PHILADELPHIA – The prescribing, counseling, and use of hormone therapy (HT) to treat menopausal symptoms is substantially more common among white women than among Black women, according to a review of published studies presented at the annual meeting of the Menopause Society (formerly The North American Menopause Society).

“Gaps in treatment can be used to inform health care providers about menopausal HT prescribing disparities, with the goal of improving equitable and advanced patient care among disadvantaged populations,” wrote Danette Conklin, PhD, an assistant professor of psychiatry and reproductive biology at Case Western Reserve University, Cleveland, and a psychologist at University Hospitals Cleveland Medical Center; Sally MacPhedran, MD, an associate professor of reproductive biology at Case Western Reserve University and an ob.gyn at MetroHealth Medical Center, also in Cleveland; and their colleagues.

The researchers combed through PubMed, CINAHL, Cochrane Library, Web of Science and PsychInfo databases to identify all studies conducted in the United States since 1940 that contained data on patient demographics and prescribing patterns for hormone therapy to treat menopausal symptoms. In addition to excluding men, children, teens, trans men, and women who had contraindications for HT, the investigators excluded randomized clinical trials so that prescribing patterns would not be based on protocols or RCT participatory criteria.

The researchers identified 20 studies, ranging from 1973 through 2015, including 9 national studies and the others across different U.S. regions. They then analyzed differences in HT prescribing according to age, race/ethnicity, education, income, insurance type, body mass index, and mental health, including alcohol or substance use.

Seven of the studies assessed HT use based on patient surveys, seven used medical or medication records showing an HT prescription, two studies used insurance claims to show an HT prescription, and one study surveyed patients about whether they received an HT prescription. Another four studies used surveys that asked patients whether they received HT counseling but did not indicate if the patients received a prescription.

Half of the studies showed racial disparities in HT prescribing. In all of them, Black women used or were prescribed or counseled on using HT less than white, Hispanic, or Asian women. White women had greater use, prescribing, or counseling than all other races/ethnicities except one study in which Hispanic women were prescribed vaginal estrogen more often than white women.

Six of the studies showed education disparities in which menopausal women with lower education levels used less HT or were prescribed or counseled on HT less than women with higher education.
 

Complex reasons

Monica Christmas, MD, an associate professor of obstetrics and gynecology at the University of Chicago and director of the Menopause Program and the Center for Women’s Integrated Health, said the study’s findings were not surprising, but the reasons for the racial disparities are likely complex.

Implicit bias in providers is likely one contributing factor, with some providers not thinking of offering HT to certain patients or not expecting the patients to be interested in it. Providers may also hesitate to prescribe HT to patients with more comorbidities because of concerns about HT risks, so if Black patients have more comorbidities, that could play a role in how many are offered or counseled on HT, she said.

“Probably the biggest take home is that it is important to be asking all of our patients about their symptoms and being proactive about talking about it,” Dr. Christmas said in an interview.

At the same time, in her anecdotal experience at a previous institution, Dr. Christmas noticed that her Black patients were less receptive to using hormone therapy than her White patients even though her Black patients tended to exhibit or report greater or more severe symptoms. But there’s been a “paradigm shift” more recently, Dr. Christmas said. With awareness about menopause growing in the media and particularly on social media, and with greater awareness about racial disparities in menopausal symptoms and care – including that shown in Dr. Christmas’s work in the SWAN Study – Dr. Christmas has had more Black patients asking about HT and other treatments for their menopausal symptoms more recently.

“Just 10 years ago, I was trying to talk to people about hormones, and I’ve been giving them to people that need them for a long time, and I couldn’t,” Dr. Christmas said. “Now people are coming in, saying ‘no one’s ever talked to me about it’ or ‘I deserve this.’ It shows you the persuasion that social media and the Internet have on our thinking too, and I think that’s going to be interesting to look at, to see how that impacts people’s perception about wanting treatment.”

Dr. Conklin agreed that reasons for the disparities likely involve a combination of factors, including providers’ assumptions about different racial groups’ knowledge and receptiveness toward different treatments. One of the studies in their review also reported provider barriers to prescribing HT, which included lack of time, lack of adequate knowledge, and concern about risks to patients’ health.

“Medical providers tend to have less time with their patients compared to PhDs, and that time factor really makes a big difference in terms of what the focus is going to be in that [short] appointment,” Dr. Conklin said in an interview. “Perhaps from a provider point of view, they are prioritizing what they think is more important to their patient and not really listening deeply to what their patient is saying.”
 

Educating clinicians

Potentially supporting that possibility, Dr. Conklin and Dr. MacPhedran also had a poster at the conference that looked at prescribing of HT in both Black and White women with a diagnosis of depression, anxiety, or bipolar disorder.

“In a population with a high percentage of Black patients known to have more menopause symptoms, the data demonstrated a surprisingly low rate of documented menopause symptoms (11%) compared to prior reports of up to 80%,” the researchers reported. “This low rate may be related to patient reporting, physician inquiry, or physician documentation of menopause symptoms.” They further found that White women with menopause symptoms and one of those psychiatric diagnosis were 40% more likely to receive an HT prescription for menopausal symptoms than Black women with the same diagnoses and symptoms.

Dr. Conklin emphasized the importance of providers not overlooking women who have mental health disorders when it comes to treating menopausal symptoms, particularly since mental health conditions and menopausal symptoms can exacerbate each other.

“Their depression could worsen irritability, and anxiety can worsen during the transition, and it could be overlooked or thought of as another [psychiatric] episode,” Dr. Conklin said. Providers may need to “dig a little deeper,” especially if patients are reporting having hot flashes or brain fog.

A key way to help overcome the racial disparities – whether they result from systemic issues, implicit bias or assumptions, or patients’ own reticence – is education, Dr. Conklin said. She recommended that providers have educational material about menopause and treatments for menopausal symptoms in the waiting room and then ask patients about their symptoms and invite patients to ask questions.

Dr. MacPhedran added that education for clinicians is key as well.

“Now is a great time – menopause is hot, menopause is interesting, and it’s getting a little bit of a push in terms of research dollars,” Dr. MacPhedran said. “That will trickle down to more emphasis in medical education, whether that’s nurse practitioners, physicians, PAs, or midwives. Everybody needs more education on menopause so they can be more comfortable asking and answering these questions.”

Dr. Conklin said she would like to see expanded education on menopause for medical residents and in health psychology curricula as well.

Among the 13 studies that found disparities in prescribing patterns by age, seven studies showed that older women used or were prescribed or counseled on HT more often than younger women. Four studies found the opposite, with older women less likely to use or be prescribed or counseled about HT. One study had mixed results, and one study had expected prescribing patterns.

Five studies found income disparities and five studies found disparities by medical conditions in terms of HT use, prescribing, or counseling. Other disparities identified in smaller numbers of studies (four or fewer) included natural versus surgical menopause, insurance coverage, body mass index, geographic region, smoking and alcohol use.

The two biggest limitations of the research were its heterogeneity and the small number of studies included, which points to how scarce research on racial disparities in HT use really are, Dr. Conklin said.

The research did not use any external funding. The authors had no industry disclosures. Dr. Christmas has done an educational video for FertilityIQ.

PHILADELPHIA – The prescribing, counseling, and use of hormone therapy (HT) to treat menopausal symptoms is substantially more common among white women than among Black women, according to a review of published studies presented at the annual meeting of the Menopause Society (formerly The North American Menopause Society).

“Gaps in treatment can be used to inform health care providers about menopausal HT prescribing disparities, with the goal of improving equitable and advanced patient care among disadvantaged populations,” wrote Danette Conklin, PhD, an assistant professor of psychiatry and reproductive biology at Case Western Reserve University, Cleveland, and a psychologist at University Hospitals Cleveland Medical Center; Sally MacPhedran, MD, an associate professor of reproductive biology at Case Western Reserve University and an ob.gyn at MetroHealth Medical Center, also in Cleveland; and their colleagues.

The researchers combed through PubMed, CINAHL, Cochrane Library, Web of Science and PsychInfo databases to identify all studies conducted in the United States since 1940 that contained data on patient demographics and prescribing patterns for hormone therapy to treat menopausal symptoms. In addition to excluding men, children, teens, trans men, and women who had contraindications for HT, the investigators excluded randomized clinical trials so that prescribing patterns would not be based on protocols or RCT participatory criteria.

The researchers identified 20 studies, ranging from 1973 through 2015, including 9 national studies and the others across different U.S. regions. They then analyzed differences in HT prescribing according to age, race/ethnicity, education, income, insurance type, body mass index, and mental health, including alcohol or substance use.

Seven of the studies assessed HT use based on patient surveys, seven used medical or medication records showing an HT prescription, two studies used insurance claims to show an HT prescription, and one study surveyed patients about whether they received an HT prescription. Another four studies used surveys that asked patients whether they received HT counseling but did not indicate if the patients received a prescription.

Half of the studies showed racial disparities in HT prescribing. In all of them, Black women used or were prescribed or counseled on using HT less than white, Hispanic, or Asian women. White women had greater use, prescribing, or counseling than all other races/ethnicities except one study in which Hispanic women were prescribed vaginal estrogen more often than white women.

Six of the studies showed education disparities in which menopausal women with lower education levels used less HT or were prescribed or counseled on HT less than women with higher education.
 

Complex reasons

Monica Christmas, MD, an associate professor of obstetrics and gynecology at the University of Chicago and director of the Menopause Program and the Center for Women’s Integrated Health, said the study’s findings were not surprising, but the reasons for the racial disparities are likely complex.

Implicit bias in providers is likely one contributing factor, with some providers not thinking of offering HT to certain patients or not expecting the patients to be interested in it. Providers may also hesitate to prescribe HT to patients with more comorbidities because of concerns about HT risks, so if Black patients have more comorbidities, that could play a role in how many are offered or counseled on HT, she said.

