow-up studies will be investigating the impact of sleep variability on neuropathologic disease progression and lymphatic system impairment, Dr. Keil said.
 

A newer approach

By linking sleep variability and daytime functioning, the study employs a “newer approach,” said Joseph M. Dzierzewski, PhD, director of behavioral medicine concentration in the department of psychology at Virginia Commonwealth University in Richmond. “While some previous work has examined night-to-night fluctuation in various sleep characteristics and cognitive functioning, what differentiates the present study from these previous works is the duration of the investigation,” he said. The “richness of data” in the Seattle Longitudinal Study and how it tracks sleep and cognition over years make it “quite unique and novel.”

Future studies, he said, should be deliberate in how they evaluate sleep and neurocognitive function across years. “Disentangling short-term moment-to-moment and day-to-day fluctuation, which may be more reversible in nature, from long-term, enduring month-to-month or year-to-year fluctuation, which may be more permanent, will be important for continuing to advance our understanding of these complex phenomena,” Dr. Dzierzewski said. “An additional important area of future investigation would be to continue the hunt for a common biological factor underpinning both sleep variability and Alzheimer’s disease.” That, he said, may help identify potential intervention targets.

Dr. Keil and Dr. Dzierzewski have no relevant disclosures.

Boston Children’s Hospital led the list of 10 children’s hospitals across the United States named to the Best Children’s Hospitals Honor Roll for 2022-2023, issued by U.S. News & World Report.

The 16th annual Best Children’s Hospitals rankings were published on June 14.

Rounding out the top 10 on the Honor Roll were Children’s Hospital of Philadelphia; Texas Children’s Hospital, Houston; Cincinnati Children’s Hospital Medical Center; Children’s Hospital Los Angeles; Children’s Hospital Colorado, Aurora; Children’s National Hospital, Washington, D.C.; Nationwide Children’s Hospital, Columbus, Ohio; UPMC Children’s Hospital of Pittsburgh; and Lucile Packard Children’s Hospital, Palo Alto, Calif.

The Honor Roll hospitals were chosen based on being highly ranked in multiple specialties, such as cancer, cardiology, and orthopedics.

For the second time, the rankings included top hospitals not only in each state, but also in seven multistate regions. The goal of the regional rankings is to help families identify the high-quality pediatric care centers closest to them, according to the U.S. News press release accompanying the rankings.

The top-ranked hospitals for the seven regions were Children’s Hospital Los Angeles (Pacific); Children’s Hospital Colorado, Aurora (Rocky Mountains); Texas Children’s Hospital, Houston (Southwest); Children’s Healthcare of Atlanta and Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, Tenn. (tie for Southeast); Cincinnati Children’s Hospital Medical Center (Midwest); Children’s Hospital of Philadelphia (Mid-Atlantic); and Boston Children’s Hospital (New England).

The 2022-2023 U.S. News rankings identify the top 50 centers across the United States in each of 10 pediatric specialties: cancer, cardiology/ heart surgery, diabetes/endocrinology, gastroenterology/gastrointestinal surgery, neonatology, nephrology, neurology/neurosurgery, orthopedics, pulmonology/lung surgery, and urology.

For the 2022-2023 rankings, U.S. News requested medical data and other information from 200 pediatric facilities across the United States; 119 responded and were evaluated in at least one specialty, and 90 were ranked in one or more specialties.

Approximately one-third of each hospital’s score was based on outcomes such as survival, infections, and surgical complications (although outcomes counted for 38.3% of scores for cardiology and heart surgery). Approximately 13% of the score was based on reputation/expert opinion, determined by an annual survey of experts in the 10 specialties (8% of scores for cardiology and heart surgery), and nearly 60% was based on patient safety, excellence, and family centeredness, according to a statement from U.S. News.

“The Best Children’s Hospitals rankings spotlight hospitals that excel in specialized care, offering parents and their pediatricians a helpful starting point in choosing the facility that’s best for their child,” said Ben Harder, chief of health analysis and managing editor at U.S. News, in a press release accompanying the rankings.

Also new to the ranking system this year was a measure to assess hospitals’ efforts to improve equity of care and to promote diversity and inclusion, which accounts for 2% of each hospital’s score in each specialty, according to U.S. News.

Boston Children’s Hospital led the list of 10 children’s hospitals across the United States named to the Best Children’s Hospitals Honor Roll for 2022-2023, issued by U.S. News & World Report.

The 16th annual Best Children’s Hospitals rankings were published on June 14.

Rounding out the top 10 on the Honor Roll were Children’s Hospital of Philadelphia; Texas Children’s Hospital, Houston; Cincinnati Children’s Hospital Medical Center; Children’s Hospital Los Angeles; Children’s Hospital Colorado, Aurora; Children’s National Hospital, Washington, D.C.; Nationwide Children’s Hospital, Columbus, Ohio; UPMC Children’s Hospital of Pittsburgh; and Lucile Packard Children’s Hospital, Palo Alto, Calif.

The Honor Roll hospitals were chosen based on being highly ranked in multiple specialties, such as cancer, cardiology, and orthopedics.

For the second time, the rankings included top hospitals not only in each state, but also in seven multistate regions. The goal of the regional rankings is to help families identify the high-quality pediatric care centers closest to them, according to the U.S. News press release accompanying the rankings.

The top-ranked hospitals for the seven regions were Children’s Hospital Los Angeles (Pacific); Children’s Hospital Colorado, Aurora (Rocky Mountains); Texas Children’s Hospital, Houston (Southwest); Children’s Healthcare of Atlanta and Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, Tenn. (tie for Southeast); Cincinnati Children’s Hospital Medical Center (Midwest); Children’s Hospital of Philadelphia (Mid-Atlantic); and Boston Children’s Hospital (New England).

The 2022-2023 U.S. News rankings identify the top 50 centers across the United States in each of 10 pediatric specialties: cancer, cardiology/ heart surgery, diabetes/endocrinology, gastroenterology/gastrointestinal surgery, neonatology, nephrology, neurology/neurosurgery, orthopedics, pulmonology/lung surgery, and urology.

For the 2022-2023 rankings, U.S. News requested medical data and other information from 200 pediatric facilities across the United States; 119 responded and were evaluated in at least one specialty, and 90 were ranked in one or more specialties.

Approximately one-third of each hospital’s score was based on outcomes such as survival, infections, and surgical complications (although outcomes counted for 38.3% of scores for cardiology and heart surgery). Approximately 13% of the score was based on reputation/expert opinion, determined by an annual survey of experts in the 10 specialties (8% of scores for cardiology and heart surgery), and nearly 60% was based on patient safety, excellence, and family centeredness, according to a statement from U.S. News.

“The Best Children’s Hospitals rankings spotlight hospitals that excel in specialized care, offering parents and their pediatricians a helpful starting point in choosing the facility that’s best for their child,” said Ben Harder, chief of health analysis and managing editor at U.S. News, in a press release accompanying the rankings.

Also new to the ranking system this year was a measure to assess hospitals’ efforts to improve equity of care and to promote diversity and inclusion, which accounts for 2% of each hospital’s score in each specialty, according to U.S. News.

Boston Children’s Hospital led the list of 10 children’s hospitals across the United States named to the Best Children’s Hospitals Honor Roll for 2022-2023, issued by U.S. News & World Report.

The 16th annual Best Children’s Hospitals rankings were published on June 14.

Rounding out the top 10 on the Honor Roll were Children’s Hospital of Philadelphia; Texas Children’s Hospital, Houston; Cincinnati Children’s Hospital Medical Center; Children’s Hospital Los Angeles; Children’s Hospital Colorado, Aurora; Children’s National Hospital, Washington, D.C.; Nationwide Children’s Hospital, Columbus, Ohio; UPMC Children’s Hospital of Pittsburgh; and Lucile Packard Children’s Hospital, Palo Alto, Calif.

The Honor Roll hospitals were chosen based on being highly ranked in multiple specialties, such as cancer, cardiology, and orthopedics.

For the second time, the rankings included top hospitals not only in each state, but also in seven multistate regions. The goal of the regional rankings is to help families identify the high-quality pediatric care centers closest to them, according to the U.S. News press release accompanying the rankings.

The top-ranked hospitals for the seven regions were Children’s Hospital Los Angeles (Pacific); Children’s Hospital Colorado, Aurora (Rocky Mountains); Texas Children’s Hospital, Houston (Southwest); Children’s Healthcare of Atlanta and Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, Tenn. (tie for Southeast); Cincinnati Children’s Hospital Medical Center (Midwest); Children’s Hospital of Philadelphia (Mid-Atlantic); and Boston Children’s Hospital (New England).

The 2022-2023 U.S. News rankings identify the top 50 centers across the United States in each of 10 pediatric specialties: cancer, cardiology/ heart surgery, diabetes/endocrinology, gastroenterology/gastrointestinal surgery, neonatology, nephrology, neurology/neurosurgery, orthopedics, pulmonology/lung surgery, and urology.

For the 2022-2023 rankings, U.S. News requested medical data and other information from 200 pediatric facilities across the United States; 119 responded and were evaluated in at least one specialty, and 90 were ranked in one or more specialties.

Approximately one-third of each hospital’s score was based on outcomes such as survival, infections, and surgical complications (although outcomes counted for 38.3% of scores for cardiology and heart surgery). Approximately 13% of the score was based on reputation/expert opinion, determined by an annual survey of experts in the 10 specialties (8% of scores for cardiology and heart surgery), and nearly 60% was based on patient safety, excellence, and family centeredness, according to a statement from U.S. News.

“The Best Children’s Hospitals rankings spotlight hospitals that excel in specialized care, offering parents and their pediatricians a helpful starting point in choosing the facility that’s best for their child,” said Ben Harder, chief of health analysis and managing editor at U.S. News, in a press release accompanying the rankings.

Also new to the ranking system this year was a measure to assess hospitals’ efforts to improve equity of care and to promote diversity and inclusion, which accounts for 2% of each hospital’s score in each specialty, according to U.S. News.

The development of depression after a rheumatoid arthritis diagnosis increased the risk for death “more than sixfold” when compared with having no depression at diagnosis, according to Danish researchers.

Cumulative mortality at 10 years was approximately 37% in patients with comorbid RA and depression versus around 13.5% of RA patients with no depression, Jens Kristian Pedersen, MD, PhD, of Odense (Denmark) University Hospital–Svendborg Hospital and the department of clinical research at the University of Southern Denmark, also in Odense, reported at the annual European Congress of Rheumatology.

“According to [antidepressant] exposure status, the cumulative mortality followed two clearly different paths,” Dr. Pedersen said. “The mortality curves separated early and already within the first and second year of follow-up.”
 

RA, depression, and mortality

Rates of depression in patients with RA are high, Dr. Pedersen said, and while it’s previously been reported that their coexistence can increase mortality, this is the first time that the link has been investigated in a population newly diagnosed with RA.

In this study, Dr. Pedersen and collaborators wanted to look at the association in incident RA and defined depression as the first filling of an antidepressant prescription.

“Although antidepressants are used for different indications, we have recently described that in RA the most frequent indication for filling antidepressants is depression,” he explained. Moreover, that research found that “the frequency of filling coincides with the occurrence of depressive disorder previously reported in the scientific literature.”
 

Data sourced from multiple Danish registers

To examine the mortality risk associated with newly diagnosed RA and new-onset depression, Dr. Pedersen described how five different Danish registers were used.

First, data from the DANBIO register were used to identify patients with incident RA living in Denmark over a 10-year period ending in December 2018. Although perhaps widely known as a biologics register, DANBIO is required by the Danish National Board of Health to collect information on all patients with RA, regardless of their treatment.

Next, the Danish National Prescription Register and Danish National Patient Register were consulted to obtain data on patients who had a first prescription for antidepressant treatment and information on those who developed a diagnosis of depression. Demographic, vital status, and socioeconomic data were collated from the Danish Civil Registration System and Statistics Denmark databases.

To be sure they were looking at incident cases of RA and new cases of depression, the researchers excluded anyone with an existing prescription of antidepressants or methotrexate, or who had a confirmed diagnosis of either disorder 3 years prior to the index date of Jan. 1, 2008.

This meant that, from a total population of 18,000 patients in the DANBIO database, there were just over 11,000 who could be included in the analyses.

Overall, the median age at RA diagnosis was 61 years, two-thirds were female, and two-thirds had seropositive disease.

New-onset depression in incident RA

“During follow-up, about 10% filled a prescription of antidepressants,” said Dr. Pedersen, adding that there were 671 deaths, representing around 57,000 person-years at risk.

“The majority died from natural causes,” he said, although the cause of death was unknown in 30% of cases.

Comparing those who did and did not have a prescription for antidepressants, there were some differences in the age at which death occurred, the percentage of females to males, the presence of other comorbidities, and levels of higher education and income. These were all adjusted for in the analyses.

Adjusted hazard rate ratios were calculated to look at the mortality risk in patients who had antidepressant exposure. The highest HRR for mortality with antidepressant use was seen in patients aged 55 years or younger at 6.66, with the next highest HRRs being for male gender (3.70) and seropositive RA (3.45).

But HRRs for seronegative RA, female gender, and age 55-70 years or older than 75 years were all still around 3.0.
 

Depression definition questioned

“My only concern is about the definition of depression in your analysis,” said a member of the audience at the congress.

“You used antidepressant use as a proxy of depression diagnosis, but it might be that most or many patients have taken [medication] like duloxetine for pain control, and you are just seeing higher disease activity and more aggressive RA.”

Dr. Pedersen responded: “After the EULAR 2022 submission deadline, we reanalyzed our data using two other measures of depression.

“First, we use treatment with antidepressants with a positive indication of depression, according to the prescribing physician, and secondly, we used first diagnosis with depression according to ICD-10 Code F32 – ‘depressive episode after discharge from hospital as an outpatient,’ ” he said.

“All definitions end up with a hazard rate ratio of about three. So, in my opinion, it doesn’t matter whether you focus on one measure of depression or the other.”

David Isenberg, MD, FRCP, professor of rheumatology at University College London, wanted to know more about the antecedent history of depression and whether people who had been depressed maybe a decade or 2 decades before, were more likely to get RA.

That calculation has not been done, Dr. Pedersen said, adding that the study also can’t account for people who may have had recurrent depression. Depression treatment guidelines often recommend nonpharmacologic intervention in the first instance, “so we do not necessarily get the right picture of recurrent depression if we look further back.”

Pointing out that the sixfold increase in mortality was impressive, another delegate asked about whether it was because of a higher disease activity or joint damage and if the mortality risk might be lower in patients who are in remission.

“We don’t know that yet,” Dr. Pedersen answered. “We haven’t done the calculations, but there is the issue of residual confounding if we don’t take all relevant covariates into account. So, we need to do that calculation as well.”

The study was supported by the Danish Rheumatism Association. Dr. Pedersen had no conflicts of interest to disclose.
 

The development of depression after a rheumatoid arthritis diagnosis increased the risk for death “more than sixfold” when compared with having no depression at diagnosis, according to Danish researchers.

Cumulative mortality at 10 years was approximately 37% in patients with comorbid RA and depression versus around 13.5% of RA patients with no depression, Jens Kristian Pedersen, MD, PhD, of Odense (Denmark) University Hospital–Svendborg Hospital and the department of clinical research at the University of Southern Denmark, also in Odense, reported at the annual European Congress of Rheumatology.

“According to [antidepressant] exposure status, the cumulative mortality followed two clearly different paths,” Dr. Pedersen said. “The mortality curves separated early and already within the first and second year of follow-up.”
 

RA, depression, and mortality

Rates of depression in patients with RA are high, Dr. Pedersen said, and while it’s previously been reported that their coexistence can increase mortality, this is the first time that the link has been investigated in a population newly diagnosed with RA.

In this study, Dr. Pedersen and collaborators wanted to look at the association in incident RA and defined depression as the first filling of an antidepressant prescription.

“Although antidepressants are used for different indications, we have recently described that in RA the most frequent indication for filling antidepressants is depression,” he explained. Moreover, that research found that “the frequency of filling coincides with the occurrence of depressive disorder previously reported in the scientific literature.”
 

Data sourced from multiple Danish registers

To examine the mortality risk associated with newly diagnosed RA and new-onset depression, Dr. Pedersen described how five different Danish registers were used.

First, data from the DANBIO register were used to identify patients with incident RA living in Denmark over a 10-year period ending in December 2018. Although perhaps widely known as a biologics register, DANBIO is required by the Danish National Board of Health to collect information on all patients with RA, regardless of their treatment.

Next, the Danish National Prescription Register and Danish National Patient Register were consulted to obtain data on patients who had a first prescription for antidepressant treatment and information on those who developed a diagnosis of depression. Demographic, vital status, and socioeconomic data were collated from the Danish Civil Registration System and Statistics Denmark databases.

To be sure they were looking at incident cases of RA and new cases of depression, the researchers excluded anyone with an existing prescription of antidepressants or methotrexate, or who had a confirmed diagnosis of either disorder 3 years prior to the index date of Jan. 1, 2008.

This meant that, from a total population of 18,000 patients in the DANBIO database, there were just over 11,000 who could be included in the analyses.

Overall, the median age at RA diagnosis was 61 years, two-thirds were female, and two-thirds had seropositive disease.

New-onset depression in incident RA

“During follow-up, about 10% filled a prescription of antidepressants,” said Dr. Pedersen, adding that there were 671 deaths, representing around 57,000 person-years at risk.

“The majority died from natural causes,” he said, although the cause of death was unknown in 30% of cases.

Comparing those who did and did not have a prescription for antidepressants, there were some differences in the age at which death occurred, the percentage of females to males, the presence of other comorbidities, and levels of higher education and income. These were all adjusted for in the analyses.

Adjusted hazard rate ratios were calculated to look at the mortality risk in patients who had antidepressant exposure. The highest HRR for mortality with antidepressant use was seen in patients aged 55 years or younger at 6.66, with the next highest HRRs being for male gender (3.70) and seropositive RA (3.45).

But HRRs for seronegative RA, female gender, and age 55-70 years or older than 75 years were all still around 3.0.
 

Depression definition questioned

“My only concern is about the definition of depression in your analysis,” said a member of the audience at the congress.

“You used antidepressant use as a proxy of depression diagnosis, but it might be that most or many patients have taken [medication] like duloxetine for pain control, and you are just seeing higher disease activity and more aggressive RA.”

Dr. Pedersen responded: “After the EULAR 2022 submission deadline, we reanalyzed our data using two other measures of depression.

“First, we use treatment with antidepressants with a positive indication of depression, according to the prescribing physician, and secondly, we used first diagnosis with depression according to ICD-10 Code F32 – ‘depressive episode after discharge from hospital as an outpatient,’ ” he said.

“All definitions end up with a hazard rate ratio of about three. So, in my opinion, it doesn’t matter whether you focus on one measure of depression or the other.”

David Isenberg, MD, FRCP, professor of rheumatology at University College London, wanted to know more about the antecedent history of depression and whether people who had been depressed maybe a decade or 2 decades before, were more likely to get RA.

That calculation has not been done, Dr. Pedersen said, adding that the study also can’t account for people who may have had recurrent depression. Depression treatment guidelines often recommend nonpharmacologic intervention in the first instance, “so we do not necessarily get the right picture of recurrent depression if we look further back.”

Pointing out that the sixfold increase in mortality was impressive, another delegate asked about whether it was because of a higher disease activity or joint damage and if the mortality risk might be lower in patients who are in remission.

“We don’t know that yet,” Dr. Pedersen answered. “We haven’t done the calculations, but there is the issue of residual confounding if we don’t take all relevant covariates into account. So, we need to do that calculation as well.”

The study was supported by the Danish Rheumatism Association. Dr. Pedersen had no conflicts of interest to disclose.
 

The development of depression after a rheumatoid arthritis diagnosis increased the risk for death “more than sixfold” when compared with having no depression at diagnosis, according to Danish researchers.