“Probably the biggest take home is that it is important to be asking all of our patients about their symptoms and being proactive about talking about it,” Dr. Christmas said in an interview.

At the same time, in her anecdotal experience at a previous institution, Dr. Christmas noticed that her Black patients were less receptive to using hormone therapy than her White patients even though her Black patients tended to exhibit or report greater or more severe symptoms. But there’s been a “paradigm shift” more recently, Dr. Christmas said. With awareness about menopause growing in the media and particularly on social media, and with greater awareness about racial disparities in menopausal symptoms and care – including that shown in Dr. Christmas’s work in the SWAN Study – Dr. Christmas has had more Black patients asking about HT and other treatments for their menopausal symptoms more recently.

“Just 10 years ago, I was trying to talk to people about hormones, and I’ve been giving them to people that need them for a long time, and I couldn’t,” Dr. Christmas said. “Now people are coming in, saying ‘no one’s ever talked to me about it’ or ‘I deserve this.’ It shows you the persuasion that social media and the Internet have on our thinking too, and I think that’s going to be interesting to look at, to see how that impacts people’s perception about wanting treatment.”

Dr. Conklin agreed that reasons for the disparities likely involve a combination of factors, including providers’ assumptions about different racial groups’ knowledge and receptiveness toward different treatments. One of the studies in their review also reported provider barriers to prescribing HT, which included lack of time, lack of adequate knowledge, and concern about risks to patients’ health.

“Medical providers tend to have less time with their patients compared to PhDs, and that time factor really makes a big difference in terms of what the focus is going to be in that [short] appointment,” Dr. Conklin said in an interview. “Perhaps from a provider point of view, they are prioritizing what they think is more important to their patient and not really listening deeply to what their patient is saying.”
 

Educating clinicians

Potentially supporting that possibility, Dr. Conklin and Dr. MacPhedran also had a poster at the conference that looked at prescribing of HT in both Black and White women with a diagnosis of depression, anxiety, or bipolar disorder.

“In a population with a high percentage of Black patients known to have more menopause symptoms, the data demonstrated a surprisingly low rate of documented menopause symptoms (11%) compared to prior reports of up to 80%,” the researchers reported. “This low rate may be related to patient reporting, physician inquiry, or physician documentation of menopause symptoms.” They further found that White women with menopause symptoms and one of those psychiatric diagnosis were 40% more likely to receive an HT prescription for menopausal symptoms than Black women with the same diagnoses and symptoms.

Dr. Conklin emphasized the importance of providers not overlooking women who have mental health disorders when it comes to treating menopausal symptoms, particularly since mental health conditions and menopausal symptoms can exacerbate each other.

“Their depression could worsen irritability, and anxiety can worsen during the transition, and it could be overlooked or thought of as another [psychiatric] episode,” Dr. Conklin said. Providers may need to “dig a little deeper,” especially if patients are reporting having hot flashes or brain fog.

A key way to help overcome the racial disparities – whether they result from systemic issues, implicit bias or assumptions, or patients’ own reticence – is education, Dr. Conklin said. She recommended that providers have educational material about menopause and treatments for menopausal symptoms in the waiting room and then ask patients about their symptoms and invite patients to ask questions.

Dr. MacPhedran added that education for clinicians is key as well.

“Now is a great time – menopause is hot, menopause is interesting, and it’s getting a little bit of a push in terms of research dollars,” Dr. MacPhedran said. “That will trickle down to more emphasis in medical education, whether that’s nurse practitioners, physicians, PAs, or midwives. Everybody needs more education on menopause so they can be more comfortable asking and answering these questions.”

Dr. Conklin said she would like to see expanded education on menopause for medical residents and in health psychology curricula as well.

Among the 13 studies that found disparities in prescribing patterns by age, seven studies showed that older women used or were prescribed or counseled on HT more often than younger women. Four studies found the opposite, with older women less likely to use or be prescribed or counseled about HT. One study had mixed results, and one study had expected prescribing patterns.

Five studies found income disparities and five studies found disparities by medical conditions in terms of HT use, prescribing, or counseling. Other disparities identified in smaller numbers of studies (four or fewer) included natural versus surgical menopause, insurance coverage, body mass index, geographic region, smoking and alcohol use.

The two biggest limitations of the research were its heterogeneity and the small number of studies included, which points to how scarce research on racial disparities in HT use really are, Dr. Conklin said.

The research did not use any external funding. The authors had no industry disclosures. Dr. Christmas has done an educational video for FertilityIQ.

PHILADELPHIA – The prescribing, counseling, and use of hormone therapy (HT) to treat menopausal symptoms is substantially more common among white women than among Black women, according to a review of published studies presented at the annual meeting of the Menopause Society (formerly The North American Menopause Society).

“Gaps in treatment can be used to inform health care providers about menopausal HT prescribing disparities, with the goal of improving equitable and advanced patient care among disadvantaged populations,” wrote Danette Conklin, PhD, an assistant professor of psychiatry and reproductive biology at Case Western Reserve University, Cleveland, and a psychologist at University Hospitals Cleveland Medical Center; Sally MacPhedran, MD, an associate professor of reproductive biology at Case Western Reserve University and an ob.gyn at MetroHealth Medical Center, also in Cleveland; and their colleagues.

The researchers combed through PubMed, CINAHL, Cochrane Library, Web of Science and PsychInfo databases to identify all studies conducted in the United States since 1940 that contained data on patient demographics and prescribing patterns for hormone therapy to treat menopausal symptoms. In addition to excluding men, children, teens, trans men, and women who had contraindications for HT, the investigators excluded randomized clinical trials so that prescribing patterns would not be based on protocols or RCT participatory criteria.

The researchers identified 20 studies, ranging from 1973 through 2015, including 9 national studies and the others across different U.S. regions. They then analyzed differences in HT prescribing according to age, race/ethnicity, education, income, insurance type, body mass index, and mental health, including alcohol or substance use.

Seven of the studies assessed HT use based on patient surveys, seven used medical or medication records showing an HT prescription, two studies used insurance claims to show an HT prescription, and one study surveyed patients about whether they received an HT prescription. Another four studies used surveys that asked patients whether they received HT counseling but did not indicate if the patients received a prescription.

Half of the studies showed racial disparities in HT prescribing. In all of them, Black women used or were prescribed or counseled on using HT less than white, Hispanic, or Asian women. White women had greater use, prescribing, or counseling than all other races/ethnicities except one study in which Hispanic women were prescribed vaginal estrogen more often than white women.

Six of the studies showed education disparities in which menopausal women with lower education levels used less HT or were prescribed or counseled on HT less than women with higher education.
 

Complex reasons

Monica Christmas, MD, an associate professor of obstetrics and gynecology at the University of Chicago and director of the Menopause Program and the Center for Women’s Integrated Health, said the study’s findings were not surprising, but the reasons for the racial disparities are likely complex.

Implicit bias in providers is likely one contributing factor, with some providers not thinking of offering HT to certain patients or not expecting the patients to be interested in it. Providers may also hesitate to prescribe HT to patients with more comorbidities because of concerns about HT risks, so if Black patients have more comorbidities, that could play a role in how many are offered or counseled on HT, she said.

“Probably the biggest take home is that it is important to be asking all of our patients about their symptoms and being proactive about talking about it,” Dr. Christmas said in an interview.

At the same time, in her anecdotal experience at a previous institution, Dr. Christmas noticed that her Black patients were less receptive to using hormone therapy than her White patients even though her Black patients tended to exhibit or report greater or more severe symptoms. But there’s been a “paradigm shift” more recently, Dr. Christmas said. With awareness about menopause growing in the media and particularly on social media, and with greater awareness about racial disparities in menopausal symptoms and care – including that shown in Dr. Christmas’s work in the SWAN Study – Dr. Christmas has had more Black patients asking about HT and other treatments for their menopausal symptoms more recently.

“Just 10 years ago, I was trying to talk to people about hormones, and I’ve been giving them to people that need them for a long time, and I couldn’t,” Dr. Christmas said. “Now people are coming in, saying ‘no one’s ever talked to me about it’ or ‘I deserve this.’ It shows you the persuasion that social media and the Internet have on our thinking too, and I think that’s going to be interesting to look at, to see how that impacts people’s perception about wanting treatment.”

Dr. Conklin agreed that reasons for the disparities likely involve a combination of factors, including providers’ assumptions about different racial groups’ knowledge and receptiveness toward different treatments. One of the studies in their review also reported provider barriers to prescribing HT, which included lack of time, lack of adequate knowledge, and concern about risks to patients’ health.

“Medical providers tend to have less time with their patients compared to PhDs, and that time factor really makes a big difference in terms of what the focus is going to be in that [short] appointment,” Dr. Conklin said in an interview. “Perhaps from a provider point of view, they are prioritizing what they think is more important to their patient and not really listening deeply to what their patient is saying.”
 

Educating clinicians

Potentially supporting that possibility, Dr. Conklin and Dr. MacPhedran also had a poster at the conference that looked at prescribing of HT in both Black and White women with a diagnosis of depression, anxiety, or bipolar disorder.

“In a population with a high percentage of Black patients known to have more menopause symptoms, the data demonstrated a surprisingly low rate of documented menopause symptoms (11%) compared to prior reports of up to 80%,” the researchers reported. “This low rate may be related to patient reporting, physician inquiry, or physician documentation of menopause symptoms.” They further found that White women with menopause symptoms and one of those psychiatric diagnosis were 40% more likely to receive an HT prescription for menopausal symptoms than Black women with the same diagnoses and symptoms.

Dr. Conklin emphasized the importance of providers not overlooking women who have mental health disorders when it comes to treating menopausal symptoms, particularly since mental health conditions and menopausal symptoms can exacerbate each other.

“Their depression could worsen irritability, and anxiety can worsen during the transition, and it could be overlooked or thought of as another [psychiatric] episode,” Dr. Conklin said. Providers may need to “dig a little deeper,” especially if patients are reporting having hot flashes or brain fog.