Cumulative mortality at 10 years was approximately 37% in patients with comorbid RA and depression versus around 13.5% of RA patients with no depression, Jens Kristian Pedersen, MD, PhD, of Odense (Denmark) University Hospital–Svendborg Hospital and the department of clinical research at the University of Southern Denmark, also in Odense, reported at the annual European Congress of Rheumatology.

“According to [antidepressant] exposure status, the cumulative mortality followed two clearly different paths,” Dr. Pedersen said. “The mortality curves separated early and already within the first and second year of follow-up.”
 

RA, depression, and mortality

Rates of depression in patients with RA are high, Dr. Pedersen said, and while it’s previously been reported that their coexistence can increase mortality, this is the first time that the link has been investigated in a population newly diagnosed with RA.

In this study, Dr. Pedersen and collaborators wanted to look at the association in incident RA and defined depression as the first filling of an antidepressant prescription.

“Although antidepressants are used for different indications, we have recently described that in RA the most frequent indication for filling antidepressants is depression,” he explained. Moreover, that research found that “the frequency of filling coincides with the occurrence of depressive disorder previously reported in the scientific literature.”
 

Data sourced from multiple Danish registers

To examine the mortality risk associated with newly diagnosed RA and new-onset depression, Dr. Pedersen described how five different Danish registers were used.

First, data from the DANBIO register were used to identify patients with incident RA living in Denmark over a 10-year period ending in December 2018. Although perhaps widely known as a biologics register, DANBIO is required by the Danish National Board of Health to collect information on all patients with RA, regardless of their treatment.

Next, the Danish National Prescription Register and Danish National Patient Register were consulted to obtain data on patients who had a first prescription for antidepressant treatment and information on those who developed a diagnosis of depression. Demographic, vital status, and socioeconomic data were collated from the Danish Civil Registration System and Statistics Denmark databases.

To be sure they were looking at incident cases of RA and new cases of depression, the researchers excluded anyone with an existing prescription of antidepressants or methotrexate, or who had a confirmed diagnosis of either disorder 3 years prior to the index date of Jan. 1, 2008.

This meant that, from a total population of 18,000 patients in the DANBIO database, there were just over 11,000 who could be included in the analyses.

Overall, the median age at RA diagnosis was 61 years, two-thirds were female, and two-thirds had seropositive disease.

New-onset depression in incident RA

“During follow-up, about 10% filled a prescription of antidepressants,” said Dr. Pedersen, adding that there were 671 deaths, representing around 57,000 person-years at risk.

“The majority died from natural causes,” he said, although the cause of death was unknown in 30% of cases.

Comparing those who did and did not have a prescription for antidepressants, there were some differences in the age at which death occurred, the percentage of females to males, the presence of other comorbidities, and levels of higher education and income. These were all adjusted for in the analyses.

Adjusted hazard rate ratios were calculated to look at the mortality risk in patients who had antidepressant exposure. The highest HRR for mortality with antidepressant use was seen in patients aged 55 years or younger at 6.66, with the next highest HRRs being for male gender (3.70) and seropositive RA (3.45).

But HRRs for seronegative RA, female gender, and age 55-70 years or older than 75 years were all still around 3.0.
 

Depression definition questioned

“My only concern is about the definition of depression in your analysis,” said a member of the audience at the congress.

“You used antidepressant use as a proxy of depression diagnosis, but it might be that most or many patients have taken [medication] like duloxetine for pain control, and you are just seeing higher disease activity and more aggressive RA.”

Dr. Pedersen responded: “After the EULAR 2022 submission deadline, we reanalyzed our data using two other measures of depression.

“First, we use treatment with antidepressants with a positive indication of depression, according to the prescribing physician, and secondly, we used first diagnosis with depression according to ICD-10 Code F32 – ‘depressive episode after discharge from hospital as an outpatient,’ ” he said.

“All definitions end up with a hazard rate ratio of about three. So, in my opinion, it doesn’t matter whether you focus on one measure of depression or the other.”

David Isenberg, MD, FRCP, professor of rheumatology at University College London, wanted to know more about the antecedent history of depression and whether people who had been depressed maybe a decade or 2 decades before, were more likely to get RA.

That calculation has not been done, Dr. Pedersen said, adding that the study also can’t account for people who may have had recurrent depression. Depression treatment guidelines often recommend nonpharmacologic intervention in the first instance, “so we do not necessarily get the right picture of recurrent depression if we look further back.”

Pointing out that the sixfold increase in mortality was impressive, another delegate asked about whether it was because of a higher disease activity or joint damage and if the mortality risk might be lower in patients who are in remission.

“We don’t know that yet,” Dr. Pedersen answered. “We haven’t done the calculations, but there is the issue of residual confounding if we don’t take all relevant covariates into account. So, we need to do that calculation as well.”

The study was supported by the Danish Rheumatism Association. Dr. Pedersen had no conflicts of interest to disclose.
 

ILLUSTRATIVE CASE

A 35-year-old woman with no significant past medical history presents for follow-up of migraine. At the previous visit, she was prescribed sumatriptan for abortive therapy. However, she has been having significant adverse effect intolerance from the oral formulation, and the nasal formulation is cost prohibitive. What can you recommend as an alternative abortive therapy for this patient’s migraine?

Migraine is among the most common causes of disability worldwide, affecting more than 10% of the global population.² The prevalence of migraine is between 2.6% and 21.7% across multiple countries.³ On a scale of 0% to 100%, disability caused by migraine is 43.3%, comparable to the first 2 days after an acute myocardial infarction (42.2%) and severe dementia (43.8%).⁴

Abortive therapy for acute migraine includes nonsteroidal anti-inflammatory drugs (NSAIDs), triptans, ergots, and antiemetics. However, these options are predominantly administered by mouth; non-oral formulations tend to be cost prohibitive and difficult to obtain.

Nausea and vomiting, common components of migraine (that are included in International Classification of Headache Disorders, 3rd edition [ICHD-3] criteria for migraine⁵) present obstacles to effective oral administration if experienced by the patient. In addition, for migraine refractory to first-line treatments, abortive options—including the recently approved calcitonin gene-related peptide (CGRP) receptor antagonists ubrogepant and rimegepant—are also cost prohibitive, potentially costing more than $1000 for 10 tablets (100 mg), depending on insurance coverage.⁶

Two oral beta-blockers, propranolol and timolol, are approved by the US Food and Drug Administration for migraine prophylaxis. Unfortunately, oral beta-blockers are ineffective for abortive treatment.⁷ Ophthalmic timolol is typically used in the treatment of glaucoma, but there have been case reports describing its benefits in acute migraine treatment.^8,9 In addition, ophthalmic timolol is far cheaper than medications such as ubrogepant.¹⁰ A 2014 case series of 7 patients discussed ophthalmic beta-blockers as an effective and possibly cheaper option for acute migraine treatment.⁸ A randomized, crossover, placebo-controlled pilot study of 198 migraine attacks in 10 participants using timolol eyedrops for abortive therapy found timolol was not significantly more effective than placebo.⁹ However, it was an underpowered pilot study, with a lack of masking and an imperfect placebo. The trial discussed here was a controlled, prospective study investigating topical beta-blockers for acute migraine treatment.

STUDY SUMMARY

Crossover study achieved primary endpoint in pain reduction

This randomized, single-center, double-masked, crossover trial compared timolol maleate ophthalmic solution 0.5% with placebo among 43 patients ages 12 or older presenting with a diagnosis of migraine based on ICHD-3 (beta) criteria. Patients were eligible if they had not taken any antimigraine medications for at least 1 month prior to the study and were excluded if they had taken systemic beta-blockers at baseline, or had asthma, bradyarrhythmias, or cardiac dysfunction.

Patients were randomized 1:1 to treatment with timolol maleate 0.5% eyedrops or placebo. At the earliest onset of migraine, patients used 1 drop of timolol maleate 0.5% or placebo in each eye; if they experienced no relief after 10 minutes, they used a second drop or matching placebo. Patients were instructed to score their headache pain on a 10-point scale prior to using the eyedrops and then again 20 minutes after treatment. If a patient had migraine with aura, they were asked to use the eyedrops at the onset of the aura but measure their score at headache onset. If no headaches developed within 20 minutes of the aura, the episode was not included for analysis. All patients were permitted to use their standard oral rescue medication if no relief occurred after 20 minutes of pain onset.

Continue to: The groups were observed...

The groups were observed for 3 months and then followed for a 1-month washout period, during which they received no study medications. The groups were then crossed over to the other treatment and were observed for another 3 months. The primary outcome was a reduction in pain score by 4 or more points, or to 0 on a 10-point pain scale, 20 minutes after treatment. The secondary outcome was nonuse of oral rescue medication.

The primary outcome was achieved in 233 of 284 (82%) timolol-treated migraines, compared to 38 of 271 (14%) placebo-treated migraines.

Forty-three patients were included in a modified intention-to-treat analysis. The primary outcome was achieved in 233 of 284 (82%) timolol-treated migraines, compared to 38 of 271 (14%) placebo-treated migraines (percentage difference = 68 percentage points; 95% CI, 62-74 percentage points; P < .001). The mean pain score at the onset of migraine attacks was 6.01 for those treated with timolol and 5.93 for those treated with placebo. Patients treated with timolol had a reduction in pain of 5.98 points, compared with 0.93 points after using placebo (difference = 5.05; 95% CI, 4.19-5.91). No attacks included in the data required oral rescue medications, and there were no systemic adverse effects from the timolol eyedrops.

WHAT’S NEW

Evidence of benefit as abortive therapy for acute migraine

This randomized controlled trial (RCT) showed evidence to support timolol maleate ophthalmic solution 0.5% vs placebo for treatment of acute migraine by significantly reducing pain when taken at the onset of an acute migraine attack.

CAVEATS

Single-center trial, measuring limited response time

The generalizability of this RCT is limited because it was a single-center trial with a study population from a single region in India. It is unknown whether pain relief, adverse effects, or adherence would differ for the global population. Additionally, only migraines with headache were included in the analysis, limiting non-headache migraine subgroup-directed treatment. Also, this trial evaluated only the response to treatment at 20 minutes, and it is unknown if pain response continued for several hours. Headaches that began more than 20 minutes after the onset of aura were not evaluated.

CHALLENGES TO IMPLEMENTATION

Timolol’s systemic adverse effects require caution

Systemic beta-blocker effects (eg, bradycardia, hypotension, drowsiness, and bronchospasm) from topical timolol have been reported. Caution should be used when prescribing timolol for patients with current cardiovascular and pulmonary conditions. 

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 35-year-old woman with no significant past medical history presents for follow-up of migraine. At the previous visit, she was prescribed sumatriptan for abortive therapy. However, she has been having significant adverse effect intolerance from the oral formulation, and the nasal formulation is cost prohibitive. What can you recommend as an alternative abortive therapy for this patient’s migraine?

Migraine is among the most common causes of disability worldwide, affecting more than 10% of the global population.² The prevalence of migraine is between 2.6% and 21.7% across multiple countries.³ On a scale of 0% to 100%, disability caused by migraine is 43.3%, comparable to the first 2 days after an acute myocardial infarction (42.2%) and severe dementia (43.8%).⁴

Abortive therapy for acute migraine includes nonsteroidal anti-inflammatory drugs (NSAIDs), triptans, ergots, and antiemetics. However, these options are predominantly administered by mouth; non-oral formulations tend to be cost prohibitive and difficult to obtain.

Nausea and vomiting, common components of migraine (that are included in International Classification of Headache Disorders, 3rd edition [ICHD-3] criteria for migraine⁵) present obstacles to effective oral administration if experienced by the patient. In addition, for migraine refractory to first-line treatments, abortive options—including the recently approved calcitonin gene-related peptide (CGRP) receptor antagonists ubrogepant and rimegepant—are also cost prohibitive, potentially costing more than $1000 for 10 tablets (100 mg), depending on insurance coverage.⁶

Two oral beta-blockers, propranolol and timolol, are approved by the US Food and Drug Administration for migraine prophylaxis. Unfortunately, oral beta-blockers are ineffective for abortive treatment.⁷ Ophthalmic timolol is typically used in the treatment of glaucoma, but there have been case reports describing its benefits in acute migraine treatment.^8,9 In addition, ophthalmic timolol is far cheaper than medications such as ubrogepant.¹⁰ A 2014 case series of 7 patients discussed ophthalmic beta-blockers as an effective and possibly cheaper option for acute migraine treatment.⁸ A randomized, crossover, placebo-controlled pilot study of 198 migraine attacks in 10 participants using timolol eyedrops for abortive therapy found timolol was not significantly more effective than placebo.⁹ However, it was an underpowered pilot study, with a lack of masking and an imperfect placebo. The trial discussed here was a controlled, prospective study investigating topical beta-blockers for acute migraine treatment.

STUDY SUMMARY

Crossover study achieved primary endpoint in pain reduction

This randomized, single-center, double-masked, crossover trial compared timolol maleate ophthalmic solution 0.5% with placebo among 43 patients ages 12 or older presenting with a diagnosis of migraine based on ICHD-3 (beta) criteria. Patients were eligible if they had not taken any antimigraine medications for at least 1 month prior to the study and were excluded if they had taken systemic beta-blockers at baseline, or had asthma, bradyarrhythmias, or cardiac dysfunction.

Patients were randomized 1:1 to treatment with timolol maleate 0.5% eyedrops or placebo. At the earliest onset of migraine, patients used 1 drop of timolol maleate 0.5% or placebo in each eye; if they experienced no relief after 10 minutes, they used a second drop or matching placebo. Patients were instructed to score their headache pain on a 10-point scale prior to using the eyedrops and then again 20 minutes after treatment. If a patient had migraine with aura, they were asked to use the eyedrops at the onset of the aura but measure their score at headache onset. If no headaches developed within 20 minutes of the aura, the episode was not included for analysis. All patients were permitted to use their standard oral rescue medication if no relief occurred after 20 minutes of pain onset.

Continue to: The groups were observed...

The groups were observed for 3 months and then followed for a 1-month washout period, during which they received no study medications. The groups were then crossed over to the other treatment and were observed for another 3 months. The primary outcome was a reduction in pain score by 4 or more points, or to 0 on a 10-point pain scale, 20 minutes after treatment. The secondary outcome was nonuse of oral rescue medication.

The primary outcome was achieved in 233 of 284 (82%) timolol-treated migraines, compared to 38 of 271 (14%) placebo-treated migraines.

Forty-three patients were included in a modified intention-to-treat analysis. The primary outcome was achieved in 233 of 284 (82%) timolol-treated migraines, compared to 38 of 271 (14%) placebo-treated migraines (percentage difference = 68 percentage points; 95% CI, 62-74 percentage points; P < .001). The mean pain score at the onset of migraine attacks was 6.01 for those treated with timolol and 5.93 for those treated with placebo. Patients treated with timolol had a reduction in pain of 5.98 points, compared with 0.93 points after using placebo (difference = 5.05; 95% CI, 4.19-5.91). No attacks included in the data required oral rescue medications, and there were no systemic adverse effects from the timolol eyedrops.

WHAT’S NEW

Evidence of benefit as abortive therapy for acute migraine

This randomized controlled trial (RCT) showed evidence to support timolol maleate ophthalmic solution 0.5% vs placebo for treatment of acute migraine by significantly reducing pain when taken at the onset of an acute migraine attack.

CAVEATS

Single-center trial, measuring limited response time

The generalizability of this RCT is limited because it was a single-center trial with a study population from a single region in India. It is unknown whether pain relief, adverse effects, or adherence would differ for the global population. Additionally, only migraines with headache were included in the analysis, limiting non-headache migraine subgroup-directed treatment. Also, this trial evaluated only the response to treatment at 20 minutes, and it is unknown if pain response continued for several hours. Headaches that began more than 20 minutes after the onset of aura were not evaluated.

CHALLENGES TO IMPLEMENTATION

Timolol’s systemic adverse effects require caution

Systemic beta-blocker effects (eg, bradycardia, hypotension, drowsiness, and bronchospasm) from topical timolol have been reported. Caution should be used when prescribing timolol for patients with current cardiovascular and pulmonary conditions. 

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 35-year-old woman with no significant past medical history presents for follow-up of migraine. At the previous visit, she was prescribed sumatriptan for abortive therapy. However, she has been having significant adverse effect intolerance from the oral formulation, and the nasal formulation is cost prohibitive. What can you recommend as an alternative abortive therapy for this patient’s migraine?

Migraine is among the most common causes of disability worldwide, affecting more than 10% of the global population.² The prevalence of migraine is between 2.6% and 21.7% across multiple countries.³ On a scale of 0% to 100%, disability caused by migraine is 43.3%, comparable to the first 2 days after an acute myocardial infarction (42.2%) and severe dementia (43.8%).⁴

Abortive therapy for acute migraine includes nonsteroidal anti-inflammatory drugs (NSAIDs), triptans, ergots, and antiemetics. However, these options are predominantly administered by mouth; non-oral formulations tend to be cost prohibitive and difficult to obtain.

Nausea and vomiting, common components of migraine (that are included in International Classification of Headache Disorders, 3rd edition [ICHD-3] criteria for migraine⁵) present obstacles to effective oral administration if experienced by the patient. In addition, for migraine refractory to first-line treatments, abortive options—including the recently approved calcitonin gene-related peptide (CGRP) receptor antagonists ubrogepant and rimegepant—are also cost prohibitive, potentially costing more than $1000 for 10 tablets (100 mg), depending on insurance coverage.⁶

Two oral beta-blockers, propranolol and timolol, are approved by the US Food and Drug Administration for migraine prophylaxis. Unfortunately, oral beta-blockers are ineffective for abortive treatment.⁷ Ophthalmic timolol is typically used in the treatment of glaucoma, but there have been case reports describing its benefits in acute migraine treatment.^8,9 In addition, ophthalmic timolol is far cheaper than medications such as ubrogepant.¹⁰ A 2014 case series of 7 patients discussed ophthalmic beta-blockers as an effective and possibly cheaper option for acute migraine treatment.⁸ A randomized, crossover, placebo-controlled pilot study of 198 migraine attacks in 10 participants using timolol eyedrops for abortive therapy found timolol was not significantly more effective than placebo.⁹ However, it was an underpowered pilot study, with a lack of masking and an imperfect placebo. The trial discussed here was a controlled, prospective study investigating topical beta-blockers for acute migraine treatment.

STUDY SUMMARY

Crossover study achieved primary endpoint in pain reduction

This randomized, single-center, double-masked, crossover trial compared timolol maleate ophthalmic solution 0.5% with placebo among 43 patients ages 12 or older presenting with a diagnosis of migraine based on ICHD-3 (beta) criteria. Patients were eligible if they had not taken any antimigraine medications for at least 1 month prior to the study and were excluded if they had taken systemic beta-blockers at baseline, or had asthma, bradyarrhythmias, or cardiac dysfunction.

Patients were randomized 1:1 to treatment with timolol maleate 0.5% eyedrops or placebo. At the earliest onset of migraine, patients used 1 drop of timolol maleate 0.5% or placebo in each eye; if they experienced no relief after 10 minutes, they used a second drop or matching placebo. Patients were instructed to score their headache pain on a 10-point scale prior to using the eyedrops and then again 20 minutes after treatment. If a patient had migraine with aura, they were asked to use the eyedrops at the onset of the aura but measure their score at headache onset. If no headaches developed within 20 minutes of the aura, the episode was not included for analysis. All patients were permitted to use their standard oral rescue medication if no relief occurred after 20 minutes of pain onset.

Continue to: The groups were observed...

The groups were observed for 3 months and then followed for a 1-month washout period, during which they received no study medications. The groups were then crossed over to the other treatment and were observed for another 3 months. The primary outcome was a reduction in pain score by 4 or more points, or to 0 on a 10-point pain scale, 20 minutes after treatment. The secondary outcome was nonuse of oral rescue medication.

The primary outcome was achieved in 233 of 284 (82%) timolol-treated migraines, compared to 38 of 271 (14%) placebo-treated migraines.

Forty-three patients were included in a modified intention-to-treat analysis. The primary outcome was achieved in 233 of 284 (82%) timolol-treated migraines, compared to 38 of 271 (14%) placebo-treated migraines (percentage difference = 68 percentage points; 95% CI, 62-74 percentage points; P < .001). The mean pain score at the onset of migraine attacks was 6.01 for those treated with timolol and 5.93 for those treated with placebo. Patients treated with timolol had a reduction in pain of 5.98 points, compared with 0.93 points after using placebo (difference = 5.05; 95% CI, 4.19-5.91). No attacks included in the data required oral rescue medications, and there were no systemic adverse effects from the timolol eyedrops.

WHAT’S NEW

Evidence of benefit as abortive therapy for acute migraine

This randomized controlled trial (RCT) showed evidence to support timolol maleate ophthalmic solution 0.5% vs placebo for treatment of acute migraine by significantly reducing pain when taken at the onset of an acute migraine attack.

CAVEATS

Single-center trial, measuring limited response time

The generalizability of this RCT is limited because it was a single-center trial with a study population from a single region in India. It is unknown whether pain relief, adverse effects, or adherence would differ for the global population. Additionally, only migraines with headache were included in the analysis, limiting non-headache migraine subgroup-directed treatment. Also, this trial evaluated only the response to treatment at 20 minutes, and it is unknown if pain response continued for several hours. Headaches that began more than 20 minutes after the onset of aura were not evaluated.

CHALLENGES TO IMPLEMENTATION

Timolol’s systemic adverse effects require caution

Systemic beta-blocker effects (eg, bradycardia, hypotension, drowsiness, and bronchospasm) from topical timolol have been reported. Caution should be used when prescribing timolol for patients with current cardiovascular and pulmonary conditions. 

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Interventional approaches are being used as a standard of care more and more to provide image-guided techniques to perform minimally invasive procedures. With this being said, what are some indications and best practices used with interventional radiology for the treatment of uterine fibroids?

Dr. Boone:  Interventional radiologists offer minimally invasive non-surgical treatment options for the management of symptomatic uterine fibroids. These approaches include uterine artery embolization or UAE. It may also be called uterine fibroid embolization or UFE.  In this procedure, the uterine arteries are embolized with permanent embolic particles to block blood flow to the fibroids.

The goal of this treatment is to shrink the fibroids. It usually leads to a gradual shrinkage of fibroids and can also be particularly effective for reducing bleeding from fibroids. This procedure has been around for more than 20 years and has a lot of data describing its safety and efficacy.

Another treatment, which is non-invasive, but some interventional radiologists offer, is magnetic resonance-guided focused ultrasound. This might also be called high intensity focused ultrasound or HIFU. In this treatment, MRI is used to direct high intensity ultrasound waves onto the fibroid. This focused application of these high intensity ultrasound waves generates heat and leads to coagulative necrosis of the fibroid.

This procedure is newer than uterine artery embolization, but it has some benefits of avoiding ionizing radiation. Although, it can have longer procedure times. For both procedures, the indications are symptomatic uterine fibroids.

The symptoms we're concerned about include menorrhagia, which can result in anemia. There are also “bulk” symptoms, related to the actual bulk of the fibroids, which can cause bladder or bowel dysfunction. Some patients also have protrusion of their abdomen, dysmenorrhea, and infertility.

The goal is to help reduce those symptoms. The Society for Interventional Radiology has published best practices. For expected outcomes, with the uterine artery embolization, it is 50% to 60% reduction in the size of fibroid of the fibroids themselves, 40% to 50% reduction in the size of the uterus, 88% to 92% of reduction of the bulk symptoms.

Every consultation should discuss the range of treatment options—the medical, surgical, and non-surgical or interventional. I wanted to point out that there is a real need for this. The Society for Interventional Radiology commissioned a poll in 2017 of patients–women  who had been diagnosed with uterine fibroids—and found that 44% of patients noted never hearing of uterine artery embolization. Eleven percent of these patients believed that hysterectomy was their only treatment option. Further, a recent article from NPR noted concerns about disparities in which women of color, particularly Black women, were not offered or made aware of more minimally invasive options during consultations. Very broad patient education about the range of treatment options is important.

In addition, we want to consider other differential diagnoses that patients may have, such as adenomyosis or rare malignancies. Leiomyosarcoma can present with similar symptoms to uterine fibroids or can even coexist with uterine fibroids. In the case of leiomyosarcoma, the treatment pathway may be completely different, and we don't want to undertreat or delay diagnosis. Other considerations that can have bearing on the selection of treatment can be the number and the size of the fibroids.

To help with the decision-making process, these patients need a complete workup. We want to get lab tests. We want to also make sure they have a complete gynecologic evaluation, which includes an ultrasound and an MRI. Particularly, contrast-enhanced MRI has great accuracy for evaluating fibroid location because we’re imaging the entire pelvis. We can see where everything is and map out our target fibroids.

We can also see the enhancement characteristics of the fibroids. Some fibroids are not just supplied by uterine arteries but ovarian arteries, which can affect the efficacy of the treatment and even some of the risks of the treatment.

What is your role and particularly what is the role of the Nurse Practitioner when thinking about diagnosis and treatment and how do you and the nurse practitioner work together?

Dr. Boone: I would say the specific roles for the physicians and nurse practitioners on an interventional radiology team can vary with a lot of different factors. It could depend on the practice setting, such as, whether you're in a busy academic center or in a small private practice. It can depend on the types of cases we're doing. Even some of the local regulations of the institution and state can come into play. The roles tend to be laid out and specified by the supervising physician based on this context.

For example, ideally, all of that work up and planning is happening in that clinic setting before the patient even comes down to the suite for the procedure. In this setting, nurse practitioners can provide a significant role in obtaining the data that we need. They'll perform the history and physical exam, which helps the team learn about the patients. It helps answer relevant questions: What symptoms is the patient having? What are their wishes for the procedure? What are the things they're hoping to avoid or hoping to get from having the procedure done? They review for those relevant labs and imaging, and in order to recognize the information we don’t have.

The next step is developing the assessment and plan which is usually done in conjunction with the interventional radiologist. This is especially important with new patients. Once that assessment and plan are determined, the nurse practitioner can be helpful in explaining the process in depth to the patient and their family or caregivers while they're in the clinic.

Another important role for nurse practitioners in this setting is the consent. I can talk a little bit more about that later, but informed consent is critical. It can be a pretty extensive discussion, especially if we want to talk about this wide range of treatment options. So that is substantial value added by the nurse practitioner.

The other important role is the follow up visits, which may be almost completely independently by a nurse practitioner. They see patients post-procedure, evaluating how they’re doing and what's changed. This is critical because we need to determine: 1. Have we gotten the result that we want? 2. Do we want to give more time to see changes? and;  3. Do we need to do another procedure? We also want to follow these patients and their response to treatment to look out for something concerning that might raise concern for malignancy, such as the fibroid continuing to grow rapidly. Those follow up visits are also a critical role for NPs.

In the inpatient setting, the attending and senior interventional radiology residents may actually determine the roles and tasks the other team members are going to perform to help the IR service run smoothly. And typically, nurse practitioners and also physician assistants will share many of those responsibilities of running that interventional radiology service outside of the procedure room.

There are also cases where nurse practitioners and physician assistants can have a dedicated role in performing certain procedures. Personally, I've seen physician assistants in these cases, where they were our dedicated bone marrow biopsy providers. Throughout the day, they would do all the bone marrow biopsy cases. Another example I saw was placement of vascular access catheters, whether for ports or dialysis. NPs see many patients throughout the day and perform these procedures. This is helpful because these are very popular procedures and are needed. While those are being done, it frees up time for the other members of the team to do other, more time-consuming, procedures as well.

In all cases, we work closely together. We're sharing this responsibility of patient care. We communicate frequently and it's a valuable team dynamic. NPs are fantastic team members

Dr. Boone, you talked about the treatments and how you work together with NPs. Can you touch on the interventional procedures and the value or benefit over conservative treatments and drugs, particularly, where you receive support or recommendations from nurse practitioners at this stage?

Dr. Boone: Regarding more conservative treatment,  there’s expectant management where the patients may not want to undergo an intervention at that time. You’re following the patient and watching for possible worsening of symptoms that may lead to a change in management.

There’s also medical management, which generally gets broken down into hormonal or non-hormonal medications. Among these, there's a lot of different drugs that are available. Among the more frequently used hormonal therapies would be gonadotropin-releasing hormone agonists.

The non-hormonal therapies such as, NSAIDs, or procoagulation medications, like tranexamic acid, are more targeted at symptom control. Particularly, these target the abnormal uterine bleeding and the pain.

For these therapies, the limitations can be side-effect profiles. Sometimes these side effects are just not acceptable to patients. Hormonal therapies like the gonadotropin-releasing hormone agonists create this hypoestrogenic state. Patients may not like having the menopause-like symptoms.

Additionally, medications are more short-term in their benefit. For example, with the cessation of gonadotropin-releasing hormone agonists, the fibroids actually can show rapid rebound growth. Some of the non-surgical interventions can provide longer term benefit, even if they may require re-intervention more frequently compared to surgical interventions.

For interventional radiology, we primarily focus on the procedures. We don't typically manage the medical therapy. These treatment approaches are cultivated more by gynecology or other clinicians.

When it comes to interventional radiology treatment for uterine fibroids in your day-to-day practices, which you've talked a lot about today, what has been your experience in working with Nurse Practitioners overall and where do they, should they or could they potentially add even more value?

Dr. Boone: Nurse practitioners play an integral role on the team and, I think, they provide a lot of value. They have an important role in teaching settings, were they provide continuity of care. They can also greatly impact with teaching of trainees.

In teaching settings, there's a substantial turnover of trainees because -- and this includes residents, medical students, in some cases fellows -- they're  rotating between different hospitals every few weeks. Even at the end of the year, the most senior residents, the most experience trainees, leave to go to new jobs. Nurse practitioners on the IR team are a critical source of continuity and consistency for patients and for the rest of the team because they spend the most time on the service and they know the team members well. They also know how to get things done efficiently and really know the system.

They've also honed the skills that trainees, particularly junior residents, are learning. In my experience, I first learned to place and remove tunneled catheters and bone marrow biopsies by spending the day with a physician assistant and a nurse practitioner. Both from the educational standpoint and also consistent, efficient care standpoint, having NPs and PAs on our team is hugely valuable.

Emphasizing that role in teaching is highly valuable. I would encourage nurse practitioners on an IR team with trainees to take ownership of teaching a particular skill or a certain topic, because they're going to bring a different perspective and that's extremely valuable.

Another arena where there's a lot of value, is  in the informed consent and patient education portion of patient care. Interventional radiology is not the most familiar medical field for a lot of people. Interventional radiologists also perform a wide array of procedures and they can be very different. Even treatments for the same problem, uterine artery embolization and MRI-guided focused ultrasound, are very different procedures in terms of how they're actually performed.

For example, if you mentioned surgery to most people, there is some idea of what that entails and who performs it. But if you say embolization to most people, they may not entirely understand all those components. For a patient to sufficiently be informed and able to consent, they do need to understand not only their disease and the treatment being offered, but also the risks, the benefits, and the alternatives. They need to understand what to expect from the procedure.

Doing this well can take a substantial amount of time, but it is important. From a physician standpoint, that entails balancing. Along with performing the procedures and reviewing patient imaging as well as other clinical duties this is very  challenging. Nurse practitioners can really leverage their expertise in patient communication and education to fill in those knowledge gaps and best serve the patient while also helping the IR service. These are just two of many areas in which NPs can be highly valuable to an IR practice.

Interventional approaches are being used as a standard of care more and more to provide image-guided techniques to perform minimally invasive procedures. With this being said, what are some indications and best practices used with interventional radiology for the treatment of uterine fibroids?

Dr. Boone:  Interventional radiologists offer minimally invasive non-surgical treatment options for the management of symptomatic uterine fibroids. These approaches include uterine artery embolization or UAE. It may also be called uterine fibroid embolization or UFE.  In this procedure, the uterine arteries are embolized with permanent embolic particles to block blood flow to the fibroids.

The goal of this treatment is to shrink the fibroids. It usually leads to a gradual shrinkage of fibroids and can also be particularly effective for reducing bleeding from fibroids. This procedure has been around for more than 20 years and has a lot of data describing its safety and efficacy.

Another treatment, which is non-invasive, but some interventional radiologists offer, is magnetic resonance-guided focused ultrasound. This might also be called high intensity focused ultrasound or HIFU. In this treatment, MRI is used to direct high intensity ultrasound waves onto the fibroid. This focused application of these high intensity ultrasound waves generates heat and leads to coagulative necrosis of the fibroid.

This procedure is newer than uterine artery embolization, but it has some benefits of avoiding ionizing radiation. Although, it can have longer procedure times. For both procedures, the indications are symptomatic uterine fibroids.

The symptoms we're concerned about include menorrhagia, which can result in anemia. There are also “bulk” symptoms, related to the actual bulk of the fibroids, which can cause bladder or bowel dysfunction. Some patients also have protrusion of their abdomen, dysmenorrhea, and infertility.

The goal is to help reduce those symptoms. The Society for Interventional Radiology has published best practices. For expected outcomes, with the uterine artery embolization, it is 50% to 60% reduction in the size of fibroid of the fibroids themselves, 40% to 50% reduction in the size of the uterus, 88% to 92% of reduction of the bulk symptoms.

Every consultation should discuss the range of treatment options—the medical, surgical, and non-surgical or interventional. I wanted to point out that there is a real need for this. The Society for Interventional Radiology commissioned a poll in 2017 of patients–women  who had been diagnosed with uterine fibroids—and found that 44% of patients noted never hearing of uterine artery embolization. Eleven percent of these patients believed that hysterectomy was their only treatment option. Further, a recent article from NPR noted concerns about disparities in which women of color, particularly Black women, were not offered or made aware of more minimally invasive options during consultations. Very broad patient education about the range of treatment options is important.

In addition, we want to consider other differential diagnoses that patients may have, such as adenomyosis or rare malignancies. Leiomyosarcoma can present with similar symptoms to uterine fibroids or can even coexist with uterine fibroids. In the case of leiomyosarcoma, the treatment pathway may be completely different, and we don't want to undertreat or delay diagnosis. Other considerations that can have bearing on the selection of treatment can be the number and the size of the fibroids.

To help with the decision-making process, these patients need a complete workup. We want to get lab tests. We want to also make sure they have a complete gynecologic evaluation, which includes an ultrasound and an MRI. Particularly, contrast-enhanced MRI has great accuracy for evaluating fibroid location because we’re imaging the entire pelvis. We can see where everything is and map out our target fibroids.

We can also see the enhancement characteristics of the fibroids. Some fibroids are not just supplied by uterine arteries but ovarian arteries, which can affect the efficacy of the treatment and even some of the risks of the treatment.

What is your role and particularly what is the role of the Nurse Practitioner when thinking about diagnosis and treatment and how do you and the nurse practitioner work together?

Dr. Boone: I would say the specific roles for the physicians and nurse practitioners on an interventional radiology team can vary with a lot of different factors. It could depend on the practice setting, such as, whether you're in a busy academic center or in a small private practice. It can depend on the types of cases we're doing. Even some of the local regulations of the institution and state can come into play. The roles tend to be laid out and specified by the supervising physician based on this context.

For example, ideally, all of that work up and planning is happening in that clinic setting before the patient even comes down to the suite for the procedure. In this setting, nurse practitioners can provide a significant role in obtaining the data that we need. They'll perform the history and physical exam, which helps the team learn about the patients. It helps answer relevant questions: What symptoms is the patient having? What are their wishes for the procedure? What are the things they're hoping to avoid or hoping to get from having the procedure done? They review for those relevant labs and imaging, and in order to recognize the information we don’t have.

The next step is developing the assessment and plan which is usually done in conjunction with the interventional radiologist. This is especially important with new patients. Once that assessment and plan are determined, the nurse practitioner can be helpful in explaining the process in depth to the patient and their family or caregivers while they're in the clinic.

Another important role for nurse practitioners in this setting is the consent. I can talk a little bit more about that later, but informed consent is critical. It can be a pretty extensive discussion, especially if we want to talk about this wide range of treatment options. So that is substantial value added by the nurse practitioner.

The other important role is the follow up visits, which may be almost completely independently by a nurse practitioner. They see patients post-procedure, evaluating how they’re doing and what's changed. This is critical because we need to determine: 1. Have we gotten the result that we want? 2. Do we want to give more time to see changes? and;  3. Do we need to do another procedure? We also want to follow these patients and their response to treatment to look out for something concerning that might raise concern for malignancy, such as the fibroid continuing to grow rapidly. Those follow up visits are also a critical role for NPs.

In the inpatient setting, the attending and senior interventional radiology residents may actually determine the roles and tasks the other team members are going to perform to help the IR service run smoothly. And typically, nurse practitioners and also physician assistants will share many of those responsibilities of running that interventional radiology service outside of the procedure room.

There are also cases where nurse practitioners and physician assistants can have a dedicated role in performing certain procedures. Personally, I've seen physician assistants in these cases, where they were our dedicated bone marrow biopsy providers. Throughout the day, they would do all the bone marrow biopsy cases. Another example I saw was placement of vascular access catheters, whether for ports or dialysis. NPs see many patients throughout the day and perform these procedures. This is helpful because these are very popular procedures and are needed. While those are being done, it frees up time for the other members of the team to do other, more time-consuming, procedures as well.

In all cases, we work closely together. We're sharing this responsibility of patient care. We communicate frequently and it's a valuable team dynamic. NPs are fantastic team members

Dr. Boone, you talked about the treatments and how you work together with NPs. Can you touch on the interventional procedures and the value or benefit over conservative treatments and drugs, particularly, where you receive support or recommendations from nurse practitioners at this stage?

Dr. Boone: Regarding more conservative treatment,  there’s expectant management where the patients may not want to undergo an intervention at that time. You’re following the patient and watching for possible worsening of symptoms that may lead to a change in management.

There’s also medical management, which generally gets broken down into hormonal or non-hormonal medications. Among these, there's a lot of different drugs that are available. Among the more frequently used hormonal therapies would be gonadotropin-releasing hormone agonists.

The non-hormonal therapies such as, NSAIDs, or procoagulation medications, like tranexamic acid, are more targeted at symptom control. Particularly, these target the abnormal uterine bleeding and the pain.

For these therapies, the limitations can be side-effect profiles. Sometimes these side effects are just not acceptable to patients. Hormonal therapies like the gonadotropin-releasing hormone agonists create this hypoestrogenic state. Patients may not like having the menopause-like symptoms.

Additionally, medications are more short-term in their benefit. For example, with the cessation of gonadotropin-releasing hormone agonists, the fibroids actually can show rapid rebound growth. Some of the non-surgical interventions can provide longer term benefit, even if they may require re-intervention more frequently compared to surgical interventions.

For interventional radiology, we primarily focus on the procedures. We don't typically manage the medical therapy. These treatment approaches are cultivated more by gynecology or other clinicians.

When it comes to interventional radiology treatment for uterine fibroids in your day-to-day practices, which you've talked a lot about today, what has been your experience in working with Nurse Practitioners overall and where do they, should they or could they potentially add even more value?

Dr. Boone: Nurse practitioners play an integral role on the team and, I think, they provide a lot of value. They have an important role in teaching settings, were they provide continuity of care. They can also greatly impact with teaching of trainees.

In teaching settings, there's a substantial turnover of trainees because -- and this includes residents, medical students, in some cases fellows -- they're  rotating between different hospitals every few weeks. Even at the end of the year, the most senior residents, the most experience trainees, leave to go to new jobs. Nurse practitioners on the IR team are a critical source of continuity and consistency for patients and for the rest of the team because they spend the most time on the service and they know the team members well. They also know how to get things done efficiently and really know the system.