A key way to help overcome the racial disparities – whether they result from systemic issues, implicit bias or assumptions, or patients’ own reticence – is education, Dr. Conklin said. She recommended that providers have educational material about menopause and treatments for menopausal symptoms in the waiting room and then ask patients about their symptoms and invite patients to ask questions.

Dr. MacPhedran added that education for clinicians is key as well.

“Now is a great time – menopause is hot, menopause is interesting, and it’s getting a little bit of a push in terms of research dollars,” Dr. MacPhedran said. “That will trickle down to more emphasis in medical education, whether that’s nurse practitioners, physicians, PAs, or midwives. Everybody needs more education on menopause so they can be more comfortable asking and answering these questions.”

Dr. Conklin said she would like to see expanded education on menopause for medical residents and in health psychology curricula as well.

Among the 13 studies that found disparities in prescribing patterns by age, seven studies showed that older women used or were prescribed or counseled on HT more often than younger women. Four studies found the opposite, with older women less likely to use or be prescribed or counseled about HT. One study had mixed results, and one study had expected prescribing patterns.

Five studies found income disparities and five studies found disparities by medical conditions in terms of HT use, prescribing, or counseling. Other disparities identified in smaller numbers of studies (four or fewer) included natural versus surgical menopause, insurance coverage, body mass index, geographic region, smoking and alcohol use.

The two biggest limitations of the research were its heterogeneity and the small number of studies included, which points to how scarce research on racial disparities in HT use really are, Dr. Conklin said.

The research did not use any external funding. The authors had no industry disclosures. Dr. Christmas has done an educational video for FertilityIQ.

I’ve worked hard to get rid of paper, or at least minimize it.

I use e-fax for sending and receiving as much as possible. I send scripts and order digitally when I can.

But, 23 years into a paperless practice, the stuff isn’t going away soon. Nor I do I want it to.

For many applications paper is just easier (at least to me) to use. When I have a meeting and know I’ll need to read from notes, I’d much rather have them on paper than a screen, so I print them up. Even a grocery list is easier to scribble down on something and look at as I wander the aisles, rather than navigate to an app every 2 minutes. Paper isn’t susceptible to the whims of battery power, signal strength, being dropped, or software glitches.

I’m also not particularly good at taking notes on a computer. I’m sure most of the current generation of physicians is (or they just use a scribe), but I’m old school. Since day one I’ve had a note pad on my desk, jotting points and observations down on the fly (I use a pencil, too, if anyone remembers what that is). Then, when I have time, I type up my notes from the paper.

I also still have patients who, for whatever reason, want a handwritten prescription. Or sometimes need the legendary “doctor’s note” for work or school. Or need me to fill out forms.

Having grown up with paper, and been through school and residency with paper, it’s not easy to give it up entirely. There’s something reassuring about the tactile nature of flipping pages as opposed to scrolling up and down.

I’m not complaining about its decreased use, though. A digital world is, for the most part, much, much easier. Even now paper is just a transient medium for me. It’s either going to be scanned or shredded (or scanned, then shredded) when I’m done. I don’t want the hassle of paper charts as my repository of information. Currently I have 23 years of charts sitting on a Mac-Mini, and accessible from wherever I am on Earth (as long as I have a decent signal). You definitely can’t do that with paper.

On a larger scale paper has other, more significant, drawbacks: deforestation, pollution, freshwater and petroleum usage, and others. I’m aware of this, use only scratch paper for my scribbles and lists, and buy recycled paper products as much as possible.

Certainly I wish we had less use of it. For one thing, I’d love to be rid of all the junk mail that comes to my house, which far outnumbers anything of importance. I always send it straight to recycling, but it would be far better if it had never been created in the first place.

Realistically, though, it’s still a key part of medical practice and everyday life. I don’t see that changing anytime soon, nor do I really want it to. I’ll leave it to a future generation of doctors to make that break.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

I’ve worked hard to get rid of paper, or at least minimize it.

I use e-fax for sending and receiving as much as possible. I send scripts and order digitally when I can.

But, 23 years into a paperless practice, the stuff isn’t going away soon. Nor I do I want it to.

For many applications paper is just easier (at least to me) to use. When I have a meeting and know I’ll need to read from notes, I’d much rather have them on paper than a screen, so I print them up. Even a grocery list is easier to scribble down on something and look at as I wander the aisles, rather than navigate to an app every 2 minutes. Paper isn’t susceptible to the whims of battery power, signal strength, being dropped, or software glitches.

I’m also not particularly good at taking notes on a computer. I’m sure most of the current generation of physicians is (or they just use a scribe), but I’m old school. Since day one I’ve had a note pad on my desk, jotting points and observations down on the fly (I use a pencil, too, if anyone remembers what that is). Then, when I have time, I type up my notes from the paper.

I also still have patients who, for whatever reason, want a handwritten prescription. Or sometimes need the legendary “doctor’s note” for work or school. Or need me to fill out forms.

Having grown up with paper, and been through school and residency with paper, it’s not easy to give it up entirely. There’s something reassuring about the tactile nature of flipping pages as opposed to scrolling up and down.

I’m not complaining about its decreased use, though. A digital world is, for the most part, much, much easier. Even now paper is just a transient medium for me. It’s either going to be scanned or shredded (or scanned, then shredded) when I’m done. I don’t want the hassle of paper charts as my repository of information. Currently I have 23 years of charts sitting on a Mac-Mini, and accessible from wherever I am on Earth (as long as I have a decent signal). You definitely can’t do that with paper.

On a larger scale paper has other, more significant, drawbacks: deforestation, pollution, freshwater and petroleum usage, and others. I’m aware of this, use only scratch paper for my scribbles and lists, and buy recycled paper products as much as possible.

Certainly I wish we had less use of it. For one thing, I’d love to be rid of all the junk mail that comes to my house, which far outnumbers anything of importance. I always send it straight to recycling, but it would be far better if it had never been created in the first place.

Realistically, though, it’s still a key part of medical practice and everyday life. I don’t see that changing anytime soon, nor do I really want it to. I’ll leave it to a future generation of doctors to make that break.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

I’ve worked hard to get rid of paper, or at least minimize it.

I use e-fax for sending and receiving as much as possible. I send scripts and order digitally when I can.

But, 23 years into a paperless practice, the stuff isn’t going away soon. Nor I do I want it to.

For many applications paper is just easier (at least to me) to use. When I have a meeting and know I’ll need to read from notes, I’d much rather have them on paper than a screen, so I print them up. Even a grocery list is easier to scribble down on something and look at as I wander the aisles, rather than navigate to an app every 2 minutes. Paper isn’t susceptible to the whims of battery power, signal strength, being dropped, or software glitches.

I’m also not particularly good at taking notes on a computer. I’m sure most of the current generation of physicians is (or they just use a scribe), but I’m old school. Since day one I’ve had a note pad on my desk, jotting points and observations down on the fly (I use a pencil, too, if anyone remembers what that is). Then, when I have time, I type up my notes from the paper.

I also still have patients who, for whatever reason, want a handwritten prescription. Or sometimes need the legendary “doctor’s note” for work or school. Or need me to fill out forms.

Having grown up with paper, and been through school and residency with paper, it’s not easy to give it up entirely. There’s something reassuring about the tactile nature of flipping pages as opposed to scrolling up and down.

I’m not complaining about its decreased use, though. A digital world is, for the most part, much, much easier. Even now paper is just a transient medium for me. It’s either going to be scanned or shredded (or scanned, then shredded) when I’m done. I don’t want the hassle of paper charts as my repository of information. Currently I have 23 years of charts sitting on a Mac-Mini, and accessible from wherever I am on Earth (as long as I have a decent signal). You definitely can’t do that with paper.

On a larger scale paper has other, more significant, drawbacks: deforestation, pollution, freshwater and petroleum usage, and others. I’m aware of this, use only scratch paper for my scribbles and lists, and buy recycled paper products as much as possible.

Certainly I wish we had less use of it. For one thing, I’d love to be rid of all the junk mail that comes to my house, which far outnumbers anything of importance. I always send it straight to recycling, but it would be far better if it had never been created in the first place.

Realistically, though, it’s still a key part of medical practice and everyday life. I don’t see that changing anytime soon, nor do I really want it to. I’ll leave it to a future generation of doctors to make that break.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

When children have a serious illness, some families choose not to disclose the severity to them, reasoning that knowing the extent of the illness may take away their hope. Deciding whether to tell children or adolescents about the seriousness of their disease is a complex judgment and can pose legal, ethical, and moral challenges for parents and care providers.

Default should be inclusion

The American Academy of Pediatrics (AAP) recommends in a new clinical report that the default should be to include children in conversations about their illness in a developmentally appropriate way, to the extent parents are comfortable.

The report, written by Sara Taub, MD and Robert Macauley, MD, MDiv, both in the department of pediatrics at Oregon Health & Science University in Portland, on behalf of the AAP Committee on Bioethics, was published online and appears in the October issue of Pediatrics.

“Rather than taking away hope, as some may fear, this approach of openness may create a space for children to ask their questions, share their concerns, and set goals that are appropriate to the circumstances,” the authors wrote in a press release.

The report offers strategies based on ethical, historical, legal, and cultural considerations when discussing what to share with a child or adolescent.

Some of the AAP’s other recommendations include the following:

• If the parents request nondisclosure, the first response should be seeking to understand why they prefer that stance. The care team members should also explain their position to parents.
• If there is no consensus on disclosure, establishing what each party believes is the minimum information that should be shared is important.
• Additional resources to navigate disagreement may be helpful, such as hospital ethics committees, mediators and patient advocates.
• Conversations with the family should be documented in the medical record.

Children may know more than you think

Dr. Taub said that even very young children may know more about their disease than adults believe.