They've also honed the skills that trainees, particularly junior residents, are learning. In my experience, I first learned to place and remove tunneled catheters and bone marrow biopsies by spending the day with a physician assistant and a nurse practitioner. Both from the educational standpoint and also consistent, efficient care standpoint, having NPs and PAs on our team is hugely valuable.

Emphasizing that role in teaching is highly valuable. I would encourage nurse practitioners on an IR team with trainees to take ownership of teaching a particular skill or a certain topic, because they're going to bring a different perspective and that's extremely valuable.

Another arena where there's a lot of value, is  in the informed consent and patient education portion of patient care. Interventional radiology is not the most familiar medical field for a lot of people. Interventional radiologists also perform a wide array of procedures and they can be very different. Even treatments for the same problem, uterine artery embolization and MRI-guided focused ultrasound, are very different procedures in terms of how they're actually performed.

For example, if you mentioned surgery to most people, there is some idea of what that entails and who performs it. But if you say embolization to most people, they may not entirely understand all those components. For a patient to sufficiently be informed and able to consent, they do need to understand not only their disease and the treatment being offered, but also the risks, the benefits, and the alternatives. They need to understand what to expect from the procedure.

Doing this well can take a substantial amount of time, but it is important. From a physician standpoint, that entails balancing. Along with performing the procedures and reviewing patient imaging as well as other clinical duties this is very  challenging. Nurse practitioners can really leverage their expertise in patient communication and education to fill in those knowledge gaps and best serve the patient while also helping the IR service. These are just two of many areas in which NPs can be highly valuable to an IR practice.

Interventional approaches are being used as a standard of care more and more to provide image-guided techniques to perform minimally invasive procedures. With this being said, what are some indications and best practices used with interventional radiology for the treatment of uterine fibroids?

Dr. Boone:  Interventional radiologists offer minimally invasive non-surgical treatment options for the management of symptomatic uterine fibroids. These approaches include uterine artery embolization or UAE. It may also be called uterine fibroid embolization or UFE.  In this procedure, the uterine arteries are embolized with permanent embolic particles to block blood flow to the fibroids.

The goal of this treatment is to shrink the fibroids. It usually leads to a gradual shrinkage of fibroids and can also be particularly effective for reducing bleeding from fibroids. This procedure has been around for more than 20 years and has a lot of data describing its safety and efficacy.

Another treatment, which is non-invasive, but some interventional radiologists offer, is magnetic resonance-guided focused ultrasound. This might also be called high intensity focused ultrasound or HIFU. In this treatment, MRI is used to direct high intensity ultrasound waves onto the fibroid. This focused application of these high intensity ultrasound waves generates heat and leads to coagulative necrosis of the fibroid.

This procedure is newer than uterine artery embolization, but it has some benefits of avoiding ionizing radiation. Although, it can have longer procedure times. For both procedures, the indications are symptomatic uterine fibroids.

The symptoms we're concerned about include menorrhagia, which can result in anemia. There are also “bulk” symptoms, related to the actual bulk of the fibroids, which can cause bladder or bowel dysfunction. Some patients also have protrusion of their abdomen, dysmenorrhea, and infertility.

The goal is to help reduce those symptoms. The Society for Interventional Radiology has published best practices. For expected outcomes, with the uterine artery embolization, it is 50% to 60% reduction in the size of fibroid of the fibroids themselves, 40% to 50% reduction in the size of the uterus, 88% to 92% of reduction of the bulk symptoms.

Every consultation should discuss the range of treatment options—the medical, surgical, and non-surgical or interventional. I wanted to point out that there is a real need for this. The Society for Interventional Radiology commissioned a poll in 2017 of patients–women  who had been diagnosed with uterine fibroids—and found that 44% of patients noted never hearing of uterine artery embolization. Eleven percent of these patients believed that hysterectomy was their only treatment option. Further, a recent article from NPR noted concerns about disparities in which women of color, particularly Black women, were not offered or made aware of more minimally invasive options during consultations. Very broad patient education about the range of treatment options is important.

In addition, we want to consider other differential diagnoses that patients may have, such as adenomyosis or rare malignancies. Leiomyosarcoma can present with similar symptoms to uterine fibroids or can even coexist with uterine fibroids. In the case of leiomyosarcoma, the treatment pathway may be completely different, and we don't want to undertreat or delay diagnosis. Other considerations that can have bearing on the selection of treatment can be the number and the size of the fibroids.

To help with the decision-making process, these patients need a complete workup. We want to get lab tests. We want to also make sure they have a complete gynecologic evaluation, which includes an ultrasound and an MRI. Particularly, contrast-enhanced MRI has great accuracy for evaluating fibroid location because we’re imaging the entire pelvis. We can see where everything is and map out our target fibroids.

We can also see the enhancement characteristics of the fibroids. Some fibroids are not just supplied by uterine arteries but ovarian arteries, which can affect the efficacy of the treatment and even some of the risks of the treatment.

What is your role and particularly what is the role of the Nurse Practitioner when thinking about diagnosis and treatment and how do you and the nurse practitioner work together?

Dr. Boone: I would say the specific roles for the physicians and nurse practitioners on an interventional radiology team can vary with a lot of different factors. It could depend on the practice setting, such as, whether you're in a busy academic center or in a small private practice. It can depend on the types of cases we're doing. Even some of the local regulations of the institution and state can come into play. The roles tend to be laid out and specified by the supervising physician based on this context.

For example, ideally, all of that work up and planning is happening in that clinic setting before the patient even comes down to the suite for the procedure. In this setting, nurse practitioners can provide a significant role in obtaining the data that we need. They'll perform the history and physical exam, which helps the team learn about the patients. It helps answer relevant questions: What symptoms is the patient having? What are their wishes for the procedure? What are the things they're hoping to avoid or hoping to get from having the procedure done? They review for those relevant labs and imaging, and in order to recognize the information we don’t have.

The next step is developing the assessment and plan which is usually done in conjunction with the interventional radiologist. This is especially important with new patients. Once that assessment and plan are determined, the nurse practitioner can be helpful in explaining the process in depth to the patient and their family or caregivers while they're in the clinic.

Another important role for nurse practitioners in this setting is the consent. I can talk a little bit more about that later, but informed consent is critical. It can be a pretty extensive discussion, especially if we want to talk about this wide range of treatment options. So that is substantial value added by the nurse practitioner.

The other important role is the follow up visits, which may be almost completely independently by a nurse practitioner. They see patients post-procedure, evaluating how they’re doing and what's changed. This is critical because we need to determine: 1. Have we gotten the result that we want? 2. Do we want to give more time to see changes? and;  3. Do we need to do another procedure? We also want to follow these patients and their response to treatment to look out for something concerning that might raise concern for malignancy, such as the fibroid continuing to grow rapidly. Those follow up visits are also a critical role for NPs.

In the inpatient setting, the attending and senior interventional radiology residents may actually determine the roles and tasks the other team members are going to perform to help the IR service run smoothly. And typically, nurse practitioners and also physician assistants will share many of those responsibilities of running that interventional radiology service outside of the procedure room.

There are also cases where nurse practitioners and physician assistants can have a dedicated role in performing certain procedures. Personally, I've seen physician assistants in these cases, where they were our dedicated bone marrow biopsy providers. Throughout the day, they would do all the bone marrow biopsy cases. Another example I saw was placement of vascular access catheters, whether for ports or dialysis. NPs see many patients throughout the day and perform these procedures. This is helpful because these are very popular procedures and are needed. While those are being done, it frees up time for the other members of the team to do other, more time-consuming, procedures as well.

In all cases, we work closely together. We're sharing this responsibility of patient care. We communicate frequently and it's a valuable team dynamic. NPs are fantastic team members

Dr. Boone, you talked about the treatments and how you work together with NPs. Can you touch on the interventional procedures and the value or benefit over conservative treatments and drugs, particularly, where you receive support or recommendations from nurse practitioners at this stage?

Dr. Boone: Regarding more conservative treatment,  there’s expectant management where the patients may not want to undergo an intervention at that time. You’re following the patient and watching for possible worsening of symptoms that may lead to a change in management.

There’s also medical management, which generally gets broken down into hormonal or non-hormonal medications. Among these, there's a lot of different drugs that are available. Among the more frequently used hormonal therapies would be gonadotropin-releasing hormone agonists.

The non-hormonal therapies such as, NSAIDs, or procoagulation medications, like tranexamic acid, are more targeted at symptom control. Particularly, these target the abnormal uterine bleeding and the pain.

For these therapies, the limitations can be side-effect profiles. Sometimes these side effects are just not acceptable to patients. Hormonal therapies like the gonadotropin-releasing hormone agonists create this hypoestrogenic state. Patients may not like having the menopause-like symptoms.

Additionally, medications are more short-term in their benefit. For example, with the cessation of gonadotropin-releasing hormone agonists, the fibroids actually can show rapid rebound growth. Some of the non-surgical interventions can provide longer term benefit, even if they may require re-intervention more frequently compared to surgical interventions.

For interventional radiology, we primarily focus on the procedures. We don't typically manage the medical therapy. These treatment approaches are cultivated more by gynecology or other clinicians.

When it comes to interventional radiology treatment for uterine fibroids in your day-to-day practices, which you've talked a lot about today, what has been your experience in working with Nurse Practitioners overall and where do they, should they or could they potentially add even more value?

Dr. Boone: Nurse practitioners play an integral role on the team and, I think, they provide a lot of value. They have an important role in teaching settings, were they provide continuity of care. They can also greatly impact with teaching of trainees.

In teaching settings, there's a substantial turnover of trainees because -- and this includes residents, medical students, in some cases fellows -- they're  rotating between different hospitals every few weeks. Even at the end of the year, the most senior residents, the most experience trainees, leave to go to new jobs. Nurse practitioners on the IR team are a critical source of continuity and consistency for patients and for the rest of the team because they spend the most time on the service and they know the team members well. They also know how to get things done efficiently and really know the system.

They've also honed the skills that trainees, particularly junior residents, are learning. In my experience, I first learned to place and remove tunneled catheters and bone marrow biopsies by spending the day with a physician assistant and a nurse practitioner. Both from the educational standpoint and also consistent, efficient care standpoint, having NPs and PAs on our team is hugely valuable.

Emphasizing that role in teaching is highly valuable. I would encourage nurse practitioners on an IR team with trainees to take ownership of teaching a particular skill or a certain topic, because they're going to bring a different perspective and that's extremely valuable.

Another arena where there's a lot of value, is  in the informed consent and patient education portion of patient care. Interventional radiology is not the most familiar medical field for a lot of people. Interventional radiologists also perform a wide array of procedures and they can be very different. Even treatments for the same problem, uterine artery embolization and MRI-guided focused ultrasound, are very different procedures in terms of how they're actually performed.

For example, if you mentioned surgery to most people, there is some idea of what that entails and who performs it. But if you say embolization to most people, they may not entirely understand all those components. For a patient to sufficiently be informed and able to consent, they do need to understand not only their disease and the treatment being offered, but also the risks, the benefits, and the alternatives. They need to understand what to expect from the procedure.

Doing this well can take a substantial amount of time, but it is important. From a physician standpoint, that entails balancing. Along with performing the procedures and reviewing patient imaging as well as other clinical duties this is very  challenging. Nurse practitioners can really leverage their expertise in patient communication and education to fill in those knowledge gaps and best serve the patient while also helping the IR service. These are just two of many areas in which NPs can be highly valuable to an IR practice.

Tampons may be harder to find because of supply chain challenges and inflation hikes that are causing higher prices.

Social media users have posted about bare shelves and higher costs for months, marking the latest products to face stress under global supply chain concerns after baby formula, cars, and appliances.

Other menstrual products have increased in price as well because of inflation, according to Bloomberg News. The average price for a package of menstrual pads has increased about 8% this year, and the price of a box of tampons has increased about 10%.

Andre Schulten, the chief financial officer for Procter & Gamble, which makes and sells 4.5 billion boxes of Tampax each year, said on a recent earnings call that it has been “costly and highly volatile” to acquire the raw materials needed for production.

Raw materials such as cotton, rayon, and plastic, for instance, have been used to produce personal protective gear during the pandemic, which has led to shortages. The cost of transportation for consumer goods has also nearly tripled, and pandemic policies at ports have led to shipping delays.

Edgewell Personal Care, which makes the brands Playtex and o.b., has had a severe staff shortage at its Delaware facility where tampons are made, according to Time. The FDA has classified tampons as class II medical devices, which require certain quality-control regulations and qualified workers on the assembly line, the news outlet reported.

Representatives for CVS and Walgreens confirmed that they’ve had shortages in recent weeks, according to The Washington Post. Procter & Gamble said it is working with retail partners to make feminine care products more available.

“We understand it is frustrating for consumers when they can’t find what they need,” the company told the newspaper. “We can assure you this is a temporary situation.”

Kimberly-Clark, which makes U by Kotex tampons, told the Post that it “has not experienced a product or supply shortage” in the United States, saying it is “working closely with our retail partners to keep shelves stocked.”

But the shortage may grow worse as the year goes on and the peak season for shipping approaches, the newspaper reported.

“Capacity is only going to get tighter as we move toward the end of the year,” Vaughn Moore, chief executive of AIT Worldwide Logistics, told the Post.

While the situation is being straightened out, gynecologists have recommended against extending supply at home by wearing tampons for longer stretches of time, according to The New York Times. Toxic shock syndrome is a rare but potentially fatal condition that can occur when tampons are worn for more than 8 hours.

There are other options, such as reusable menstrual pads, period underwear, and menstrual cups and discs, the Times reported. But some of these may be less appealing to use, or they may cost too much.

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

Tampons may be harder to find because of supply chain challenges and inflation hikes that are causing higher prices.

Social media users have posted about bare shelves and higher costs for months, marking the latest products to face stress under global supply chain concerns after baby formula, cars, and appliances.

Other menstrual products have increased in price as well because of inflation, according to Bloomberg News. The average price for a package of menstrual pads has increased about 8% this year, and the price of a box of tampons has increased about 10%.

Andre Schulten, the chief financial officer for Procter & Gamble, which makes and sells 4.5 billion boxes of Tampax each year, said on a recent earnings call that it has been “costly and highly volatile” to acquire the raw materials needed for production.

Raw materials such as cotton, rayon, and plastic, for instance, have been used to produce personal protective gear during the pandemic, which has led to shortages. The cost of transportation for consumer goods has also nearly tripled, and pandemic policies at ports have led to shipping delays.

Edgewell Personal Care, which makes the brands Playtex and o.b., has had a severe staff shortage at its Delaware facility where tampons are made, according to Time. The FDA has classified tampons as class II medical devices, which require certain quality-control regulations and qualified workers on the assembly line, the news outlet reported.

Representatives for CVS and Walgreens confirmed that they’ve had shortages in recent weeks, according to The Washington Post. Procter & Gamble said it is working with retail partners to make feminine care products more available.

“We understand it is frustrating for consumers when they can’t find what they need,” the company told the newspaper. “We can assure you this is a temporary situation.”

Kimberly-Clark, which makes U by Kotex tampons, told the Post that it “has not experienced a product or supply shortage” in the United States, saying it is “working closely with our retail partners to keep shelves stocked.”

But the shortage may grow worse as the year goes on and the peak season for shipping approaches, the newspaper reported.

“Capacity is only going to get tighter as we move toward the end of the year,” Vaughn Moore, chief executive of AIT Worldwide Logistics, told the Post.

While the situation is being straightened out, gynecologists have recommended against extending supply at home by wearing tampons for longer stretches of time, according to The New York Times. Toxic shock syndrome is a rare but potentially fatal condition that can occur when tampons are worn for more than 8 hours.

There are other options, such as reusable menstrual pads, period underwear, and menstrual cups and discs, the Times reported. But some of these may be less appealing to use, or they may cost too much.

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

Tampons may be harder to find because of supply chain challenges and inflation hikes that are causing higher prices.

Social media users have posted about bare shelves and higher costs for months, marking the latest products to face stress under global supply chain concerns after baby formula, cars, and appliances.

Other menstrual products have increased in price as well because of inflation, according to Bloomberg News. The average price for a package of menstrual pads has increased about 8% this year, and the price of a box of tampons has increased about 10%.

Andre Schulten, the chief financial officer for Procter & Gamble, which makes and sells 4.5 billion boxes of Tampax each year, said on a recent earnings call that it has been “costly and highly volatile” to acquire the raw materials needed for production.

Raw materials such as cotton, rayon, and plastic, for instance, have been used to produce personal protective gear during the pandemic, which has led to shortages. The cost of transportation for consumer goods has also nearly tripled, and pandemic policies at ports have led to shipping delays.

Edgewell Personal Care, which makes the brands Playtex and o.b., has had a severe staff shortage at its Delaware facility where tampons are made, according to Time. The FDA has classified tampons as class II medical devices, which require certain quality-control regulations and qualified workers on the assembly line, the news outlet reported.

Representatives for CVS and Walgreens confirmed that they’ve had shortages in recent weeks, according to The Washington Post. Procter & Gamble said it is working with retail partners to make feminine care products more available.

“We understand it is frustrating for consumers when they can’t find what they need,” the company told the newspaper. “We can assure you this is a temporary situation.”

Kimberly-Clark, which makes U by Kotex tampons, told the Post that it “has not experienced a product or supply shortage” in the United States, saying it is “working closely with our retail partners to keep shelves stocked.”

But the shortage may grow worse as the year goes on and the peak season for shipping approaches, the newspaper reported.

“Capacity is only going to get tighter as we move toward the end of the year,” Vaughn Moore, chief executive of AIT Worldwide Logistics, told the Post.

While the situation is being straightened out, gynecologists have recommended against extending supply at home by wearing tampons for longer stretches of time, according to The New York Times. Toxic shock syndrome is a rare but potentially fatal condition that can occur when tampons are worn for more than 8 hours.

There are other options, such as reusable menstrual pads, period underwear, and menstrual cups and discs, the Times reported. But some of these may be less appealing to use, or they may cost too much.

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

Adding psychotherapy to pharmacologic treatment does not appear to improve treatment outcomes for patients with major depression, new research suggests.

Results of a cross-sectional, naturalistic, multicenter European study showed there were no significant differences in response rates between patients with major depressive disorder (MDD) who received combination treatment with psychotherapy and antidepressant medication in comparison with those who received antidepressant monotherapy, even when comparing different types of psychotherapy.

This “might emphasize the fundamental role of the underlying complex biological interrelationships in MDD and its treatment,” said study investigator Lucie Bartova, MD, PhD, Clinical Division of General Psychiatry, Medical University of Vienna.

However, she noted that patients who received psychotherapy in combination with antidepressants also had “beneficial sociodemographic and clinical characteristics,” which might reflect poorer access to “psychotherapeutic techniques for patients who are more severely ill and have less socioeconomic privilege.”

The resulting selection bias may cause patients with more severe illness to “fall by the wayside,” Dr. Bartova said.

Lead researcher Siegfried Kasper, MD, also from the Medical University of Vienna, agreed, saying in a press release that, by implication, “additional psychotherapy tends to be given to more highly educated and healthier patients, which may reflect the greater availability of psychotherapy to more socially and economically advantaged patients.”

The findings, some of which were previously published in the Journal of Psychiatry Research, were presented at the virtual European Psychiatric Association 2022 Congress.
 

Inconsistent guidelines

During her presentation, Dr. Bartova said that while “numerous effective antidepressant strategies are available for the treatment of MDD, many patients do not achieve a satisfactory treatment response,” which often leads to further management refinement and the use of off-label treatments.

She continued, saying that the “most obvious” approach in these situations is to try the available treatment options in a “systematic and individualized” manner, ideally by following recommended treatment algorithms.

Meta-analyses have suggested that standardized psychotherapy with fixed, regular sessions that follows an established rationale and is based on a defined school of thought is effective in MDD, “with at least moderate effects.”

Among the psychotherapy approaches, cognitive-behavioral therapy (CBT) is the “best and most investigated,” Dr. Bartova said, but international clinical practice guidelines “lack consistency” regarding recommendations for psychotherapy.

To examine the use and impact of psychotherapy for MDD patients, the researchers studied 1,410 adult inpatients and outpatients from 10 centers in eight countries who were surveyed between 2011 and 2016 by the European Group for the Study of Resistant Depression.

Participants were assessed via the Mini–International Neuropsychiatric Interview, the Montgomery-Åsberg Depression Rating Scale, and the Hamilton Depression Rating Scale.

Results showed that among 1,279 MDD patients who were included in the final analysis, 880 (68.8%) received only antidepressants, while 399 (31.2%) received some form of structured psychotherapy as part of their treatment.

These patients included 22.8% who received CBT, 3.4% who underwent psychoanalytic psychotherapy, and 1.3% who received systemic psychotherapy. The additional psychotherapy was not specified for 3.8%.

Dr. Bartova explained that the use of psychotherapy in combination pharmacologic treatment was significantly associated with younger age, higher educational attainment, and ongoing employment in comparison with antidepressant use alone (P < .001 for all).

In addition, combination therapy was associated with an earlier average age of MDD onset, lower severity of current depressive symptoms, a lower risk of suicidality, higher rates of additional melancholic features in the patients’ symptomatology, and higher rates of comorbid asthma and migraine (P < .001 for all).

There was also a significant association between the use of psychotherapy plus pharmacologic treatment and lower average daily doses of first-line antidepressant medication (P < .001), as well as more frequent administration of agomelatine (P < .001) and a trend toward greater use of vortioxetine (P = .006).

In contrast, among patients who received antidepressants alone, there was a trend toward higher rates of additional psychotic features (P = .054), and the patients were more likely to have received selective serotonin reuptake inhibitors as their first-line antidepressant medication (P < .001).

The researchers found there was no significant difference in rates of response, nonresponse, and treatment-resistant depression (TRD) between patients who received combination psychotherapy and pharmacotherapy and those who received antidepressants alone (P = .369).

Dr. Bartova showed that 25.8% of MDD patients who received combination therapy were classified as responders, compared with 23.5% of those given only antidepressants. Nonresponse was identified in 35.6% and 33.8% of patients, respectively, while 38.6% versus 42.7% had TRD.

Dr. Bartova and colleagues performed an additional analysis to determine whether there was any difference in response depending on the type of psychotherapy.

They divided patients who received combination therapy into those who had received CBT and those who had been given another form of psychotherapy.

Again, there were no significant differences in response, nonresponse, and TRD (P = .256). The response rate was 27.1% among patients given combination CBT, versus 22.4% among those who received another psychotherapy.

“Despite clinical guidelines and studies which advocate for psychotherapy and combining psychotherapy with antidepressants, this study shows that in real life, no added value can be demonstrated for psychotherapy in those already treated with antidepressants for severe depression,” Livia De Picker, MD, PhD, Collaborative Antwerp Psychiatric Research Institute, University of Antwerp, Belgium, said in the press release.

“This doesn’t necessarily mean that psychotherapy is not useful, but it is a clear sign that the way we are currently managing these depressed patients with psychotherapy is not effective and needs critical evaluation,” added Dr. De Picker, who was not involved in the research.

However, Michael E. Thase, MD, professor of psychiatry, University of Pennsylvania, Philadelphia, told this news organization that the current study “is a secondary analysis of a naturalistic study.”

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

Adding psychotherapy to pharmacologic treatment does not appear to improve treatment outcomes for patients with major depression, new research suggests.

Results of a cross-sectional, naturalistic, multicenter European study showed there were no significant differences in response rates between patients with major depressive disorder (MDD) who received combination treatment with psychotherapy and antidepressant medication in comparison with those who received antidepressant monotherapy, even when comparing different types of psychotherapy.

This “might emphasize the fundamental role of the underlying complex biological interrelationships in MDD and its treatment,” said study investigator Lucie Bartova, MD, PhD, Clinical Division of General Psychiatry, Medical University of Vienna.

However, she noted that patients who received psychotherapy in combination with antidepressants also had “beneficial sociodemographic and clinical characteristics,” which might reflect poorer access to “psychotherapeutic techniques for patients who are more severely ill and have less socioeconomic privilege.”

The resulting selection bias may cause patients with more severe illness to “fall by the wayside,” Dr. Bartova said.

Lead researcher Siegfried Kasper, MD, also from the Medical University of Vienna, agreed, saying in a press release that, by implication, “additional psychotherapy tends to be given to more highly educated and healthier patients, which may reflect the greater availability of psychotherapy to more socially and economically advantaged patients.”

The findings, some of which were previously published in the Journal of Psychiatry Research, were presented at the virtual European Psychiatric Association 2022 Congress.
 

Inconsistent guidelines

During her presentation, Dr. Bartova said that while “numerous effective antidepressant strategies are available for the treatment of MDD, many patients do not achieve a satisfactory treatment response,” which often leads to further management refinement and the use of off-label treatments.

She continued, saying that the “most obvious” approach in these situations is to try the available treatment options in a “systematic and individualized” manner, ideally by following recommended treatment algorithms.

Meta-analyses have suggested that standardized psychotherapy with fixed, regular sessions that follows an established rationale and is based on a defined school of thought is effective in MDD, “with at least moderate effects.”

Among the psychotherapy approaches, cognitive-behavioral therapy (CBT) is the “best and most investigated,” Dr. Bartova said, but international clinical practice guidelines “lack consistency” regarding recommendations for psychotherapy.

To examine the use and impact of psychotherapy for MDD patients, the researchers studied 1,410 adult inpatients and outpatients from 10 centers in eight countries who were surveyed between 2011 and 2016 by the European Group for the Study of Resistant Depression.

Participants were assessed via the Mini–International Neuropsychiatric Interview, the Montgomery-Åsberg Depression Rating Scale, and the Hamilton Depression Rating Scale.

Results showed that among 1,279 MDD patients who were included in the final analysis, 880 (68.8%) received only antidepressants, while 399 (31.2%) received some form of structured psychotherapy as part of their treatment.

These patients included 22.8% who received CBT, 3.4% who underwent psychoanalytic psychotherapy, and 1.3% who received systemic psychotherapy. The additional psychotherapy was not specified for 3.8%.

Dr. Bartova explained that the use of psychotherapy in combination pharmacologic treatment was significantly associated with younger age, higher educational attainment, and ongoing employment in comparison with antidepressant use alone (P < .001 for all).

In addition, combination therapy was associated with an earlier average age of MDD onset, lower severity of current depressive symptoms, a lower risk of suicidality, higher rates of additional melancholic features in the patients’ symptomatology, and higher rates of comorbid asthma and migraine (P < .001 for all).

There was also a significant association between the use of psychotherapy plus pharmacologic treatment and lower average daily doses of first-line antidepressant medication (P < .001), as well as more frequent administration of agomelatine (P < .001) and a trend toward greater use of vortioxetine (P = .006).

In contrast, among patients who received antidepressants alone, there was a trend toward higher rates of additional psychotic features (P = .054), and the patients were more likely to have received selective serotonin reuptake inhibitors as their first-line antidepressant medication (P < .001).

The researchers found there was no significant difference in rates of response, nonresponse, and treatment-resistant depression (TRD) between patients who received combination psychotherapy and pharmacotherapy and those who received antidepressants alone (P = .369).

Dr. Bartova showed that 25.8% of MDD patients who received combination therapy were classified as responders, compared with 23.5% of those given only antidepressants. Nonresponse was identified in 35.6% and 33.8% of patients, respectively, while 38.6% versus 42.7% had TRD.

Dr. Bartova and colleagues performed an additional analysis to determine whether there was any difference in response depending on the type of psychotherapy.

They divided patients who received combination therapy into those who had received CBT and those who had been given another form of psychotherapy.

Again, there were no significant differences in response, nonresponse, and TRD (P = .256). The response rate was 27.1% among patients given combination CBT, versus 22.4% among those who received another psychotherapy.

“Despite clinical guidelines and studies which advocate for psychotherapy and combining psychotherapy with antidepressants, this study shows that in real life, no added value can be demonstrated for psychotherapy in those already treated with antidepressants for severe depression,” Livia De Picker, MD, PhD, Collaborative Antwerp Psychiatric Research Institute, University of Antwerp, Belgium, said in the press release.

“This doesn’t necessarily mean that psychotherapy is not useful, but it is a clear sign that the way we are currently managing these depressed patients with psychotherapy is not effective and needs critical evaluation,” added Dr. De Picker, who was not involved in the research.

However, Michael E. Thase, MD, professor of psychiatry, University of Pennsylvania, Philadelphia, told this news organization that the current study “is a secondary analysis of a naturalistic study.”

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

Adding psychotherapy to pharmacologic treatment does not appear to improve treatment outcomes for patients with major depression, new research suggests.

Results of a cross-sectional, naturalistic, multicenter European study showed there were no significant differences in response rates between patients with major depressive disorder (MDD) who received combination treatment with psychotherapy and antidepressant medication in comparison with those who received antidepressant monotherapy, even when comparing different types of psychotherapy.

This “might emphasize the fundamental role of the underlying complex biological interrelationships in MDD and its treatment,” said study investigator Lucie Bartova, MD, PhD, Clinical Division of General Psychiatry, Medical University of Vienna.

However, she noted that patients who received psychotherapy in combination with antidepressants also had “beneficial sociodemographic and clinical characteristics,” which might reflect poorer access to “psychotherapeutic techniques for patients who are more severely ill and have less socioeconomic privilege.”

The resulting selection bias may cause patients with more severe illness to “fall by the wayside,” Dr. Bartova said.

Lead researcher Siegfried Kasper, MD, also from the Medical University of Vienna, agreed, saying in a press release that, by implication, “additional psychotherapy tends to be given to more highly educated and healthier patients, which may reflect the greater availability of psychotherapy to more socially and economically advantaged patients.”

The findings, some of which were previously published in the Journal of Psychiatry Research, were presented at the virtual European Psychiatric Association 2022 Congress.
 

Inconsistent guidelines

During her presentation, Dr. Bartova said that while “numerous effective antidepressant strategies are available for the treatment of MDD, many patients do not achieve a satisfactory treatment response,” which often leads to further management refinement and the use of off-label treatments.

She continued, saying that the “most obvious” approach in these situations is to try the available treatment options in a “systematic and individualized” manner, ideally by following recommended treatment algorithms.

Meta-analyses have suggested that standardized psychotherapy with fixed, regular sessions that follows an established rationale and is based on a defined school of thought is effective in MDD, “with at least moderate effects.”

Among the psychotherapy approaches, cognitive-behavioral therapy (CBT) is the “best and most investigated,” Dr. Bartova said, but international clinical practice guidelines “lack consistency” regarding recommendations for psychotherapy.

To examine the use and impact of psychotherapy for MDD patients, the researchers studied 1,410 adult inpatients and outpatients from 10 centers in eight countries who were surveyed between 2011 and 2016 by the European Group for the Study of Resistant Depression.

Participants were assessed via the Mini–International Neuropsychiatric Interview, the Montgomery-Åsberg Depression Rating Scale, and the Hamilton Depression Rating Scale.

Results showed that among 1,279 MDD patients who were included in the final analysis, 880 (68.8%) received only antidepressants, while 399 (31.2%) received some form of structured psychotherapy as part of their treatment.

These patients included 22.8% who received CBT, 3.4% who underwent psychoanalytic psychotherapy, and 1.3% who received systemic psychotherapy. The additional psychotherapy was not specified for 3.8%.

Dr. Bartova explained that the use of psychotherapy in combination pharmacologic treatment was significantly associated with younger age, higher educational attainment, and ongoing employment in comparison with antidepressant use alone (P < .001 for all).

In addition, combination therapy was associated with an earlier average age of MDD onset, lower severity of current depressive symptoms, a lower risk of suicidality, higher rates of additional melancholic features in the patients’ symptomatology, and higher rates of comorbid asthma and migraine (P < .001 for all).

There was also a significant association between the use of psychotherapy plus pharmacologic treatment and lower average daily doses of first-line antidepressant medication (P < .001), as well as more frequent administration of agomelatine (P < .001) and a trend toward greater use of vortioxetine (P = .006).

In contrast, among patients who received antidepressants alone, there was a trend toward higher rates of additional psychotic features (P = .054), and the patients were more likely to have received selective serotonin reuptake inhibitors as their first-line antidepressant medication (P < .001).

The researchers found there was no significant difference in rates of response, nonresponse, and treatment-resistant depression (TRD) between patients who received combination psychotherapy and pharmacotherapy and those who received antidepressants alone (P = .369).

Dr. Bartova showed that 25.8% of MDD patients who received combination therapy were classified as responders, compared with 23.5% of those given only antidepressants. Nonresponse was identified in 35.6% and 33.8% of patients, respectively, while 38.6% versus 42.7% had TRD.

Dr. Bartova and colleagues performed an additional analysis to determine whether there was any difference in response depending on the type of psychotherapy.

They divided patients who received combination therapy into those who had received CBT and those who had been given another form of psychotherapy.

Again, there were no significant differences in response, nonresponse, and TRD (P = .256). The response rate was 27.1% among patients given combination CBT, versus 22.4% among those who received another psychotherapy.

“Despite clinical guidelines and studies which advocate for psychotherapy and combining psychotherapy with antidepressants, this study shows that in real life, no added value can be demonstrated for psychotherapy in those already treated with antidepressants for severe depression,” Livia De Picker, MD, PhD, Collaborative Antwerp Psychiatric Research Institute, University of Antwerp, Belgium, said in the press release.

“This doesn’t necessarily mean that psychotherapy is not useful, but it is a clear sign that the way we are currently managing these depressed patients with psychotherapy is not effective and needs critical evaluation,” added Dr. De Picker, who was not involved in the research.

However, Michael E. Thase, MD, professor of psychiatry, University of Pennsylvania, Philadelphia, told this news organization that the current study “is a secondary analysis of a naturalistic study.”

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

This article is part of a series of articles on the Home Improvements and Structural Alterations program (HISA), a home modification (HM) program within the Veterans Health Administration (VHA). HISA is a benefit awarded to veterans with disabilities (VWDs) and is instrumental in affording physical accessibility and structural alterations to veterans’ homes.¹ The overarching goals of this project are to describe and understand HISA use by VWDs. Previous work has shown geographical variation in the number of HISA prescriptions across counties in the US (Figure 1).¹ The current work seeks to describe and predict the county-level rates of HISA use. Information about what predicts HISA utilization at the county level is important because it enhances understanding of program utilization at a national level. The long-term goal of the series is to provide knowledge about HM services within VHA to improve community-based independent living of VWDs by increasing awareness and utilization of HM services. 

Background

A health care professional (HCP) approves a HM support award by evaluating the practicality of the support to improve the built environment of a given veteran’s disability.^1,2 Previously we detailed some of the preliminary research into the HISA program, including HISA user demographic and clinical characteristics, types of HMs received, user suggestions for improvement, and geospatial analysis of HISA prescriptions concentration.^1-4

The geospatial analyses of HISA prescriptions revealed clusters of high numbers of HISA users (hot spots) and low numbers of HISA users (cold spots), indicating that HISA is either not prescribed or uniformly used across the US. The previous research prompted investigation into county-level variables that may impact HISA utilization rates. This inquiry focuses on county characteristics associated with HISA use rates, such as measures of clinical care and quality of care (eg, access to health services variables, lack of insurance, preventable hospital stays), physical environment, and sociodemographic characteristics. Clinical care and quality of care measures promote the interaction with HCPs. Moreover, access to health care is an important indicator of health outcomes.^5,6 An individual’s capacity to access health services, such as a HM program, greatly impacts well-being, safety, independence, and health.^2,4 Well-being, safety, independence, and health become compromised if individuals cannot access care, if needed care is lacking in their area, if HCPs are not available, or are unwilling to provide care due to lack of insurance coverage.^7-12 In locations where health care services are minimal due to lack of specialists or health care facilities, the quality of (or access to) care may be compromised, resulting in preventable conditions becoming problematic.^13,14 These conditions may result in unnecessary hospitalizations for conditions that could have been treated during routine care. Financial barriers to care particularly among low-income people and the uninsured have proven detrimental to health.^15,16 On the other hand, preventable hospital stays are a quality of care measure (ie, a proxy for poor quality of care). HISA operates within a health care system; thus, it is imperative to include these measures impacting health. 

In this study, we sought to identify county-level predictors—in particular, county-level proxies for access to care—that may be associated with county-level HISA use. We define HISA utilization rate as the percentage of a county’s VHA patients who have received a HISA award.

Methods

This study used data from the National Prosthetics Patient Database (NPPD), US Department of Veterans Affairs (VA) medical database inpatient and outpatient datasets, VHA Support Service Center (VSSC) data cubes, and the County Health Rankings database (CHRD). First, the study cohort was identified from NPPD users who have obtained a HISA award from fiscal years (FY) 2015 to 2018. Analysis started with FY 2015 following new regulations (38 CFR § 17) governing the operations of the HISA program.² The study cohort was matched with records from NPPD and VA inpatient and outpatient datasets to obtain information about the veterans’ demographic characteristics and their HM characteristics and costs. The number of VHA end-of-year (EOY) patients per county was extracted from the VSSC Current Enrollment Cube, which was used in calculation of the county-level HISA utilization rate.¹⁷ Finally, zip code–based locational data were used to calculate approximate drive time and distance from the HISA user’s approximate location to the facility where they received their HM prescription. Drive times and drive distances were calculated with Esri ArcGIS Pro (v2.6.3) by placing zip code centroid and VHA facilities on a nationwide road network that contains both road speeds and distances.

Calculations

Patient-level data were aggregated up to county-level variables by calculating the sum, mean, or percent per county. HISA user sample characteristics, including sex, race, rurality (urban, rural), marital status, and Class 1 vs Class 2 disability-related eligibility groups, were aggregated to the county level by calculating percentages of HISA users of the given characteristics out of total HISA users in the county. Disability-related eligibility groups (Class 1 vs Class 2 HISA users) determines the maximum lifetime award dollar amount. Specifically, those with service-connected disabilities or those with a ≥ 50% disability rating (regardless of whether or not their disability is service connected) are classified as Class 1 HISA users and are eligible to receive a maximum lifetime award of $6800. Those with a recorded disability that is not connected to their military service, and who have a disability rating of < 50% are classified as Class 2 HISA users and are eligible to receive a lifetime maximum award of $2000.

The county-level number of HISA users was used as the numerator for calculation of county-level HISA utilization rate. Counties with zero HISA users were excluded. The number of EOY VHA patients per county in FY 2018 was divided by 1000 and used as the denominator in the calculation of county-level HISA utilization rate. Thus, the outcome variable is HISA utilization rate per 1000 VHA patients in FY 2018 (HISA utilization rate).

County-Level Variables

County-level variables were downloaded from the 2020 CHRD.^5,6 An explanation of the CHRD model and the factors used in this study are shown in the eAppendix (available at doi: 10.12788/fp.0279).⁶ County-level aggregated HISA user data and the CHRD data were matched using county Federal Information Processing Standards codes. Access to care measures collected from CHRD included percentages uninsured and ratios of population to primary care physicians, dentists, mental health professionals, and other primary care professionals. Other CHRD measures included those for quality of care (rate of preventable hospital stay) and housing quality (percent of households with high housing costs, percent of households with overcrowding, percent of households with lack of kitchen or plumbing, percent of households with severe housing cost burden, percent of homeownership). Of secondary interest was county population rurality, as previous research findings showed the annual average of HISA users who are from rural areas ranged from 30 to 35%.

Analysis Methods

SAS (v9.4), R (v4.0.2), and RStudio (v1.3.1093) were used for data preparation and analysis.¹⁸ Multiple regression analysis was used to predict county-level utilization rate from county-level variables. Sociodemographic characteristics from CHRD and HISA data were included as important control predictors in the regression model, though our focus for this paper are the access to care and housing quality predictors.