“Without disclosure,” she said, “as children hear the conversations around them, they glean partial information and may weave together stories that are more frightening than reality.”

Sometimes families and the care team disagree on disclosure and for that scenario, the report offers guidance in finding middle ground.

For instance, when pediatricians feel ethically obligated to share information when parents oppose sharing, “pediatricians can reframe the discussion from whether information should be shared with the patient to what information will be communicated, how, and by whom,” the authors said in a press release.
 

Should you tell 15-year-old paraplegia is likely?

The authors give a case example of a 15-year-old whose spinal tumor likely will lead to paraplegia within weeks. Very few treatment options are available.

The parents ask the care team to avoid any discussions with the child about prognosis, reasoning that the news will be crushing and it’s better to deal with it if or when it happens.

The care team, however, feels compelled to find out about specific activities important to the child that may no longer be feasible with paraplegia.

The parents cite the child’s love of soccer and desire to see the Statue of Liberty. With that information and keeping the parents’ wishes in mind, the team reframes the conversation with the child in terms of goals, acknowledging that mobility may be more difficult in the future.

That conversation leads the child and the family to discuss moving up the trip to New York they had planned.
 

Guidance where there has been little

Timothy Joos, MD, MPH, a pediatrician who practices at a community health center in Seattle, who was not part of the recommendation team, said he was glad to see the AAP issue advice on a complex topic for which there is little practical guidance.

The authors’ case examples were “heart-tugging,” he said, and will help pediatricians work through their own scenarios.

Dr. Joos agreed with the overall premise that the default should be sharing the information.

“One of the foundations of medicine is truthfulness and openness and if we depart from that, we really have to have a good reason,” Dr. Joos said.

He said that since lying to patients should be nonnegotiable for any physician, it may help to talk with the parents first before answering an inquisitive patient’s questions and then have all parties gather for a discussion.

The authors note that AAP’s clinical reports are written by medical experts and reflect the latest evidence. The reports go through several rounds of peer review before they can be approved by the AAP board of directors.

The authors and Dr. Joos report no relevant financial relationships.

When children have a serious illness, some families choose not to disclose the severity to them, reasoning that knowing the extent of the illness may take away their hope. Deciding whether to tell children or adolescents about the seriousness of their disease is a complex judgment and can pose legal, ethical, and moral challenges for parents and care providers.

Default should be inclusion

The American Academy of Pediatrics (AAP) recommends in a new clinical report that the default should be to include children in conversations about their illness in a developmentally appropriate way, to the extent parents are comfortable.

The report, written by Sara Taub, MD and Robert Macauley, MD, MDiv, both in the department of pediatrics at Oregon Health & Science University in Portland, on behalf of the AAP Committee on Bioethics, was published online and appears in the October issue of Pediatrics.

“Rather than taking away hope, as some may fear, this approach of openness may create a space for children to ask their questions, share their concerns, and set goals that are appropriate to the circumstances,” the authors wrote in a press release.

The report offers strategies based on ethical, historical, legal, and cultural considerations when discussing what to share with a child or adolescent.

Some of the AAP’s other recommendations include the following:

• If the parents request nondisclosure, the first response should be seeking to understand why they prefer that stance. The care team members should also explain their position to parents.
• If there is no consensus on disclosure, establishing what each party believes is the minimum information that should be shared is important.
• Additional resources to navigate disagreement may be helpful, such as hospital ethics committees, mediators and patient advocates.
• Conversations with the family should be documented in the medical record.

Children may know more than you think

Dr. Taub said that even very young children may know more about their disease than adults believe.

“Without disclosure,” she said, “as children hear the conversations around them, they glean partial information and may weave together stories that are more frightening than reality.”

Sometimes families and the care team disagree on disclosure and for that scenario, the report offers guidance in finding middle ground.

For instance, when pediatricians feel ethically obligated to share information when parents oppose sharing, “pediatricians can reframe the discussion from whether information should be shared with the patient to what information will be communicated, how, and by whom,” the authors said in a press release.
 

Should you tell 15-year-old paraplegia is likely?

The authors give a case example of a 15-year-old whose spinal tumor likely will lead to paraplegia within weeks. Very few treatment options are available.

The parents ask the care team to avoid any discussions with the child about prognosis, reasoning that the news will be crushing and it’s better to deal with it if or when it happens.

The care team, however, feels compelled to find out about specific activities important to the child that may no longer be feasible with paraplegia.

The parents cite the child’s love of soccer and desire to see the Statue of Liberty. With that information and keeping the parents’ wishes in mind, the team reframes the conversation with the child in terms of goals, acknowledging that mobility may be more difficult in the future.

That conversation leads the child and the family to discuss moving up the trip to New York they had planned.
 

Guidance where there has been little

Timothy Joos, MD, MPH, a pediatrician who practices at a community health center in Seattle, who was not part of the recommendation team, said he was glad to see the AAP issue advice on a complex topic for which there is little practical guidance.

The authors’ case examples were “heart-tugging,” he said, and will help pediatricians work through their own scenarios.

Dr. Joos agreed with the overall premise that the default should be sharing the information.

“One of the foundations of medicine is truthfulness and openness and if we depart from that, we really have to have a good reason,” Dr. Joos said.

He said that since lying to patients should be nonnegotiable for any physician, it may help to talk with the parents first before answering an inquisitive patient’s questions and then have all parties gather for a discussion.

The authors note that AAP’s clinical reports are written by medical experts and reflect the latest evidence. The reports go through several rounds of peer review before they can be approved by the AAP board of directors.

The authors and Dr. Joos report no relevant financial relationships.

When children have a serious illness, some families choose not to disclose the severity to them, reasoning that knowing the extent of the illness may take away their hope. Deciding whether to tell children or adolescents about the seriousness of their disease is a complex judgment and can pose legal, ethical, and moral challenges for parents and care providers.

Default should be inclusion

The American Academy of Pediatrics (AAP) recommends in a new clinical report that the default should be to include children in conversations about their illness in a developmentally appropriate way, to the extent parents are comfortable.

The report, written by Sara Taub, MD and Robert Macauley, MD, MDiv, both in the department of pediatrics at Oregon Health & Science University in Portland, on behalf of the AAP Committee on Bioethics, was published online and appears in the October issue of Pediatrics.

“Rather than taking away hope, as some may fear, this approach of openness may create a space for children to ask their questions, share their concerns, and set goals that are appropriate to the circumstances,” the authors wrote in a press release.

The report offers strategies based on ethical, historical, legal, and cultural considerations when discussing what to share with a child or adolescent.

Some of the AAP’s other recommendations include the following:

• If the parents request nondisclosure, the first response should be seeking to understand why they prefer that stance. The care team members should also explain their position to parents.
• If there is no consensus on disclosure, establishing what each party believes is the minimum information that should be shared is important.
• Additional resources to navigate disagreement may be helpful, such as hospital ethics committees, mediators and patient advocates.
• Conversations with the family should be documented in the medical record.

Children may know more than you think

Dr. Taub said that even very young children may know more about their disease than adults believe.

“Without disclosure,” she said, “as children hear the conversations around them, they glean partial information and may weave together stories that are more frightening than reality.”

Sometimes families and the care team disagree on disclosure and for that scenario, the report offers guidance in finding middle ground.

For instance, when pediatricians feel ethically obligated to share information when parents oppose sharing, “pediatricians can reframe the discussion from whether information should be shared with the patient to what information will be communicated, how, and by whom,” the authors said in a press release.
 

Should you tell 15-year-old paraplegia is likely?

The authors give a case example of a 15-year-old whose spinal tumor likely will lead to paraplegia within weeks. Very few treatment options are available.

The parents ask the care team to avoid any discussions with the child about prognosis, reasoning that the news will be crushing and it’s better to deal with it if or when it happens.

The care team, however, feels compelled to find out about specific activities important to the child that may no longer be feasible with paraplegia.

The parents cite the child’s love of soccer and desire to see the Statue of Liberty. With that information and keeping the parents’ wishes in mind, the team reframes the conversation with the child in terms of goals, acknowledging that mobility may be more difficult in the future.

That conversation leads the child and the family to discuss moving up the trip to New York they had planned.
 

Guidance where there has been little

Timothy Joos, MD, MPH, a pediatrician who practices at a community health center in Seattle, who was not part of the recommendation team, said he was glad to see the AAP issue advice on a complex topic for which there is little practical guidance.

The authors’ case examples were “heart-tugging,” he said, and will help pediatricians work through their own scenarios.

Dr. Joos agreed with the overall premise that the default should be sharing the information.

“One of the foundations of medicine is truthfulness and openness and if we depart from that, we really have to have a good reason,” Dr. Joos said.

He said that since lying to patients should be nonnegotiable for any physician, it may help to talk with the parents first before answering an inquisitive patient’s questions and then have all parties gather for a discussion.

The authors note that AAP’s clinical reports are written by medical experts and reflect the latest evidence. The reports go through several rounds of peer review before they can be approved by the AAP board of directors.

The authors and Dr. Joos report no relevant financial relationships.

TOPLINE:

Vegetarian diets may reduce the risk for gastric and colorectal cancers, according to the results of a meta-analysis.

METHODOLOGY:

• Researchers did a systematic review and meta-analysis of seven original studies (six cohorts and one case-control) involving 686,691 people.
• Pooled relative risk for gastric, colorectal, and upper gastrointestinal cancers were assessed with confidence intervals in multivariate analysis accounting for potential confounders.

TAKEAWAY:

• Compared with nonvegetarian diets, vegetarian diets were inversely associated with the risk for GI tumor development (relative risk, 0.77).
• In a subgroup analysis, vegetarian diets were negatively correlated with the risk for gastric cancer (RR, 0.41) and colorectal cancer (RR, 0.85) but not with upper GI cancer (excluding stomach; RR, 0.93).
• Vegetarian diets were negatively correlated with the risk for GI cancer in men (RR, 0.57) but not women (RR, 0.89).
• Vegetarian diets were negatively correlated with the risk for GI cancer in North American (RR, 0.76) and Asian populations (RR, 0.43) but not in European populations (RR, 0.83).