Model diagnostics (examination of model residuals, Breusch-Godfrey test, Breusch-Pagan test) revealed significant heteroskedasticity of the model; thus, robust standard errors and associated P values were computed using the R estimatr package (v0.30.2).¹⁹ Some predictor variables of interest (eg, ratio of mental health professionals) were removed during the model building process either due to problems of multicollinearity or excessive missingness that would have resulted in listwise deletion.

Results

County-level HISA utilization rate per 1000 EOY VHA patients ranged from 0.09 to 59.7%, with a 6.6% mean and 5% median (Figure 2). The data were highly positively skewed. The final model included 33 total predictor variables (Table 1). The final regression model was a significantly better predictor of county-level HISA utilization rate than a null model (F[33-2184], 10.18; P < .001). The adjusted model R² showed that the overall model accounted for approximately 23% of variance in county-level HISA utilization rate (Table 2).

Among the primary variables of interest, percent uninsured adults and rate of preventable hospital stays emerged as significant predictors of county-level HISA utilization rate. Specifically, county percentage of uninsured adults was negatively related to county-level HISA utilization rate (b = -8.99, P = .005), indicating that the higher the proportion of uninsured adults—with all other predictors held constant—the lower the HISA utilization rate. Percent uninsured adults ranged from 2.7 to 42.4% across counties, with a mean (SD) of 12.7% (5.8%) and 11.4% median.

Discussion

This study examined whether county-level characteristics, specifically variables for access to care, quality of care, and housing quality, were predictive of a county’s HISA utilization rate. Given that this series of work on the HISA program is (to our knowledge) the first of its kind, and given the exploratory nature of this analysis, we did not have specific predictions for the effects of any one given variable. Nevertheless, some of the results were surprising, and we believe they warrant additional study. In particular, the opposing direction of effects for access to care and quality of care variables were hard to reconcile.

The county percent of uninsured adults (an access to care variable, specifically, a proxy for poor access to care) was negatively associated with county-level HISA utilization rate, whereas the county rate of preventable hospital stays (a quality of care variable, but also potentially an access to care variable, and specifically, proxies for poor quality of care or poor access to care) was positively associated with county-level HISA utilization rate. To describe the relationships more generally, one coefficient in the regression model indicated that the poorer the access to care, the lower the HISA utilization rate (higher percent of uninsured adults predicts lower HISA utilization rate), while another coefficient in the regression model indicated the poorer the quality of and access to care, the higher the HISA utilization rate (higher rate of preventable hospital stays predicts higher HISA utilization rate). Future study is warranted to disentangle and reconcile the various community-level predictors of this service.

Housing quality measures (eg, percent of households with high housing costs, percent of households with overcrowding, percent of households with lack of kitchen or plumbing, percent of households with severe housing cost burden, and percent of homeownership) are important in the consideration of whether a HM will be performed or should be performed. For example, if a person is cost burdened by the amount of expenditure spent in housing there will be little discretionary funds to perform a HM. Individuals who do not own their home may experience complications in obtaining permission from landlords to perform a HM. County-level predictors of housing quality (percent of households with high housing costs, overcrowding, and lack of kitchen or plumbing) were not significantly associated with county-level HISA utilization rate but are also nevertheless relevant to the discussion of home modifications. Of particular interest is the percent of households with lack of kitchen or plumbing variable, which was positively related to county-level HISA utilization rate although not statistically significant. HM elements related to the kitchen (eg, heighten countertop) add to the accessibility of the home allowing for the performing of activities of daily living such as cooking. Between FY 2015 and FY 2018, we discovered 131 prescriptions for kitchen (n = 90) and plumbing (n = 41) HMs, which is a very small proportion of the 30,780 total HMs (there were 24,397 bathroom HMs). The nonsignificant coefficient for this variable may reflect the small number of veterans that obtained these HM.

Limitations

The potentially conflicting direction of effects for a significant access to care variable (percent uninsured adults) and a significant access to care and quality of care variable (preventable hospital stays) are interesting and warrant additional study, but the inability to interpret or explain this apparent inconsistency constitutes a limitation of the current data and analyses presented here. Another limitation is that this analysis uses county-level predictors for what is ultimately an individual-level outcome. It would have been ideal to have both individual- and county-level data to conduct a multilevel analysis; in particular, individual-level data within counties of individuals (both veterans and nonveterans) who did not receive a HISA award (including both those who applied and were denied, and who did not apply) would be highly valuable.

Conclusions

Our continuing research into veterans’ use of HM fills a gap in the literature about the characteristics of HISA users, the impact of county-level variables on the use of HISA, and the geographic distribution and use of HISA within the VHA. While it is important to examine the influence of broader systems on individual outcomes, there could be myriad other factors that are more proximal and more closely related to whether any one individual applies for, let alone receives, a HISA award. Indeed, a low overall adjusted model R² indicates that there is considerable variability in county-level HISA utilization rate that was not accounted for by the current model; this further speaks to warranted additional study.

More research is needed to understand and account for geographical variation in HISA utilization rate across the US. However, this work serves as an exploratory first step at quantifying and predicting HISA utilization rate at a broad level, with the ultimate goal of increasing access to HMs for veterans with disabilities.

Acknowledgments

This research was supported by grant 15521 from the US Department of Veterans Affairs, Office of Rural Health. Furthermore, the research was supported in part by grant K12 HD055929 from the National Institutes of Health. We want to acknowledge Cheri E. Knecht, Project Coordinator, for her assistance throughout all aspects of our research study and for her thoughtful contributions during the writing of this manuscript.

This article is part of a series of articles on the Home Improvements and Structural Alterations program (HISA), a home modification (HM) program within the Veterans Health Administration (VHA). HISA is a benefit awarded to veterans with disabilities (VWDs) and is instrumental in affording physical accessibility and structural alterations to veterans’ homes.¹ The overarching goals of this project are to describe and understand HISA use by VWDs. Previous work has shown geographical variation in the number of HISA prescriptions across counties in the US (Figure 1).¹ The current work seeks to describe and predict the county-level rates of HISA use. Information about what predicts HISA utilization at the county level is important because it enhances understanding of program utilization at a national level. The long-term goal of the series is to provide knowledge about HM services within VHA to improve community-based independent living of VWDs by increasing awareness and utilization of HM services. 

Background

A health care professional (HCP) approves a HM support award by evaluating the practicality of the support to improve the built environment of a given veteran’s disability.^1,2 Previously we detailed some of the preliminary research into the HISA program, including HISA user demographic and clinical characteristics, types of HMs received, user suggestions for improvement, and geospatial analysis of HISA prescriptions concentration.^1-4

The geospatial analyses of HISA prescriptions revealed clusters of high numbers of HISA users (hot spots) and low numbers of HISA users (cold spots), indicating that HISA is either not prescribed or uniformly used across the US. The previous research prompted investigation into county-level variables that may impact HISA utilization rates. This inquiry focuses on county characteristics associated with HISA use rates, such as measures of clinical care and quality of care (eg, access to health services variables, lack of insurance, preventable hospital stays), physical environment, and sociodemographic characteristics. Clinical care and quality of care measures promote the interaction with HCPs. Moreover, access to health care is an important indicator of health outcomes.^5,6 An individual’s capacity to access health services, such as a HM program, greatly impacts well-being, safety, independence, and health.^2,4 Well-being, safety, independence, and health become compromised if individuals cannot access care, if needed care is lacking in their area, if HCPs are not available, or are unwilling to provide care due to lack of insurance coverage.^7-12 In locations where health care services are minimal due to lack of specialists or health care facilities, the quality of (or access to) care may be compromised, resulting in preventable conditions becoming problematic.^13,14 These conditions may result in unnecessary hospitalizations for conditions that could have been treated during routine care. Financial barriers to care particularly among low-income people and the uninsured have proven detrimental to health.^15,16 On the other hand, preventable hospital stays are a quality of care measure (ie, a proxy for poor quality of care). HISA operates within a health care system; thus, it is imperative to include these measures impacting health. 

In this study, we sought to identify county-level predictors—in particular, county-level proxies for access to care—that may be associated with county-level HISA use. We define HISA utilization rate as the percentage of a county’s VHA patients who have received a HISA award.

Methods

This study used data from the National Prosthetics Patient Database (NPPD), US Department of Veterans Affairs (VA) medical database inpatient and outpatient datasets, VHA Support Service Center (VSSC) data cubes, and the County Health Rankings database (CHRD). First, the study cohort was identified from NPPD users who have obtained a HISA award from fiscal years (FY) 2015 to 2018. Analysis started with FY 2015 following new regulations (38 CFR § 17) governing the operations of the HISA program.² The study cohort was matched with records from NPPD and VA inpatient and outpatient datasets to obtain information about the veterans’ demographic characteristics and their HM characteristics and costs. The number of VHA end-of-year (EOY) patients per county was extracted from the VSSC Current Enrollment Cube, which was used in calculation of the county-level HISA utilization rate.¹⁷ Finally, zip code–based locational data were used to calculate approximate drive time and distance from the HISA user’s approximate location to the facility where they received their HM prescription. Drive times and drive distances were calculated with Esri ArcGIS Pro (v2.6.3) by placing zip code centroid and VHA facilities on a nationwide road network that contains both road speeds and distances.

Calculations

Patient-level data were aggregated up to county-level variables by calculating the sum, mean, or percent per county. HISA user sample characteristics, including sex, race, rurality (urban, rural), marital status, and Class 1 vs Class 2 disability-related eligibility groups, were aggregated to the county level by calculating percentages of HISA users of the given characteristics out of total HISA users in the county. Disability-related eligibility groups (Class 1 vs Class 2 HISA users) determines the maximum lifetime award dollar amount. Specifically, those with service-connected disabilities or those with a ≥ 50% disability rating (regardless of whether or not their disability is service connected) are classified as Class 1 HISA users and are eligible to receive a maximum lifetime award of $6800. Those with a recorded disability that is not connected to their military service, and who have a disability rating of < 50% are classified as Class 2 HISA users and are eligible to receive a lifetime maximum award of $2000.

The county-level number of HISA users was used as the numerator for calculation of county-level HISA utilization rate. Counties with zero HISA users were excluded. The number of EOY VHA patients per county in FY 2018 was divided by 1000 and used as the denominator in the calculation of county-level HISA utilization rate. Thus, the outcome variable is HISA utilization rate per 1000 VHA patients in FY 2018 (HISA utilization rate).

County-Level Variables

County-level variables were downloaded from the 2020 CHRD.^5,6 An explanation of the CHRD model and the factors used in this study are shown in the eAppendix (available at doi: 10.12788/fp.0279).⁶ County-level aggregated HISA user data and the CHRD data were matched using county Federal Information Processing Standards codes. Access to care measures collected from CHRD included percentages uninsured and ratios of population to primary care physicians, dentists, mental health professionals, and other primary care professionals. Other CHRD measures included those for quality of care (rate of preventable hospital stay) and housing quality (percent of households with high housing costs, percent of households with overcrowding, percent of households with lack of kitchen or plumbing, percent of households with severe housing cost burden, percent of homeownership). Of secondary interest was county population rurality, as previous research findings showed the annual average of HISA users who are from rural areas ranged from 30 to 35%.

Analysis Methods

SAS (v9.4), R (v4.0.2), and RStudio (v1.3.1093) were used for data preparation and analysis.¹⁸ Multiple regression analysis was used to predict county-level utilization rate from county-level variables. Sociodemographic characteristics from CHRD and HISA data were included as important control predictors in the regression model, though our focus for this paper are the access to care and housing quality predictors.

Model diagnostics (examination of model residuals, Breusch-Godfrey test, Breusch-Pagan test) revealed significant heteroskedasticity of the model; thus, robust standard errors and associated P values were computed using the R estimatr package (v0.30.2).¹⁹ Some predictor variables of interest (eg, ratio of mental health professionals) were removed during the model building process either due to problems of multicollinearity or excessive missingness that would have resulted in listwise deletion.

Results

County-level HISA utilization rate per 1000 EOY VHA patients ranged from 0.09 to 59.7%, with a 6.6% mean and 5% median (Figure 2). The data were highly positively skewed. The final model included 33 total predictor variables (Table 1). The final regression model was a significantly better predictor of county-level HISA utilization rate than a null model (F[33-2184], 10.18; P < .001). The adjusted model R² showed that the overall model accounted for approximately 23% of variance in county-level HISA utilization rate (Table 2).

Among the primary variables of interest, percent uninsured adults and rate of preventable hospital stays emerged as significant predictors of county-level HISA utilization rate. Specifically, county percentage of uninsured adults was negatively related to county-level HISA utilization rate (b = -8.99, P = .005), indicating that the higher the proportion of uninsured adults—with all other predictors held constant—the lower the HISA utilization rate. Percent uninsured adults ranged from 2.7 to 42.4% across counties, with a mean (SD) of 12.7% (5.8%) and 11.4% median.

Discussion

This study examined whether county-level characteristics, specifically variables for access to care, quality of care, and housing quality, were predictive of a county’s HISA utilization rate. Given that this series of work on the HISA program is (to our knowledge) the first of its kind, and given the exploratory nature of this analysis, we did not have specific predictions for the effects of any one given variable. Nevertheless, some of the results were surprising, and we believe they warrant additional study. In particular, the opposing direction of effects for access to care and quality of care variables were hard to reconcile.

The county percent of uninsured adults (an access to care variable, specifically, a proxy for poor access to care) was negatively associated with county-level HISA utilization rate, whereas the county rate of preventable hospital stays (a quality of care variable, but also potentially an access to care variable, and specifically, proxies for poor quality of care or poor access to care) was positively associated with county-level HISA utilization rate. To describe the relationships more generally, one coefficient in the regression model indicated that the poorer the access to care, the lower the HISA utilization rate (higher percent of uninsured adults predicts lower HISA utilization rate), while another coefficient in the regression model indicated the poorer the quality of and access to care, the higher the HISA utilization rate (higher rate of preventable hospital stays predicts higher HISA utilization rate). Future study is warranted to disentangle and reconcile the various community-level predictors of this service.

Housing quality measures (eg, percent of households with high housing costs, percent of households with overcrowding, percent of households with lack of kitchen or plumbing, percent of households with severe housing cost burden, and percent of homeownership) are important in the consideration of whether a HM will be performed or should be performed. For example, if a person is cost burdened by the amount of expenditure spent in housing there will be little discretionary funds to perform a HM. Individuals who do not own their home may experience complications in obtaining permission from landlords to perform a HM. County-level predictors of housing quality (percent of households with high housing costs, overcrowding, and lack of kitchen or plumbing) were not significantly associated with county-level HISA utilization rate but are also nevertheless relevant to the discussion of home modifications. Of particular interest is the percent of households with lack of kitchen or plumbing variable, which was positively related to county-level HISA utilization rate although not statistically significant. HM elements related to the kitchen (eg, heighten countertop) add to the accessibility of the home allowing for the performing of activities of daily living such as cooking. Between FY 2015 and FY 2018, we discovered 131 prescriptions for kitchen (n = 90) and plumbing (n = 41) HMs, which is a very small proportion of the 30,780 total HMs (there were 24,397 bathroom HMs). The nonsignificant coefficient for this variable may reflect the small number of veterans that obtained these HM.

Limitations

The potentially conflicting direction of effects for a significant access to care variable (percent uninsured adults) and a significant access to care and quality of care variable (preventable hospital stays) are interesting and warrant additional study, but the inability to interpret or explain this apparent inconsistency constitutes a limitation of the current data and analyses presented here. Another limitation is that this analysis uses county-level predictors for what is ultimately an individual-level outcome. It would have been ideal to have both individual- and county-level data to conduct a multilevel analysis; in particular, individual-level data within counties of individuals (both veterans and nonveterans) who did not receive a HISA award (including both those who applied and were denied, and who did not apply) would be highly valuable.

Conclusions

Our continuing research into veterans’ use of HM fills a gap in the literature about the characteristics of HISA users, the impact of county-level variables on the use of HISA, and the geographic distribution and use of HISA within the VHA. While it is important to examine the influence of broader systems on individual outcomes, there could be myriad other factors that are more proximal and more closely related to whether any one individual applies for, let alone receives, a HISA award. Indeed, a low overall adjusted model R² indicates that there is considerable variability in county-level HISA utilization rate that was not accounted for by the current model; this further speaks to warranted additional study.

More research is needed to understand and account for geographical variation in HISA utilization rate across the US. However, this work serves as an exploratory first step at quantifying and predicting HISA utilization rate at a broad level, with the ultimate goal of increasing access to HMs for veterans with disabilities.

Acknowledgments

This research was supported by grant 15521 from the US Department of Veterans Affairs, Office of Rural Health. Furthermore, the research was supported in part by grant K12 HD055929 from the National Institutes of Health. We want to acknowledge Cheri E. Knecht, Project Coordinator, for her assistance throughout all aspects of our research study and for her thoughtful contributions during the writing of this manuscript.

This article is part of a series of articles on the Home Improvements and Structural Alterations program (HISA), a home modification (HM) program within the Veterans Health Administration (VHA). HISA is a benefit awarded to veterans with disabilities (VWDs) and is instrumental in affording physical accessibility and structural alterations to veterans’ homes.¹ The overarching goals of this project are to describe and understand HISA use by VWDs. Previous work has shown geographical variation in the number of HISA prescriptions across counties in the US (Figure 1).¹ The current work seeks to describe and predict the county-level rates of HISA use. Information about what predicts HISA utilization at the county level is important because it enhances understanding of program utilization at a national level. The long-term goal of the series is to provide knowledge about HM services within VHA to improve community-based independent living of VWDs by increasing awareness and utilization of HM services. 

Background

A health care professional (HCP) approves a HM support award by evaluating the practicality of the support to improve the built environment of a given veteran’s disability.^1,2 Previously we detailed some of the preliminary research into the HISA program, including HISA user demographic and clinical characteristics, types of HMs received, user suggestions for improvement, and geospatial analysis of HISA prescriptions concentration.^1-4

The geospatial analyses of HISA prescriptions revealed clusters of high numbers of HISA users (hot spots) and low numbers of HISA users (cold spots), indicating that HISA is either not prescribed or uniformly used across the US. The previous research prompted investigation into county-level variables that may impact HISA utilization rates. This inquiry focuses on county characteristics associated with HISA use rates, such as measures of clinical care and quality of care (eg, access to health services variables, lack of insurance, preventable hospital stays), physical environment, and sociodemographic characteristics. Clinical care and quality of care measures promote the interaction with HCPs. Moreover, access to health care is an important indicator of health outcomes.^5,6 An individual’s capacity to access health services, such as a HM program, greatly impacts well-being, safety, independence, and health.^2,4 Well-being, safety, independence, and health become compromised if individuals cannot access care, if needed care is lacking in their area, if HCPs are not available, or are unwilling to provide care due to lack of insurance coverage.^7-12 In locations where health care services are minimal due to lack of specialists or health care facilities, the quality of (or access to) care may be compromised, resulting in preventable conditions becoming problematic.^13,14 These conditions may result in unnecessary hospitalizations for conditions that could have been treated during routine care. Financial barriers to care particularly among low-income people and the uninsured have proven detrimental to health.^15,16 On the other hand, preventable hospital stays are a quality of care measure (ie, a proxy for poor quality of care). HISA operates within a health care system; thus, it is imperative to include these measures impacting health. 

In this study, we sought to identify county-level predictors—in particular, county-level proxies for access to care—that may be associated with county-level HISA use. We define HISA utilization rate as the percentage of a county’s VHA patients who have received a HISA award.

Methods

This study used data from the National Prosthetics Patient Database (NPPD), US Department of Veterans Affairs (VA) medical database inpatient and outpatient datasets, VHA Support Service Center (VSSC) data cubes, and the County Health Rankings database (CHRD). First, the study cohort was identified from NPPD users who have obtained a HISA award from fiscal years (FY) 2015 to 2018. Analysis started with FY 2015 following new regulations (38 CFR § 17) governing the operations of the HISA program.² The study cohort was matched with records from NPPD and VA inpatient and outpatient datasets to obtain information about the veterans’ demographic characteristics and their HM characteristics and costs. The number of VHA end-of-year (EOY) patients per county was extracted from the VSSC Current Enrollment Cube, which was used in calculation of the county-level HISA utilization rate.¹⁷ Finally, zip code–based locational data were used to calculate approximate drive time and distance from the HISA user’s approximate location to the facility where they received their HM prescription. Drive times and drive distances were calculated with Esri ArcGIS Pro (v2.6.3) by placing zip code centroid and VHA facilities on a nationwide road network that contains both road speeds and distances.

Calculations

Patient-level data were aggregated up to county-level variables by calculating the sum, mean, or percent per county. HISA user sample characteristics, including sex, race, rurality (urban, rural), marital status, and Class 1 vs Class 2 disability-related eligibility groups, were aggregated to the county level by calculating percentages of HISA users of the given characteristics out of total HISA users in the county. Disability-related eligibility groups (Class 1 vs Class 2 HISA users) determines the maximum lifetime award dollar amount. Specifically, those with service-connected disabilities or those with a ≥ 50% disability rating (regardless of whether or not their disability is service connected) are classified as Class 1 HISA users and are eligible to receive a maximum lifetime award of $6800. Those with a recorded disability that is not connected to their military service, and who have a disability rating of < 50% are classified as Class 2 HISA users and are eligible to receive a lifetime maximum award of $2000.

The county-level number of HISA users was used as the numerator for calculation of county-level HISA utilization rate. Counties with zero HISA users were excluded. The number of EOY VHA patients per county in FY 2018 was divided by 1000 and used as the denominator in the calculation of county-level HISA utilization rate. Thus, the outcome variable is HISA utilization rate per 1000 VHA patients in FY 2018 (HISA utilization rate).

County-Level Variables

County-level variables were downloaded from the 2020 CHRD.^5,6 An explanation of the CHRD model and the factors used in this study are shown in the eAppendix (available at doi: 10.12788/fp.0279).⁶ County-level aggregated HISA user data and the CHRD data were matched using county Federal Information Processing Standards codes. Access to care measures collected from CHRD included percentages uninsured and ratios of population to primary care physicians, dentists, mental health professionals, and other primary care professionals. Other CHRD measures included those for quality of care (rate of preventable hospital stay) and housing quality (percent of households with high housing costs, percent of households with overcrowding, percent of households with lack of kitchen or plumbing, percent of households with severe housing cost burden, percent of homeownership). Of secondary interest was county population rurality, as previous research findings showed the annual average of HISA users who are from rural areas ranged from 30 to 35%.

Analysis Methods

SAS (v9.4), R (v4.0.2), and RStudio (v1.3.1093) were used for data preparation and analysis.¹⁸ Multiple regression analysis was used to predict county-level utilization rate from county-level variables. Sociodemographic characteristics from CHRD and HISA data were included as important control predictors in the regression model, though our focus for this paper are the access to care and housing quality predictors.

Model diagnostics (examination of model residuals, Breusch-Godfrey test, Breusch-Pagan test) revealed significant heteroskedasticity of the model; thus, robust standard errors and associated P values were computed using the R estimatr package (v0.30.2).¹⁹ Some predictor variables of interest (eg, ratio of mental health professionals) were removed during the model building process either due to problems of multicollinearity or excessive missingness that would have resulted in listwise deletion.

Results

County-level HISA utilization rate per 1000 EOY VHA patients ranged from 0.09 to 59.7%, with a 6.6% mean and 5% median (Figure 2). The data were highly positively skewed. The final model included 33 total predictor variables (Table 1). The final regression model was a significantly better predictor of county-level HISA utilization rate than a null model (F[33-2184], 10.18; P < .001). The adjusted model R² showed that the overall model accounted for approximately 23% of variance in county-level HISA utilization rate (Table 2).

Among the primary variables of interest, percent uninsured adults and rate of preventable hospital stays emerged as significant predictors of county-level HISA utilization rate. Specifically, county percentage of uninsured adults was negatively related to county-level HISA utilization rate (b = -8.99, P = .005), indicating that the higher the proportion of uninsured adults—with all other predictors held constant—the lower the HISA utilization rate. Percent uninsured adults ranged from 2.7 to 42.4% across counties, with a mean (SD) of 12.7% (5.8%) and 11.4% median.

Discussion

This study examined whether county-level characteristics, specifically variables for access to care, quality of care, and housing quality, were predictive of a county’s HISA utilization rate. Given that this series of work on the HISA program is (to our knowledge) the first of its kind, and given the exploratory nature of this analysis, we did not have specific predictions for the effects of any one given variable. Nevertheless, some of the results were surprising, and we believe they warrant additional study. In particular, the opposing direction of effects for access to care and quality of care variables were hard to reconcile.

The county percent of uninsured adults (an access to care variable, specifically, a proxy for poor access to care) was negatively associated with county-level HISA utilization rate, whereas the county rate of preventable hospital stays (a quality of care variable, but also potentially an access to care variable, and specifically, proxies for poor quality of care or poor access to care) was positively associated with county-level HISA utilization rate. To describe the relationships more generally, one coefficient in the regression model indicated that the poorer the access to care, the lower the HISA utilization rate (higher percent of uninsured adults predicts lower HISA utilization rate), while another coefficient in the regression model indicated the poorer the quality of and access to care, the higher the HISA utilization rate (higher rate of preventable hospital stays predicts higher HISA utilization rate). Future study is warranted to disentangle and reconcile the various community-level predictors of this service.

Housing quality measures (eg, percent of households with high housing costs, percent of households with overcrowding, percent of households with lack of kitchen or plumbing, percent of households with severe housing cost burden, and percent of homeownership) are important in the consideration of whether a HM will be performed or should be performed. For example, if a person is cost burdened by the amount of expenditure spent in housing there will be little discretionary funds to perform a HM. Individuals who do not own their home may experience complications in obtaining permission from landlords to perform a HM. County-level predictors of housing quality (percent of households with high housing costs, overcrowding, and lack of kitchen or plumbing) were not significantly associated with county-level HISA utilization rate but are also nevertheless relevant to the discussion of home modifications. Of particular interest is the percent of households with lack of kitchen or plumbing variable, which was positively related to county-level HISA utilization rate although not statistically significant. HM elements related to the kitchen (eg, heighten countertop) add to the accessibility of the home allowing for the performing of activities of daily living such as cooking. Between FY 2015 and FY 2018, we discovered 131 prescriptions for kitchen (n = 90) and plumbing (n = 41) HMs, which is a very small proportion of the 30,780 total HMs (there were 24,397 bathroom HMs). The nonsignificant coefficient for this variable may reflect the small number of veterans that obtained these HM.

Limitations

The potentially conflicting direction of effects for a significant access to care variable (percent uninsured adults) and a significant access to care and quality of care variable (preventable hospital stays) are interesting and warrant additional study, but the inability to interpret or explain this apparent inconsistency constitutes a limitation of the current data and analyses presented here. Another limitation is that this analysis uses county-level predictors for what is ultimately an individual-level outcome. It would have been ideal to have both individual- and county-level data to conduct a multilevel analysis; in particular, individual-level data within counties of individuals (both veterans and nonveterans) who did not receive a HISA award (including both those who applied and were denied, and who did not apply) would be highly valuable.

Conclusions

Our continuing research into veterans’ use of HM fills a gap in the literature about the characteristics of HISA users, the impact of county-level variables on the use of HISA, and the geographic distribution and use of HISA within the VHA. While it is important to examine the influence of broader systems on individual outcomes, there could be myriad other factors that are more proximal and more closely related to whether any one individual applies for, let alone receives, a HISA award. Indeed, a low overall adjusted model R² indicates that there is considerable variability in county-level HISA utilization rate that was not accounted for by the current model; this further speaks to warranted additional study.

More research is needed to understand and account for geographical variation in HISA utilization rate across the US. However, this work serves as an exploratory first step at quantifying and predicting HISA utilization rate at a broad level, with the ultimate goal of increasing access to HMs for veterans with disabilities.

Acknowledgments

This research was supported by grant 15521 from the US Department of Veterans Affairs, Office of Rural Health. Furthermore, the research was supported in part by grant K12 HD055929 from the National Institutes of Health. We want to acknowledge Cheri E. Knecht, Project Coordinator, for her assistance throughout all aspects of our research study and for her thoughtful contributions during the writing of this manuscript.

Synthetic opioid use in the United States increased by almost 800% over 7 years, new research shows.

The results of a national urine drug test (UDT) study come as the United States is reporting a record-high number of drug overdose deaths – more than 80% of which involved fentanyl or other synthetic opioids and prompting a push for better surveillance models.

Researchers found that UDTs can be used to accurately identify which drugs are circulating in a community, revealing in just a matter of days critically important drug use trends that current surveillance methods take a month or longer to report.

The faster turnaround could potentially allow clinicians and public health officials to be more proactive with targeted overdose prevention and harm-reduction strategies such as distribution of naloxone and fentanyl test strips.

“We’re talking about trying to come up with an early-warning system,” study author Steven Passik, PhD, vice president for scientific affairs for Millennium Health, San Diego, Calif., told this news organization. “We’re trying to find out if we can let people in the harm reduction and treatment space know about what might be coming weeks or a month or more in advance so that some interventions could be marshaled.”

The study was published online in JAMA Network Open.
 

Call for better surveillance

More than 100,000 people in the United States died of an unintended drug overdose in 2021, a record high and a 15% increase over 2020 figures, which also set a record.

Part of the federal government’s plan to address the crisis includes strengthening epidemiologic efforts by better collection and mining of public health surveillance data.

Sources currently used to detect drug use trends include mortality data, poison control centers, emergency departments, electronic health records, and crime laboratories. But analysis of these sources can take weeks or more.

“One of the real challenges in addressing and reducing overdose deaths has been the relative lack of accessible real-time data that can support agile responses to deployment of resources in a specific geographic region,” study coauthor Rebecca Jackson, MD, professor and associate dean for clinical and translational research at Ohio State University in Columbus, said in an interview.

Ohio State researchers partnered with scientists at Millennium Health, one of the largest urine test labs in the United States, on a cross-sectional study to find out if UDTs could be an accurate and speedier tool for drug surveillance.

They analyzed 500,000 unique urine samples from patients in substance use disorder (SUD) treatment facilities in all 50 states from 2013 to 2020, comparing levels of cocaine, heroin, methamphetamine, synthetic opioids, and other opioids found in the samples to levels of the same drugs from overdose mortality data at the national, state, and county level from the National Vital Statistics System.

On a national level, synthetic opioids and methamphetamine were highly correlated with overdose mortality data (Spearman’s rho = .96 for both). When synthetic opioids were coinvolved, methamphetamine (rho = .98), heroin (rho = .78), cocaine (rho = .94), and other opioids (rho = .83) were also highly correlated with overdose mortality data.

Similar correlations were found when examining state-level data from 24 states and at the county level upon analysis of 19 counties in Ohio.
 

A changing landscape

Researchers said the strong correlation between overdose deaths and UDT results for synthetic opioids and methamphetamine are likely explained by the drugs’ availability and lethality.

“The most important thing that we found was just the strength of the correlation, which goes right to the heart of why we considered correlation to be so critical,” lead author Penn Whitley, senior director of bioinformatics for Millennium Health, told this news organization. “We needed to demonstrate that there was a strong correlation of just the UDT positivity rates with mortality – in this case, fatal drug overdose rates – as a steppingstone to build out tools that could utilize UDT as a real-time data source.”

While the main goal of the study was to establish correlation between UDT results and national mortality data, the study also offers a view of a changing landscape in the opioid epidemic.

Overall, UDT positivity for total synthetic opioids increased from 2.1% in 2013 to 19.1% in 2020 (a 792.5% increase). Positivity rates for all included drug categories increased when synthetic opioids were present.

However, in the absence of synthetic opioids, UDT positivity decreased for almost all drug categories from 2013 to 2020 (from 7.7% to 4.7% for cocaine; 3.9% to 1.6% for heroin; 20.5% to 6.9% for other opioids).

Only methamphetamine positivity increased with or without involvement of synthetic opioids. With synthetic opioids, meth positivity rose from 0.1% in 2013 to 7.9% in 2020. Without them, meth positivity rates still rose, from 2.1% in 2013 to 13.1% in 2020.

The findings track with an earlier study showing methamphetamine-involved overdose deaths rose sharply between 2011 and 2018.

“The data from this manuscript support that the opioid epidemic is transitioning from an opioid epidemic to a polysubstance epidemic where illicit synthetic opioids, largely fentanyl, in combination with other substances are now responsible for upwards of 80% of OD deaths,” Dr. Jackson said.

In an accompanying editorial Jeffrey Brent, MD, PhD, clinical professor in internal medicine at the University of Colorado at Denver, Aurora, and Stephanie T. Weiss, MD, PhD, staff clinician in the Translational Addiction Medicine Branch at the National Institute on Drug Abuse, Baltimore, note that as new agents emerge, different harm-reduction strategies will be needed, adding that having a real-time tool to identify the trends will be key to preventing deaths.

“Surveillance systems are an integral component of reducing morbidity and mortality associated with illicit drug use. On local, regional, and national levels, information of this type is needed to most efficiently allocate limited resources to maximize benefit and save lives,” Dr. Brent and Dr. Weiss write.

The study was funded by Millennium Health and the National Center for Advancing Translational Sciences. Full disclosures are included in the original articles, but no sources reported conflicts related to the study.

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

Synthetic opioid use in the United States increased by almost 800% over 7 years, new research shows.

The results of a national urine drug test (UDT) study come as the United States is reporting a record-high number of drug overdose deaths – more than 80% of which involved fentanyl or other synthetic opioids and prompting a push for better surveillance models.

Researchers found that UDTs can be used to accurately identify which drugs are circulating in a community, revealing in just a matter of days critically important drug use trends that current surveillance methods take a month or longer to report.

The faster turnaround could potentially allow clinicians and public health officials to be more proactive with targeted overdose prevention and harm-reduction strategies such as distribution of naloxone and fentanyl test strips.

“We’re talking about trying to come up with an early-warning system,” study author Steven Passik, PhD, vice president for scientific affairs for Millennium Health, San Diego, Calif., told this news organization. “We’re trying to find out if we can let people in the harm reduction and treatment space know about what might be coming weeks or a month or more in advance so that some interventions could be marshaled.”

The study was published online in JAMA Network Open.
 

Call for better surveillance

More than 100,000 people in the United States died of an unintended drug overdose in 2021, a record high and a 15% increase over 2020 figures, which also set a record.

Part of the federal government’s plan to address the crisis includes strengthening epidemiologic efforts by better collection and mining of public health surveillance data.

Sources currently used to detect drug use trends include mortality data, poison control centers, emergency departments, electronic health records, and crime laboratories. But analysis of these sources can take weeks or more.

“One of the real challenges in addressing and reducing overdose deaths has been the relative lack of accessible real-time data that can support agile responses to deployment of resources in a specific geographic region,” study coauthor Rebecca Jackson, MD, professor and associate dean for clinical and translational research at Ohio State University in Columbus, said in an interview.

Ohio State researchers partnered with scientists at Millennium Health, one of the largest urine test labs in the United States, on a cross-sectional study to find out if UDTs could be an accurate and speedier tool for drug surveillance.

They analyzed 500,000 unique urine samples from patients in substance use disorder (SUD) treatment facilities in all 50 states from 2013 to 2020, comparing levels of cocaine, heroin, methamphetamine, synthetic opioids, and other opioids found in the samples to levels of the same drugs from overdose mortality data at the national, state, and county level from the National Vital Statistics System.

On a national level, synthetic opioids and methamphetamine were highly correlated with overdose mortality data (Spearman’s rho = .96 for both). When synthetic opioids were coinvolved, methamphetamine (rho = .98), heroin (rho = .78), cocaine (rho = .94), and other opioids (rho = .83) were also highly correlated with overdose mortality data.

Similar correlations were found when examining state-level data from 24 states and at the county level upon analysis of 19 counties in Ohio.
 

A changing landscape

Researchers said the strong correlation between overdose deaths and UDT results for synthetic opioids and methamphetamine are likely explained by the drugs’ availability and lethality.

“The most important thing that we found was just the strength of the correlation, which goes right to the heart of why we considered correlation to be so critical,” lead author Penn Whitley, senior director of bioinformatics for Millennium Health, told this news organization. “We needed to demonstrate that there was a strong correlation of just the UDT positivity rates with mortality – in this case, fatal drug overdose rates – as a steppingstone to build out tools that could utilize UDT as a real-time data source.”

While the main goal of the study was to establish correlation between UDT results and national mortality data, the study also offers a view of a changing landscape in the opioid epidemic.

Overall, UDT positivity for total synthetic opioids increased from 2.1% in 2013 to 19.1% in 2020 (a 792.5% increase). Positivity rates for all included drug categories increased when synthetic opioids were present.

However, in the absence of synthetic opioids, UDT positivity decreased for almost all drug categories from 2013 to 2020 (from 7.7% to 4.7% for cocaine; 3.9% to 1.6% for heroin; 20.5% to 6.9% for other opioids).

Only methamphetamine positivity increased with or without involvement of synthetic opioids. With synthetic opioids, meth positivity rose from 0.1% in 2013 to 7.9% in 2020. Without them, meth positivity rates still rose, from 2.1% in 2013 to 13.1% in 2020.

The findings track with an earlier study showing methamphetamine-involved overdose deaths rose sharply between 2011 and 2018.

“The data from this manuscript support that the opioid epidemic is transitioning from an opioid epidemic to a polysubstance epidemic where illicit synthetic opioids, largely fentanyl, in combination with other substances are now responsible for upwards of 80% of OD deaths,” Dr. Jackson said.

In an accompanying editorial Jeffrey Brent, MD, PhD, clinical professor in internal medicine at the University of Colorado at Denver, Aurora, and Stephanie T. Weiss, MD, PhD, staff clinician in the Translational Addiction Medicine Branch at the National Institute on Drug Abuse, Baltimore, note that as new agents emerge, different harm-reduction strategies will be needed, adding that having a real-time tool to identify the trends will be key to preventing deaths.

“Surveillance systems are an integral component of reducing morbidity and mortality associated with illicit drug use. On local, regional, and national levels, information of this type is needed to most efficiently allocate limited resources to maximize benefit and save lives,” Dr. Brent and Dr. Weiss write.

The study was funded by Millennium Health and the National Center for Advancing Translational Sciences. Full disclosures are included in the original articles, but no sources reported conflicts related to the study.

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

Synthetic opioid use in the United States increased by almost 800% over 7 years, new research shows.

The results of a national urine drug test (UDT) study come as the United States is reporting a record-high number of drug overdose deaths – more than 80% of which involved fentanyl or other synthetic opioids and prompting a push for better surveillance models.

Researchers found that UDTs can be used to accurately identify which drugs are circulating in a community, revealing in just a matter of days critically important drug use trends that current surveillance methods take a month or longer to report.

The faster turnaround could potentially allow clinicians and public health officials to be more proactive with targeted overdose prevention and harm-reduction strategies such as distribution of naloxone and fentanyl test strips.

“We’re talking about trying to come up with an early-warning system,” study author Steven Passik, PhD, vice president for scientific affairs for Millennium Health, San Diego, Calif., told this news organization. “We’re trying to find out if we can let people in the harm reduction and treatment space know about what might be coming weeks or a month or more in advance so that some interventions could be marshaled.”

The study was published online in JAMA Network Open.
 

Call for better surveillance

More than 100,000 people in the United States died of an unintended drug overdose in 2021, a record high and a 15% increase over 2020 figures, which also set a record.

Part of the federal government’s plan to address the crisis includes strengthening epidemiologic efforts by better collection and mining of public health surveillance data.

Sources currently used to detect drug use trends include mortality data, poison control centers, emergency departments, electronic health records, and crime laboratories. But analysis of these sources can take weeks or more.