IN PRACTICE:

“The results of this systematic review indicate that adherence to vegetarian diets can reduce the risk of gastrointestinal cancers, compared with non-vegetarian diets. This study provides a reference for primary prevention strategies for gastrointestinal cancers,” the authors write.

SOURCE:

The study, with first author Tongtong Bai, of Nanjing University of Chinese Medicine, was published online on in the European Journal of Gastroenterology & Hepatology.

LIMITATIONS:

The effects of vegetarian diets on GI tumorigenesis may be influenced by gender and geographical region. The heterogeneity of effects of vegetarian diets on different GI cancers could be due to the small number of studies included and could represent chance variation. The results need to be confirmed by studies of populations in other regions. There was evidence of publication bias.

DISCLOSURES:

The study had no specific funding. The authors have disclosed no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Vegetarian diets may reduce the risk for gastric and colorectal cancers, according to the results of a meta-analysis.

METHODOLOGY:

• Researchers did a systematic review and meta-analysis of seven original studies (six cohorts and one case-control) involving 686,691 people.
• Pooled relative risk for gastric, colorectal, and upper gastrointestinal cancers were assessed with confidence intervals in multivariate analysis accounting for potential confounders.

TAKEAWAY:

• Compared with nonvegetarian diets, vegetarian diets were inversely associated with the risk for GI tumor development (relative risk, 0.77).
• In a subgroup analysis, vegetarian diets were negatively correlated with the risk for gastric cancer (RR, 0.41) and colorectal cancer (RR, 0.85) but not with upper GI cancer (excluding stomach; RR, 0.93).
• Vegetarian diets were negatively correlated with the risk for GI cancer in men (RR, 0.57) but not women (RR, 0.89).
• Vegetarian diets were negatively correlated with the risk for GI cancer in North American (RR, 0.76) and Asian populations (RR, 0.43) but not in European populations (RR, 0.83).

IN PRACTICE:

“The results of this systematic review indicate that adherence to vegetarian diets can reduce the risk of gastrointestinal cancers, compared with non-vegetarian diets. This study provides a reference for primary prevention strategies for gastrointestinal cancers,” the authors write.

SOURCE:

The study, with first author Tongtong Bai, of Nanjing University of Chinese Medicine, was published online on in the European Journal of Gastroenterology & Hepatology.

LIMITATIONS:

The effects of vegetarian diets on GI tumorigenesis may be influenced by gender and geographical region. The heterogeneity of effects of vegetarian diets on different GI cancers could be due to the small number of studies included and could represent chance variation. The results need to be confirmed by studies of populations in other regions. There was evidence of publication bias.

DISCLOSURES:

The study had no specific funding. The authors have disclosed no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Vegetarian diets may reduce the risk for gastric and colorectal cancers, according to the results of a meta-analysis.

METHODOLOGY:

• Researchers did a systematic review and meta-analysis of seven original studies (six cohorts and one case-control) involving 686,691 people.
• Pooled relative risk for gastric, colorectal, and upper gastrointestinal cancers were assessed with confidence intervals in multivariate analysis accounting for potential confounders.

TAKEAWAY:

• Compared with nonvegetarian diets, vegetarian diets were inversely associated with the risk for GI tumor development (relative risk, 0.77).
• In a subgroup analysis, vegetarian diets were negatively correlated with the risk for gastric cancer (RR, 0.41) and colorectal cancer (RR, 0.85) but not with upper GI cancer (excluding stomach; RR, 0.93).
• Vegetarian diets were negatively correlated with the risk for GI cancer in men (RR, 0.57) but not women (RR, 0.89).
• Vegetarian diets were negatively correlated with the risk for GI cancer in North American (RR, 0.76) and Asian populations (RR, 0.43) but not in European populations (RR, 0.83).

IN PRACTICE:

“The results of this systematic review indicate that adherence to vegetarian diets can reduce the risk of gastrointestinal cancers, compared with non-vegetarian diets. This study provides a reference for primary prevention strategies for gastrointestinal cancers,” the authors write.

SOURCE:

The study, with first author Tongtong Bai, of Nanjing University of Chinese Medicine, was published online on in the European Journal of Gastroenterology & Hepatology.

LIMITATIONS:

The effects of vegetarian diets on GI tumorigenesis may be influenced by gender and geographical region. The heterogeneity of effects of vegetarian diets on different GI cancers could be due to the small number of studies included and could represent chance variation. The results need to be confirmed by studies of populations in other regions. There was evidence of publication bias.

DISCLOSURES:

The study had no specific funding. The authors have disclosed no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

A new study finds SARS-CoV-2 directly infects the coronary vasculature and causes plaque inflammation, which could help explain why people with COVID-19 have an increased risk for ischemic cardiovascular complications up to 1 year after infection.

METHODOLOGY:

• Researchers obtained 27 coronary autopsy specimens from eight patients who died from COVID-19, mean age 70 years and 75% male. All had coronary artery disease and most had cardiovascular risk factors such as hypertension, were overweight or obese, and had hyperlipidemia and type 2 diabetes.
• All but one patient, who was pronounced dead before hospital admission, were hospitalized for an average of 17.6 days.
• To identify SARS-CoV-2 viral RNA (vRNA) in the autoptic coronary vasculature, researchers performed RNA fluorescence in situ hybridization (RNA-FISH) analysis for the vRNA encoding the spike (S) protein; they also probed the antisense strand of the S gene (S antisense), which is only produced during viral replication.

TAKEAWAY:

• The study found evidence of SARS-CoV-2 replication in all analyzed human autopsy coronaries regardless of their pathological classification, although viral replication was highest in early-stage lesions that progress to more advanced atherosclerotic plaques.
• Findings indicated that more than 79% of macrophages (white blood cells that help remove lipids) and more than 90% of foam cells (lipid-laden macrophages that are a hallmark of atherosclerosis at all stages of the disease) are S+, and more than 40% of both cell types are S antisense+, indicating SARS-CoV-2 can infect macrophages at a high rate.
• SARS-CoV-2 induced a strong inflammatory response as evidenced by release of cytokines (including interleukin-1 beta and interluekin-6 that are linked to myocardial infarction) in both macrophages and foam cells, which may contribute to the ischemic cardiovascular complications in patients with COVID-19.

IN PRACTICE:

“Our data conclusively demonstrate that SARS-CoV-2 is capable of infecting and replicating in macrophages within the coronary vasculature of patients with COVID-19,” write the authors, adding that SARS-CoV-2 preferentially replicates in foam cells, compared with other macrophages, suggesting these cells “might act as a reservoir of SARS-CoV-2 viral debris in the atherosclerotic plaque.”

SOURCE:

The study was led by Natalia Eberhardt, PhD, postdoctoral fellow, department of medicine, division of cardiology, New York University, and colleagues. It was published online in Nature Cardiovascular Research.

LIMITATIONS:

Findings are relevant only to the original strains of SARS-CoV-2 that circulated in New York between May 2020 and May 2021, and are not generalizable to patients younger and healthier than those from whom samples were obtained for the study.

DISCLOSURES:

The study received support from the National Institutes of Health. The authors report no relevant financial relationships.

A version of this article appeared on Medscape.com.

TOPLINE:

A new study finds SARS-CoV-2 directly infects the coronary vasculature and causes plaque inflammation, which could help explain why people with COVID-19 have an increased risk for ischemic cardiovascular complications up to 1 year after infection.

METHODOLOGY:

• Researchers obtained 27 coronary autopsy specimens from eight patients who died from COVID-19, mean age 70 years and 75% male. All had coronary artery disease and most had cardiovascular risk factors such as hypertension, were overweight or obese, and had hyperlipidemia and type 2 diabetes.
• All but one patient, who was pronounced dead before hospital admission, were hospitalized for an average of 17.6 days.
• To identify SARS-CoV-2 viral RNA (vRNA) in the autoptic coronary vasculature, researchers performed RNA fluorescence in situ hybridization (RNA-FISH) analysis for the vRNA encoding the spike (S) protein; they also probed the antisense strand of the S gene (S antisense), which is only produced during viral replication.

TAKEAWAY:

• The study found evidence of SARS-CoV-2 replication in all analyzed human autopsy coronaries regardless of their pathological classification, although viral replication was highest in early-stage lesions that progress to more advanced atherosclerotic plaques.
• Findings indicated that more than 79% of macrophages (white blood cells that help remove lipids) and more than 90% of foam cells (lipid-laden macrophages that are a hallmark of atherosclerosis at all stages of the disease) are S+, and more than 40% of both cell types are S antisense+, indicating SARS-CoV-2 can infect macrophages at a high rate.
• SARS-CoV-2 induced a strong inflammatory response as evidenced by release of cytokines (including interleukin-1 beta and interluekin-6 that are linked to myocardial infarction) in both macrophages and foam cells, which may contribute to the ischemic cardiovascular complications in patients with COVID-19.

IN PRACTICE:

“Our data conclusively demonstrate that SARS-CoV-2 is capable of infecting and replicating in macrophages within the coronary vasculature of patients with COVID-19,” write the authors, adding that SARS-CoV-2 preferentially replicates in foam cells, compared with other macrophages, suggesting these cells “might act as a reservoir of SARS-CoV-2 viral debris in the atherosclerotic plaque.”

SOURCE:

The study was led by Natalia Eberhardt, PhD, postdoctoral fellow, department of medicine, division of cardiology, New York University, and colleagues. It was published online in Nature Cardiovascular Research.

LIMITATIONS:

Findings are relevant only to the original strains of SARS-CoV-2 that circulated in New York between May 2020 and May 2021, and are not generalizable to patients younger and healthier than those from whom samples were obtained for the study.

DISCLOSURES:

The study received support from the National Institutes of Health. The authors report no relevant financial relationships.

A version of this article appeared on Medscape.com.

TOPLINE:

A new study finds SARS-CoV-2 directly infects the coronary vasculature and causes plaque inflammation, which could help explain why people with COVID-19 have an increased risk for ischemic cardiovascular complications up to 1 year after infection.

METHODOLOGY:

• Researchers obtained 27 coronary autopsy specimens from eight patients who died from COVID-19, mean age 70 years and 75% male. All had coronary artery disease and most had cardiovascular risk factors such as hypertension, were overweight or obese, and had hyperlipidemia and type 2 diabetes.
• All but one patient, who was pronounced dead before hospital admission, were hospitalized for an average of 17.6 days.
• To identify SARS-CoV-2 viral RNA (vRNA) in the autoptic coronary vasculature, researchers performed RNA fluorescence in situ hybridization (RNA-FISH) analysis for the vRNA encoding the spike (S) protein; they also probed the antisense strand of the S gene (S antisense), which is only produced during viral replication.

TAKEAWAY:

• The study found evidence of SARS-CoV-2 replication in all analyzed human autopsy coronaries regardless of their pathological classification, although viral replication was highest in early-stage lesions that progress to more advanced atherosclerotic plaques.
• Findings indicated that more than 79% of macrophages (white blood cells that help remove lipids) and more than 90% of foam cells (lipid-laden macrophages that are a hallmark of atherosclerosis at all stages of the disease) are S+, and more than 40% of both cell types are S antisense+, indicating SARS-CoV-2 can infect macrophages at a high rate.
• SARS-CoV-2 induced a strong inflammatory response as evidenced by release of cytokines (including interleukin-1 beta and interluekin-6 that are linked to myocardial infarction) in both macrophages and foam cells, which may contribute to the ischemic cardiovascular complications in patients with COVID-19.

IN PRACTICE:

“Our data conclusively demonstrate that SARS-CoV-2 is capable of infecting and replicating in macrophages within the coronary vasculature of patients with COVID-19,” write the authors, adding that SARS-CoV-2 preferentially replicates in foam cells, compared with other macrophages, suggesting these cells “might act as a reservoir of SARS-CoV-2 viral debris in the atherosclerotic plaque.”

SOURCE:

The study was led by Natalia Eberhardt, PhD, postdoctoral fellow, department of medicine, division of cardiology, New York University, and colleagues. It was published online in Nature Cardiovascular Research.

LIMITATIONS:

Findings are relevant only to the original strains of SARS-CoV-2 that circulated in New York between May 2020 and May 2021, and are not generalizable to patients younger and healthier than those from whom samples were obtained for the study.

DISCLOSURES:

The study received support from the National Institutes of Health. The authors report no relevant financial relationships.

A version of this article appeared on Medscape.com.

A 36-year-old woman presents to your office for assistance with weight loss. She usually weighs around 150 lb, but she had two pregnancies in the past 4 years and has gained 70 lb. Her current weight is 220 lb with a body mass index (BMI) of 36.6 kg/m2, and she has been unable to lose any weight despite diet and exercise. She reports back pain and generalized fatigue but is primarily worried about developing type 2 diabetes, which runs in her family. Her insurance covers weight loss medications, but she is asking if she can take “Ozempic off-label” or “compounded semaglutide” instead because Wegovy isn’t available at her local pharmacy.

More and more people are turning to “medical weight management” to drop pounds and improve their health. This is a strategy that adds pharmacotherapy to lifestyle modifications to treat the chronic disease of obesity, and it is analogous to the treatment of high blood pressure or high cholesterol with medications.

This patient meets the criteria set forth by the American Heart Association, American College of Cardiology, and The Obesity Society for the management of obesity with antiobesity medications:

• BMI ≥ 30 or BMI ≥ 27 with weight-related comorbidities and
• Has been unable to achieve ≥ 5% weight loss with lifestyle changes alone.

Several U.S. Food and Drug Administration–approved antiobesity medications have been proven to cause clinically significant weight loss:

• orlistat (Alli or Xenical).
• phentermine/topiramate (Qsymia).
• naltrexone/bupropion (Contrave).
• liraglutide 3.0 mg subcutaneously daily (Saxenda).
• semaglutide 2.4 mg subcutaneously weekly (Wegovy).

When considering an antiobesity medication for a patient, it’s important to discuss efficacy, side-effect profile, contraindications, cost and coverage, and long-term use.

In this commentary, we’ll specifically focus on semaglutide (Wegovy) as it is currently the most effective FDA-approved medication for weight loss.
 

Efficacy

In a phase 3 clinical trial, patients on semaglutide 2.4 mg weekly lost an average of 15% of their body weight at 68 weeks, or approximately 33 lb. It is important to note that there is variability in treatment response to semaglutide 2.4 mg, just like with any other medication. About 1 in 3 individuals lost ≥ 20% of their weight, but about 1 in every 10 patients did not lose any weight.

In this patient, who has a family history of type 2 diabetes, weight loss with semaglutide 2.4 mg will probably reduce her risk of developing diabetes. With just 5%-10% weight loss, she will see improvements in her blood glucose, blood pressure, and cholesterol. Even greater weight loss (≥ 10%) has been associated with resolution of fatty liver and sleep apnea.
 

Side effects

Before starting semaglutide, patients should be counseled about potential gastrointestinal side effects, including nausea, upset stomach, diarrhea, constipation, and reflux.

Side effects can be managed with dietary modifications, over-the-counter treatments, and slow dose escalation. Some common tips include:

• Eat slowly.
• Eat a bland diet.
• Avoid fatty or fried foods.
• Avoid lying down immediately after eating.
• Prioritize water and fiber intake to mitigate constipation.
• Use over-the-counter treatments as needed (for example, laxative for constipation).

Most of these side effects are present only during dose escalation and resolve once the patient is on a stable dose.

Patients should be counseled about the less than 1% risk for gallbladder issues or pancreatitis. They should be instructed to go to an urgent care or emergency room if they develop severe abdominal pain, recurrent vomiting, or the inability to eat or drink.
 

Contraindications

We don’t prescribe GLP-1 receptor agonists, including semaglutide 2.4 mg, in patients with a personal or family history of medullary thyroid cancer. GLP-1 agonists are contraindicated in patients with a history of pancreatitis or gastroparesis. All FDA-approved antiobesity medications are contraindicated in women who are breastfeeding or trying for pregnancy. If this patient would like to pursue pregnancy again, semaglutide 2.4 mg should be stopped 2 months prior to conception.

Access

In this case, the patient’s insurance covered semaglutide 2.4 mg with a copay of $25 per month. Without insurance, semaglutide 2.4 mg (Wegovy) costs about $1,400 per month, and semaglutide 2.0 mg (Ozempic), the formulation approved for type 2 diabetes, costs up to $1,000 per month. These price ranges are often cost-prohibitive and unsustainable, especially because these medications are intended for long-term use.

Currently, Medicare does not cover antiobesity medications nor do most state Medicaid plans. Therefore, these medications are usually not considered by patients who have Medicare or Medicaid insurance.

Because insurance coverage varies and out-of-pocket costs can be prohibitive, many individuals seek other ways of acquiring semaglutide. The off-label use of semaglutide 2.0 mg (Ozempic) for obesity is scientifically supported and safe, whereas the use of compounded semaglutide is risky due to lack of regulation.

Compounded semaglutide should be avoided, given that these products are not controlled by the FDA, and adverse events have been reported in connection with compounded semaglutide.

In our clinical practice, patients have reported advertisements for “generic semaglutide” compounded with vitamins like vitamin B12 or B6. This is a significant area of concern because some vitamins (for instance, vitamin B6) are toxic at high doses.

We discussed the dangers of compounded semaglutide with our patient and told her that this isn’t something we recommend prescribing. If the patient didn’t want to wait for semaglutide 2.4 mg to be available at her pharmacy, we discussed alternative medications used for the management of obesity, such as other FDA-approved GLP-1 agonists (that is, liraglutide 3.0 mg) and off-label medications. In this case, the patient opted to wait for semaglutide 2.4 mg because she preferred a weekly injectable medication, given her busy lifestyle as a new mom.

Dr. Schmitz, of Weill Cornell Medicine, New York, disclosed no relevant financial relationships. Dr. Tchang, of Weill Cornell Medicine and the Iris Cantor Women's Health Center, both in New York, serves or has served as a director, officer, partner, employee, advisor, consultant, or trustee for Gelesis and Novo Nordisk, and has received income from Gelesis.

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

A 36-year-old woman presents to your office for assistance with weight loss. She usually weighs around 150 lb, but she had two pregnancies in the past 4 years and has gained 70 lb. Her current weight is 220 lb with a body mass index (BMI) of 36.6 kg/m2, and she has been unable to lose any weight despite diet and exercise. She reports back pain and generalized fatigue but is primarily worried about developing type 2 diabetes, which runs in her family. Her insurance covers weight loss medications, but she is asking if she can take “Ozempic off-label” or “compounded semaglutide” instead because Wegovy isn’t available at her local pharmacy.

More and more people are turning to “medical weight management” to drop pounds and improve their health. This is a strategy that adds pharmacotherapy to lifestyle modifications to treat the chronic disease of obesity, and it is analogous to the treatment of high blood pressure or high cholesterol with medications.

This patient meets the criteria set forth by the American Heart Association, American College of Cardiology, and The Obesity Society for the management of obesity with antiobesity medications:

• BMI ≥ 30 or BMI ≥ 27 with weight-related comorbidities and
• Has been unable to achieve ≥ 5% weight loss with lifestyle changes alone.