“One of the real challenges in addressing and reducing overdose deaths has been the relative lack of accessible real-time data that can support agile responses to deployment of resources in a specific geographic region,” study coauthor Rebecca Jackson, MD, professor and associate dean for clinical and translational research at Ohio State University in Columbus, said in an interview.

Ohio State researchers partnered with scientists at Millennium Health, one of the largest urine test labs in the United States, on a cross-sectional study to find out if UDTs could be an accurate and speedier tool for drug surveillance.

They analyzed 500,000 unique urine samples from patients in substance use disorder (SUD) treatment facilities in all 50 states from 2013 to 2020, comparing levels of cocaine, heroin, methamphetamine, synthetic opioids, and other opioids found in the samples to levels of the same drugs from overdose mortality data at the national, state, and county level from the National Vital Statistics System.

On a national level, synthetic opioids and methamphetamine were highly correlated with overdose mortality data (Spearman’s rho = .96 for both). When synthetic opioids were coinvolved, methamphetamine (rho = .98), heroin (rho = .78), cocaine (rho = .94), and other opioids (rho = .83) were also highly correlated with overdose mortality data.

Similar correlations were found when examining state-level data from 24 states and at the county level upon analysis of 19 counties in Ohio.
 

A changing landscape

Researchers said the strong correlation between overdose deaths and UDT results for synthetic opioids and methamphetamine are likely explained by the drugs’ availability and lethality.

“The most important thing that we found was just the strength of the correlation, which goes right to the heart of why we considered correlation to be so critical,” lead author Penn Whitley, senior director of bioinformatics for Millennium Health, told this news organization. “We needed to demonstrate that there was a strong correlation of just the UDT positivity rates with mortality – in this case, fatal drug overdose rates – as a steppingstone to build out tools that could utilize UDT as a real-time data source.”

While the main goal of the study was to establish correlation between UDT results and national mortality data, the study also offers a view of a changing landscape in the opioid epidemic.

Overall, UDT positivity for total synthetic opioids increased from 2.1% in 2013 to 19.1% in 2020 (a 792.5% increase). Positivity rates for all included drug categories increased when synthetic opioids were present.

However, in the absence of synthetic opioids, UDT positivity decreased for almost all drug categories from 2013 to 2020 (from 7.7% to 4.7% for cocaine; 3.9% to 1.6% for heroin; 20.5% to 6.9% for other opioids).

Only methamphetamine positivity increased with or without involvement of synthetic opioids. With synthetic opioids, meth positivity rose from 0.1% in 2013 to 7.9% in 2020. Without them, meth positivity rates still rose, from 2.1% in 2013 to 13.1% in 2020.

The findings track with an earlier study showing methamphetamine-involved overdose deaths rose sharply between 2011 and 2018.

“The data from this manuscript support that the opioid epidemic is transitioning from an opioid epidemic to a polysubstance epidemic where illicit synthetic opioids, largely fentanyl, in combination with other substances are now responsible for upwards of 80% of OD deaths,” Dr. Jackson said.

In an accompanying editorial Jeffrey Brent, MD, PhD, clinical professor in internal medicine at the University of Colorado at Denver, Aurora, and Stephanie T. Weiss, MD, PhD, staff clinician in the Translational Addiction Medicine Branch at the National Institute on Drug Abuse, Baltimore, note that as new agents emerge, different harm-reduction strategies will be needed, adding that having a real-time tool to identify the trends will be key to preventing deaths.

“Surveillance systems are an integral component of reducing morbidity and mortality associated with illicit drug use. On local, regional, and national levels, information of this type is needed to most efficiently allocate limited resources to maximize benefit and save lives,” Dr. Brent and Dr. Weiss write.

The study was funded by Millennium Health and the National Center for Advancing Translational Sciences. Full disclosures are included in the original articles, but no sources reported conflicts related to the study.

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

Schools are intended to be a safe place to acquire knowledge, try out ideas, practice socializing, and build a foundation for adulthood. Many schools fulfill this mission for most children, but for children at both extremes of ability their school experience does not suffice.

When asked, “If you had the choice, would you rather stay home or go to school?” my patients almost universally prefer school. They all know that school is where they should be; they want to be normal, accepted by peers, getting ready for the world’s coming demands, and validation that they will make it as adults. Endorsement otherwise is a warning sign.

When such important tasks of childhood are thwarted children may despair, withdraw, give up, or a small number become furious. These may profoundly resent the children who are experiencing success when they could not. They may hate the teachers and the place where they experienced failure and humiliation. Lack of a positive connection to school characterizes children who are violent toward schools as well as those who drop out.

Schools may fail to support the basic needs of children for many reasons. Schools may avoid physical violence but fail to protect the children’s self-esteem. I have heard stories of teachers calling on children to perform who are clearly struggling or shy, insulting incorrect answers, calling names, putting names on the board, reading out failed grades, posting grades publicly, even allowing peers to mock students. Teachers may deny or disregard parent complaints, or even worsen treatment of the child. Although children may at times falsify complaints, children’s and parents’ reports must be taken seriously and remain anonymous. When we hear of such toxic situations for our patients, we can get details and contact school administrators without naming the child, as often the family feels they can’t. Repeated humiliation may require not only remediation, but consequences. We can advocate for a change in classroom or request a 504 Plan if emotional health is affected.

All children learn best and experience success and even joy when the tasks they face are at or slightly beyond their skill level. But with the wide range of abilities, especially for boys, education may need to be individualized. This is very difficult in larger classrooms with fewer resources, too few adult helpers, inexperienced teachers, or high levels of student misbehavior. Basing teacher promotion mainly on standardized test results makes individualizing instruction even less likely. Smaller class size is better; even the recommended (less than 20) or regulated (less than 30) class sizes are associated with suboptimal achievement, compared with smaller ones. Some ways to attain smaller class size include split days or alternate-day sessions, although these also have disadvantages.

While we can advocate for these changes, we can also encourage parents to promote academic skills by talking to and reading to their children of all ages, trying Reach Out and Read for young children, providing counting games, board games, and math songs! Besides screening for attention-deficit/hyperactivity disorder, we can use standard paragraphs and math problems (for example, WRAT, Einstein) to check skills when performance is low or behavior is a problem the school denies. When concerned, we can write letters for parents to sign requesting testing and an individualized education plan to determine need for tutoring or special education.

While Federal legislation requiring the “least restrictive environment” for education was intended to avoid sidelining differently able children, some can’t learn in a regular class. Conversely, if instruction in a special class is adjusted to the child with the lowest skills, minimal learning may occur for others. Although we can speak with the teacher about “this child’s abilities among those in his class” we can first suggest that the parent visit class to observe. Outside tutoring or home schooling may help a child move up to a regular class.

Sometimes a child’s learning is hampered by classrooms with numerous children misbehaving; this is also a reason for resentment. We can inform school administrators about methods such as The Good Behavior Game (paxis.org) that can improve behavior and connection for the whole class.

While a social “pecking order” is universal, it is unacceptable for children to be allowed to humiliate or hurt a peer, or damage their reputation. While this moral teaching should occur at home, it needs to continue at school where peers are forced into groups they did not choose. Screening for bullying at pediatric visits is now a universal recommendation as 30% report being bullied. We need to ask all children about “mean kids in school” or gang involvement for older children.

Parents can support their children experiencing cyberbullying and switch them to a “dumb phone” with no texting option, limited phone time, or no phone at all. Policies against bullying coming from school administrators are most effective but we can inform schools about the STOPit app for children to report bullying anonymously as well as education for students to stand together against a bully (stopbullying.gov). A Lunch Bunch for younger children or a buddy system for older ones can be requested to help them make friends.

With diverse child aptitudes, schools need to offer students alternative opportunities for self-expression and contribution. We can ask about a child’s strengths and suggest related extracurriculars activities in school or outside, including volunteering. Participation on teams or in clubs must not be blocked for those with poor grades. Perhaps tying participation to tutoring would satisfy the school’s desire to motivate instead. Parents can be encouraged to advocate for music, art, and drama classes – programs that are often victims of budget cuts – that can create the essential school connection.

Students in many areas lack access to classes in trades early enough in their education. The requirements for English or math may be out of reach and result in students dropping out before trade classes are an option. We may identify our patients who may do better with a trade education and advise families to request transfer to a high school offering this.

The best connection a child can have to a school is an adult who values them. The child may identify a preferred teacher to us so that we, or the parent, can call to ask them to provide special attention. Facilitating times for students to get to know teachers may require alteration in bus schedules, lunch times, study halls, or breaks, or keeping the school open longer outside class hours. While more mental health providers are clearly needed, sometimes it is the groundskeeper, the secretary, or the lunch helper who can make the best connection with a child.

As pediatricians, we must listen to struggling youth, acknowledge their pain, and model this empathy for their parents who may be obsessing over grades. Problem-solving about how to get accommodations, informal or formal, can inspire hope. We can coach parents and youth to meet respectfully with the school about issues to avoid labeling the child as a problem.

As pediatricians, our recommendations for school funding and policies may carry extra weight. We may share ideas through talks at PTA meetings, serve on school boards, or endorse leaders planning greater resources for schools to optimize each child’s experience and connection to school.
 

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS (www.CHADIS.com). She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at [email protected].

Schools are intended to be a safe place to acquire knowledge, try out ideas, practice socializing, and build a foundation for adulthood. Many schools fulfill this mission for most children, but for children at both extremes of ability their school experience does not suffice.

When asked, “If you had the choice, would you rather stay home or go to school?” my patients almost universally prefer school. They all know that school is where they should be; they want to be normal, accepted by peers, getting ready for the world’s coming demands, and validation that they will make it as adults. Endorsement otherwise is a warning sign.

When such important tasks of childhood are thwarted children may despair, withdraw, give up, or a small number become furious. These may profoundly resent the children who are experiencing success when they could not. They may hate the teachers and the place where they experienced failure and humiliation. Lack of a positive connection to school characterizes children who are violent toward schools as well as those who drop out.

Schools may fail to support the basic needs of children for many reasons. Schools may avoid physical violence but fail to protect the children’s self-esteem. I have heard stories of teachers calling on children to perform who are clearly struggling or shy, insulting incorrect answers, calling names, putting names on the board, reading out failed grades, posting grades publicly, even allowing peers to mock students. Teachers may deny or disregard parent complaints, or even worsen treatment of the child. Although children may at times falsify complaints, children’s and parents’ reports must be taken seriously and remain anonymous. When we hear of such toxic situations for our patients, we can get details and contact school administrators without naming the child, as often the family feels they can’t. Repeated humiliation may require not only remediation, but consequences. We can advocate for a change in classroom or request a 504 Plan if emotional health is affected.

All children learn best and experience success and even joy when the tasks they face are at or slightly beyond their skill level. But with the wide range of abilities, especially for boys, education may need to be individualized. This is very difficult in larger classrooms with fewer resources, too few adult helpers, inexperienced teachers, or high levels of student misbehavior. Basing teacher promotion mainly on standardized test results makes individualizing instruction even less likely. Smaller class size is better; even the recommended (less than 20) or regulated (less than 30) class sizes are associated with suboptimal achievement, compared with smaller ones. Some ways to attain smaller class size include split days or alternate-day sessions, although these also have disadvantages.

While we can advocate for these changes, we can also encourage parents to promote academic skills by talking to and reading to their children of all ages, trying Reach Out and Read for young children, providing counting games, board games, and math songs! Besides screening for attention-deficit/hyperactivity disorder, we can use standard paragraphs and math problems (for example, WRAT, Einstein) to check skills when performance is low or behavior is a problem the school denies. When concerned, we can write letters for parents to sign requesting testing and an individualized education plan to determine need for tutoring or special education.

While Federal legislation requiring the “least restrictive environment” for education was intended to avoid sidelining differently able children, some can’t learn in a regular class. Conversely, if instruction in a special class is adjusted to the child with the lowest skills, minimal learning may occur for others. Although we can speak with the teacher about “this child’s abilities among those in his class” we can first suggest that the parent visit class to observe. Outside tutoring or home schooling may help a child move up to a regular class.

Sometimes a child’s learning is hampered by classrooms with numerous children misbehaving; this is also a reason for resentment. We can inform school administrators about methods such as The Good Behavior Game (paxis.org) that can improve behavior and connection for the whole class.

While a social “pecking order” is universal, it is unacceptable for children to be allowed to humiliate or hurt a peer, or damage their reputation. While this moral teaching should occur at home, it needs to continue at school where peers are forced into groups they did not choose. Screening for bullying at pediatric visits is now a universal recommendation as 30% report being bullied. We need to ask all children about “mean kids in school” or gang involvement for older children.

Parents can support their children experiencing cyberbullying and switch them to a “dumb phone” with no texting option, limited phone time, or no phone at all. Policies against bullying coming from school administrators are most effective but we can inform schools about the STOPit app for children to report bullying anonymously as well as education for students to stand together against a bully (stopbullying.gov). A Lunch Bunch for younger children or a buddy system for older ones can be requested to help them make friends.

With diverse child aptitudes, schools need to offer students alternative opportunities for self-expression and contribution. We can ask about a child’s strengths and suggest related extracurriculars activities in school or outside, including volunteering. Participation on teams or in clubs must not be blocked for those with poor grades. Perhaps tying participation to tutoring would satisfy the school’s desire to motivate instead. Parents can be encouraged to advocate for music, art, and drama classes – programs that are often victims of budget cuts – that can create the essential school connection.

Students in many areas lack access to classes in trades early enough in their education. The requirements for English or math may be out of reach and result in students dropping out before trade classes are an option. We may identify our patients who may do better with a trade education and advise families to request transfer to a high school offering this.

The best connection a child can have to a school is an adult who values them. The child may identify a preferred teacher to us so that we, or the parent, can call to ask them to provide special attention. Facilitating times for students to get to know teachers may require alteration in bus schedules, lunch times, study halls, or breaks, or keeping the school open longer outside class hours. While more mental health providers are clearly needed, sometimes it is the groundskeeper, the secretary, or the lunch helper who can make the best connection with a child.

As pediatricians, we must listen to struggling youth, acknowledge their pain, and model this empathy for their parents who may be obsessing over grades. Problem-solving about how to get accommodations, informal or formal, can inspire hope. We can coach parents and youth to meet respectfully with the school about issues to avoid labeling the child as a problem.

As pediatricians, our recommendations for school funding and policies may carry extra weight. We may share ideas through talks at PTA meetings, serve on school boards, or endorse leaders planning greater resources for schools to optimize each child’s experience and connection to school.
 

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS (www.CHADIS.com). She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at [email protected].

Schools are intended to be a safe place to acquire knowledge, try out ideas, practice socializing, and build a foundation for adulthood. Many schools fulfill this mission for most children, but for children at both extremes of ability their school experience does not suffice.

When asked, “If you had the choice, would you rather stay home or go to school?” my patients almost universally prefer school. They all know that school is where they should be; they want to be normal, accepted by peers, getting ready for the world’s coming demands, and validation that they will make it as adults. Endorsement otherwise is a warning sign.

When such important tasks of childhood are thwarted children may despair, withdraw, give up, or a small number become furious. These may profoundly resent the children who are experiencing success when they could not. They may hate the teachers and the place where they experienced failure and humiliation. Lack of a positive connection to school characterizes children who are violent toward schools as well as those who drop out.

Schools may fail to support the basic needs of children for many reasons. Schools may avoid physical violence but fail to protect the children’s self-esteem. I have heard stories of teachers calling on children to perform who are clearly struggling or shy, insulting incorrect answers, calling names, putting names on the board, reading out failed grades, posting grades publicly, even allowing peers to mock students. Teachers may deny or disregard parent complaints, or even worsen treatment of the child. Although children may at times falsify complaints, children’s and parents’ reports must be taken seriously and remain anonymous. When we hear of such toxic situations for our patients, we can get details and contact school administrators without naming the child, as often the family feels they can’t. Repeated humiliation may require not only remediation, but consequences. We can advocate for a change in classroom or request a 504 Plan if emotional health is affected.

All children learn best and experience success and even joy when the tasks they face are at or slightly beyond their skill level. But with the wide range of abilities, especially for boys, education may need to be individualized. This is very difficult in larger classrooms with fewer resources, too few adult helpers, inexperienced teachers, or high levels of student misbehavior. Basing teacher promotion mainly on standardized test results makes individualizing instruction even less likely. Smaller class size is better; even the recommended (less than 20) or regulated (less than 30) class sizes are associated with suboptimal achievement, compared with smaller ones. Some ways to attain smaller class size include split days or alternate-day sessions, although these also have disadvantages.

While we can advocate for these changes, we can also encourage parents to promote academic skills by talking to and reading to their children of all ages, trying Reach Out and Read for young children, providing counting games, board games, and math songs! Besides screening for attention-deficit/hyperactivity disorder, we can use standard paragraphs and math problems (for example, WRAT, Einstein) to check skills when performance is low or behavior is a problem the school denies. When concerned, we can write letters for parents to sign requesting testing and an individualized education plan to determine need for tutoring or special education.

While Federal legislation requiring the “least restrictive environment” for education was intended to avoid sidelining differently able children, some can’t learn in a regular class. Conversely, if instruction in a special class is adjusted to the child with the lowest skills, minimal learning may occur for others. Although we can speak with the teacher about “this child’s abilities among those in his class” we can first suggest that the parent visit class to observe. Outside tutoring or home schooling may help a child move up to a regular class.

Sometimes a child’s learning is hampered by classrooms with numerous children misbehaving; this is also a reason for resentment. We can inform school administrators about methods such as The Good Behavior Game (paxis.org) that can improve behavior and connection for the whole class.

While a social “pecking order” is universal, it is unacceptable for children to be allowed to humiliate or hurt a peer, or damage their reputation. While this moral teaching should occur at home, it needs to continue at school where peers are forced into groups they did not choose. Screening for bullying at pediatric visits is now a universal recommendation as 30% report being bullied. We need to ask all children about “mean kids in school” or gang involvement for older children.

Parents can support their children experiencing cyberbullying and switch them to a “dumb phone” with no texting option, limited phone time, or no phone at all. Policies against bullying coming from school administrators are most effective but we can inform schools about the STOPit app for children to report bullying anonymously as well as education for students to stand together against a bully (stopbullying.gov). A Lunch Bunch for younger children or a buddy system for older ones can be requested to help them make friends.

With diverse child aptitudes, schools need to offer students alternative opportunities for self-expression and contribution. We can ask about a child’s strengths and suggest related extracurriculars activities in school or outside, including volunteering. Participation on teams or in clubs must not be blocked for those with poor grades. Perhaps tying participation to tutoring would satisfy the school’s desire to motivate instead. Parents can be encouraged to advocate for music, art, and drama classes – programs that are often victims of budget cuts – that can create the essential school connection.

Students in many areas lack access to classes in trades early enough in their education. The requirements for English or math may be out of reach and result in students dropping out before trade classes are an option. We may identify our patients who may do better with a trade education and advise families to request transfer to a high school offering this.

The best connection a child can have to a school is an adult who values them. The child may identify a preferred teacher to us so that we, or the parent, can call to ask them to provide special attention. Facilitating times for students to get to know teachers may require alteration in bus schedules, lunch times, study halls, or breaks, or keeping the school open longer outside class hours. While more mental health providers are clearly needed, sometimes it is the groundskeeper, the secretary, or the lunch helper who can make the best connection with a child.

As pediatricians, we must listen to struggling youth, acknowledge their pain, and model this empathy for their parents who may be obsessing over grades. Problem-solving about how to get accommodations, informal or formal, can inspire hope. We can coach parents and youth to meet respectfully with the school about issues to avoid labeling the child as a problem.

As pediatricians, our recommendations for school funding and policies may carry extra weight. We may share ideas through talks at PTA meetings, serve on school boards, or endorse leaders planning greater resources for schools to optimize each child’s experience and connection to school.
 

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS (www.CHADIS.com). She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at [email protected].