Several U.S. Food and Drug Administration–approved antiobesity medications have been proven to cause clinically significant weight loss:

• orlistat (Alli or Xenical).
• phentermine/topiramate (Qsymia).
• naltrexone/bupropion (Contrave).
• liraglutide 3.0 mg subcutaneously daily (Saxenda).
• semaglutide 2.4 mg subcutaneously weekly (Wegovy).

When considering an antiobesity medication for a patient, it’s important to discuss efficacy, side-effect profile, contraindications, cost and coverage, and long-term use.

In this commentary, we’ll specifically focus on semaglutide (Wegovy) as it is currently the most effective FDA-approved medication for weight loss.
 

Efficacy

In a phase 3 clinical trial, patients on semaglutide 2.4 mg weekly lost an average of 15% of their body weight at 68 weeks, or approximately 33 lb. It is important to note that there is variability in treatment response to semaglutide 2.4 mg, just like with any other medication. About 1 in 3 individuals lost ≥ 20% of their weight, but about 1 in every 10 patients did not lose any weight.

In this patient, who has a family history of type 2 diabetes, weight loss with semaglutide 2.4 mg will probably reduce her risk of developing diabetes. With just 5%-10% weight loss, she will see improvements in her blood glucose, blood pressure, and cholesterol. Even greater weight loss (≥ 10%) has been associated with resolution of fatty liver and sleep apnea.
 

Side effects

Before starting semaglutide, patients should be counseled about potential gastrointestinal side effects, including nausea, upset stomach, diarrhea, constipation, and reflux.

Side effects can be managed with dietary modifications, over-the-counter treatments, and slow dose escalation. Some common tips include:

• Eat slowly.
• Eat a bland diet.
• Avoid fatty or fried foods.
• Avoid lying down immediately after eating.
• Prioritize water and fiber intake to mitigate constipation.
• Use over-the-counter treatments as needed (for example, laxative for constipation).

Most of these side effects are present only during dose escalation and resolve once the patient is on a stable dose.

Patients should be counseled about the less than 1% risk for gallbladder issues or pancreatitis. They should be instructed to go to an urgent care or emergency room if they develop severe abdominal pain, recurrent vomiting, or the inability to eat or drink.
 

Contraindications

We don’t prescribe GLP-1 receptor agonists, including semaglutide 2.4 mg, in patients with a personal or family history of medullary thyroid cancer. GLP-1 agonists are contraindicated in patients with a history of pancreatitis or gastroparesis. All FDA-approved antiobesity medications are contraindicated in women who are breastfeeding or trying for pregnancy. If this patient would like to pursue pregnancy again, semaglutide 2.4 mg should be stopped 2 months prior to conception.

Access

In this case, the patient’s insurance covered semaglutide 2.4 mg with a copay of $25 per month. Without insurance, semaglutide 2.4 mg (Wegovy) costs about $1,400 per month, and semaglutide 2.0 mg (Ozempic), the formulation approved for type 2 diabetes, costs up to $1,000 per month. These price ranges are often cost-prohibitive and unsustainable, especially because these medications are intended for long-term use.

Currently, Medicare does not cover antiobesity medications nor do most state Medicaid plans. Therefore, these medications are usually not considered by patients who have Medicare or Medicaid insurance.

Because insurance coverage varies and out-of-pocket costs can be prohibitive, many individuals seek other ways of acquiring semaglutide. The off-label use of semaglutide 2.0 mg (Ozempic) for obesity is scientifically supported and safe, whereas the use of compounded semaglutide is risky due to lack of regulation.

Compounded semaglutide should be avoided, given that these products are not controlled by the FDA, and adverse events have been reported in connection with compounded semaglutide.

In our clinical practice, patients have reported advertisements for “generic semaglutide” compounded with vitamins like vitamin B12 or B6. This is a significant area of concern because some vitamins (for instance, vitamin B6) are toxic at high doses.

We discussed the dangers of compounded semaglutide with our patient and told her that this isn’t something we recommend prescribing. If the patient didn’t want to wait for semaglutide 2.4 mg to be available at her pharmacy, we discussed alternative medications used for the management of obesity, such as other FDA-approved GLP-1 agonists (that is, liraglutide 3.0 mg) and off-label medications. In this case, the patient opted to wait for semaglutide 2.4 mg because she preferred a weekly injectable medication, given her busy lifestyle as a new mom.

Dr. Schmitz, of Weill Cornell Medicine, New York, disclosed no relevant financial relationships. Dr. Tchang, of Weill Cornell Medicine and the Iris Cantor Women's Health Center, both in New York, serves or has served as a director, officer, partner, employee, advisor, consultant, or trustee for Gelesis and Novo Nordisk, and has received income from Gelesis.

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

A 36-year-old woman presents to your office for assistance with weight loss. She usually weighs around 150 lb, but she had two pregnancies in the past 4 years and has gained 70 lb. Her current weight is 220 lb with a body mass index (BMI) of 36.6 kg/m2, and she has been unable to lose any weight despite diet and exercise. She reports back pain and generalized fatigue but is primarily worried about developing type 2 diabetes, which runs in her family. Her insurance covers weight loss medications, but she is asking if she can take “Ozempic off-label” or “compounded semaglutide” instead because Wegovy isn’t available at her local pharmacy.

More and more people are turning to “medical weight management” to drop pounds and improve their health. This is a strategy that adds pharmacotherapy to lifestyle modifications to treat the chronic disease of obesity, and it is analogous to the treatment of high blood pressure or high cholesterol with medications.

This patient meets the criteria set forth by the American Heart Association, American College of Cardiology, and The Obesity Society for the management of obesity with antiobesity medications:

• BMI ≥ 30 or BMI ≥ 27 with weight-related comorbidities and
• Has been unable to achieve ≥ 5% weight loss with lifestyle changes alone.

Several U.S. Food and Drug Administration–approved antiobesity medications have been proven to cause clinically significant weight loss:

• orlistat (Alli or Xenical).
• phentermine/topiramate (Qsymia).
• naltrexone/bupropion (Contrave).
• liraglutide 3.0 mg subcutaneously daily (Saxenda).
• semaglutide 2.4 mg subcutaneously weekly (Wegovy).

When considering an antiobesity medication for a patient, it’s important to discuss efficacy, side-effect profile, contraindications, cost and coverage, and long-term use.

In this commentary, we’ll specifically focus on semaglutide (Wegovy) as it is currently the most effective FDA-approved medication for weight loss.
 

Efficacy

In a phase 3 clinical trial, patients on semaglutide 2.4 mg weekly lost an average of 15% of their body weight at 68 weeks, or approximately 33 lb. It is important to note that there is variability in treatment response to semaglutide 2.4 mg, just like with any other medication. About 1 in 3 individuals lost ≥ 20% of their weight, but about 1 in every 10 patients did not lose any weight.

In this patient, who has a family history of type 2 diabetes, weight loss with semaglutide 2.4 mg will probably reduce her risk of developing diabetes. With just 5%-10% weight loss, she will see improvements in her blood glucose, blood pressure, and cholesterol. Even greater weight loss (≥ 10%) has been associated with resolution of fatty liver and sleep apnea.
 

Side effects

Before starting semaglutide, patients should be counseled about potential gastrointestinal side effects, including nausea, upset stomach, diarrhea, constipation, and reflux.

Side effects can be managed with dietary modifications, over-the-counter treatments, and slow dose escalation. Some common tips include:

• Eat slowly.
• Eat a bland diet.
• Avoid fatty or fried foods.
• Avoid lying down immediately after eating.
• Prioritize water and fiber intake to mitigate constipation.
• Use over-the-counter treatments as needed (for example, laxative for constipation).

Most of these side effects are present only during dose escalation and resolve once the patient is on a stable dose.

Patients should be counseled about the less than 1% risk for gallbladder issues or pancreatitis. They should be instructed to go to an urgent care or emergency room if they develop severe abdominal pain, recurrent vomiting, or the inability to eat or drink.
 

Contraindications

We don’t prescribe GLP-1 receptor agonists, including semaglutide 2.4 mg, in patients with a personal or family history of medullary thyroid cancer. GLP-1 agonists are contraindicated in patients with a history of pancreatitis or gastroparesis. All FDA-approved antiobesity medications are contraindicated in women who are breastfeeding or trying for pregnancy. If this patient would like to pursue pregnancy again, semaglutide 2.4 mg should be stopped 2 months prior to conception.

Access

In this case, the patient’s insurance covered semaglutide 2.4 mg with a copay of $25 per month. Without insurance, semaglutide 2.4 mg (Wegovy) costs about $1,400 per month, and semaglutide 2.0 mg (Ozempic), the formulation approved for type 2 diabetes, costs up to $1,000 per month. These price ranges are often cost-prohibitive and unsustainable, especially because these medications are intended for long-term use.

Currently, Medicare does not cover antiobesity medications nor do most state Medicaid plans. Therefore, these medications are usually not considered by patients who have Medicare or Medicaid insurance.

Because insurance coverage varies and out-of-pocket costs can be prohibitive, many individuals seek other ways of acquiring semaglutide. The off-label use of semaglutide 2.0 mg (Ozempic) for obesity is scientifically supported and safe, whereas the use of compounded semaglutide is risky due to lack of regulation.

Compounded semaglutide should be avoided, given that these products are not controlled by the FDA, and adverse events have been reported in connection with compounded semaglutide.

In our clinical practice, patients have reported advertisements for “generic semaglutide” compounded with vitamins like vitamin B12 or B6. This is a significant area of concern because some vitamins (for instance, vitamin B6) are toxic at high doses.

We discussed the dangers of compounded semaglutide with our patient and told her that this isn’t something we recommend prescribing. If the patient didn’t want to wait for semaglutide 2.4 mg to be available at her pharmacy, we discussed alternative medications used for the management of obesity, such as other FDA-approved GLP-1 agonists (that is, liraglutide 3.0 mg) and off-label medications. In this case, the patient opted to wait for semaglutide 2.4 mg because she preferred a weekly injectable medication, given her busy lifestyle as a new mom.

Dr. Schmitz, of Weill Cornell Medicine, New York, disclosed no relevant financial relationships. Dr. Tchang, of Weill Cornell Medicine and the Iris Cantor Women's Health Center, both in New York, serves or has served as a director, officer, partner, employee, advisor, consultant, or trustee for Gelesis and Novo Nordisk, and has received income from Gelesis.

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

TOPLINE:

Use of a novel clinical-decision support tool and shared decision-making in elderly patients with type 2 diabetes managed in a primary care practice and at high risk for hypoglycemic episodes led to a 46% decrease in the number of at-risk patients and discontinuation of hypoglycemic agents in 20% in a prospective, 6-month, single-arm study with 94 patients.

METHODOLOGY:

• The HypoPrevent study enrolled 94 people from a Pennsylvania primary care practice who were at least 65 years old with type 2 diabetes and at risk for hypoglycemia because of treatment with insulin or sulfonylureas, and having a hemoglobin A1c of less than 7.0%.
• Clinicians and patients used a newly devised hypoglycemia reduction clinical-decision support tool developed by the Endocrine Society and a health care consulting company to help guide shared decision-making for a goal A1c level, potential changes to treatment, and other steps to reduce the risk of hypoglycemia.
• Primary outcomes during 6-month follow-up were impact of the intervention on A1c, changes in use of insulin or sulfonylureas, change in the number of study patients at risk for hypoglycemia, and impact on the incidence of nonsevere hypoglycemic events (NSHEs) measured with the Treatment-Related Impact Measure–Non-severe Hypoglycemic Events (TRIM-HYPO) survey.

TAKEAWAY:

• Patients averaged 74 years old, 57% were women, 95% were White, 61% had diabetes for more than 10 years, 48% had chronic kidney disease, 51% were on insulin, 47% on a sulfonylurea, and 80 of the 94 enrolled patients completed all three study visits.
• Nineteen patients (20%) reduced their dose of or discontinued insulin or sulfonylurea.
• In patients with both baseline and follow-up A1c measures, A1c rose from 6.29% at baseline to 6.82%.
• Fifty patients set an A1c goal and had a timely follow-up A1c measurement, and in this subgroup the number of patients at risk for hypoglycemia decreased by 46%, a significant change.
• Patients who reported at least one NSHE at baseline had a significant reduction between the baseline survey and follow-up visits in both the total score as well as each of the five scored domains.

IN PRACTICE:

The HypoPrevent study results “show the potential of a decision support tool and shared decision making to reduce the risk of hypoglycemia in older persons with type 2 diabetes,” and that “the tested decision tool can be effectively used by a busy primary care practice with positive results,” concluded the researchers in their report.

SOURCE:

The HypoPrevent study was funded and organized by the Endocrine Society in collaboration with a multicenter team of researchers. The report appeared in the Journal of the American Geriatrics Society.

LIMITATIONS:

Lack of a control group makes it impossible to conclusively determine whether the intervention led to the observed increases in A1c levels, nor can the study exclude regression to the mean as the cause for lowered A1c levels.

DISCLOSURES:

The study received funding from Abbott, Lilly, Merck, Novo Nordisk, and Sanofi. Two coauthors had individual disclosures listed in the report; the other six coauthors had no disclosures.

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

TOPLINE:

Use of a novel clinical-decision support tool and shared decision-making in elderly patients with type 2 diabetes managed in a primary care practice and at high risk for hypoglycemic episodes led to a 46% decrease in the number of at-risk patients and discontinuation of hypoglycemic agents in 20% in a prospective, 6-month, single-arm study with 94 patients.

METHODOLOGY:

• The HypoPrevent study enrolled 94 people from a Pennsylvania primary care practice who were at least 65 years old with type 2 diabetes and at risk for hypoglycemia because of treatment with insulin or sulfonylureas, and having a hemoglobin A1c of less than 7.0%.
• Clinicians and patients used a newly devised hypoglycemia reduction clinical-decision support tool developed by the Endocrine Society and a health care consulting company to help guide shared decision-making for a goal A1c level, potential changes to treatment, and other steps to reduce the risk of hypoglycemia.
• Primary outcomes during 6-month follow-up were impact of the intervention on A1c, changes in use of insulin or sulfonylureas, change in the number of study patients at risk for hypoglycemia, and impact on the incidence of nonsevere hypoglycemic events (NSHEs) measured with the Treatment-Related Impact Measure–Non-severe Hypoglycemic Events (TRIM-HYPO) survey.

TAKEAWAY:

• Patients averaged 74 years old, 57% were women, 95% were White, 61% had diabetes for more than 10 years, 48% had chronic kidney disease, 51% were on insulin, 47% on a sulfonylurea, and 80 of the 94 enrolled patients completed all three study visits.
• Nineteen patients (20%) reduced their dose of or discontinued insulin or sulfonylurea.
• In patients with both baseline and follow-up A1c measures, A1c rose from 6.29% at baseline to 6.82%.
• Fifty patients set an A1c goal and had a timely follow-up A1c measurement, and in this subgroup the number of patients at risk for hypoglycemia decreased by 46%, a significant change.
• Patients who reported at least one NSHE at baseline had a significant reduction between the baseline survey and follow-up visits in both the total score as well as each of the five scored domains.

IN PRACTICE:

The HypoPrevent study results “show the potential of a decision support tool and shared decision making to reduce the risk of hypoglycemia in older persons with type 2 diabetes,” and that “the tested decision tool can be effectively used by a busy primary care practice with positive results,” concluded the researchers in their report.

SOURCE:

The HypoPrevent study was funded and organized by the Endocrine Society in collaboration with a multicenter team of researchers. The report appeared in the Journal of the American Geriatrics Society.

LIMITATIONS:

Lack of a control group makes it impossible to conclusively determine whether the intervention led to the observed increases in A1c levels, nor can the study exclude regression to the mean as the cause for lowered A1c levels.

DISCLOSURES:

The study received funding from Abbott, Lilly, Merck, Novo Nordisk, and Sanofi. Two coauthors had individual disclosures listed in the report; the other six coauthors had no disclosures.

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

TOPLINE:

Use of a novel clinical-decision support tool and shared decision-making in elderly patients with type 2 diabetes managed in a primary care practice and at high risk for hypoglycemic episodes led to a 46% decrease in the number of at-risk patients and discontinuation of hypoglycemic agents in 20% in a prospective, 6-month, single-arm study with 94 patients.

METHODOLOGY:

• The HypoPrevent study enrolled 94 people from a Pennsylvania primary care practice who were at least 65 years old with type 2 diabetes and at risk for hypoglycemia because of treatment with insulin or sulfonylureas, and having a hemoglobin A1c of less than 7.0%.
• Clinicians and patients used a newly devised hypoglycemia reduction clinical-decision support tool developed by the Endocrine Society and a health care consulting company to help guide shared decision-making for a goal A1c level, potential changes to treatment, and other steps to reduce the risk of hypoglycemia.
• Primary outcomes during 6-month follow-up were impact of the intervention on A1c, changes in use of insulin or sulfonylureas, change in the number of study patients at risk for hypoglycemia, and impact on the incidence of nonsevere hypoglycemic events (NSHEs) measured with the Treatment-Related Impact Measure–Non-severe Hypoglycemic Events (TRIM-HYPO) survey.

TAKEAWAY:

• Patients averaged 74 years old, 57% were women, 95% were White, 61% had diabetes for more than 10 years, 48% had chronic kidney disease, 51% were on insulin, 47% on a sulfonylurea, and 80 of the 94 enrolled patients completed all three study visits.
• Nineteen patients (20%) reduced their dose of or discontinued insulin or sulfonylurea.
• In patients with both baseline and follow-up A1c measures, A1c rose from 6.29% at baseline to 6.82%.
• Fifty patients set an A1c goal and had a timely follow-up A1c measurement, and in this subgroup the number of patients at risk for hypoglycemia decreased by 46%, a significant change.
• Patients who reported at least one NSHE at baseline had a significant reduction between the baseline survey and follow-up visits in both the total score as well as each of the five scored domains.

IN PRACTICE:

The HypoPrevent study results “show the potential of a decision support tool and shared decision making to reduce the risk of hypoglycemia in older persons with type 2 diabetes,” and that “the tested decision tool can be effectively used by a busy primary care practice with positive results,” concluded the researchers in their report.

SOURCE:

The HypoPrevent study was funded and organized by the Endocrine Society in collaboration with a multicenter team of researchers. The report appeared in the Journal of the American Geriatrics Society.

LIMITATIONS:

Lack of a control group makes it impossible to conclusively determine whether the intervention led to the observed increases in A1c levels, nor can the study exclude regression to the mean as the cause for lowered A1c levels.

DISCLOSURES:

The study received funding from Abbott, Lilly, Merck, Novo Nordisk, and Sanofi. Two coauthors had individual disclosures listed in the report; the other six coauthors had no disclosures.

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

There have been several recent developments in the treatment of B-cell lymphoma; however, one of the most significant advances has been the development of chimeric antigen receptor (CAR) T-cell therapy. CAR T-cell therapy is a type of personalized immunotherapy that can help cure some people with aggressive non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), the most common form of aggressive NHL. CAR T-cell therapy has revolutionized the treatment of hematologic malignancies over the past 5 years, with impressive response rates and durable remissions for patients who previously had no viable options. This strategy is highly effective in patients with relapsed/refractory DLBCL, as well as mantle cell lymphoma, follicular lymphoma, acute lymphoblastic leukemia (ALL), and multiple myeloma, as evidenced by recent regulatory approvals. 

The initial products, axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel)— both FDA approved in 2017—involve administration of autologous T-cells programmed to express a CAR targeting the B-cell marker CD19. 

In 2021, the FDA also approved lisocabtagene maraleucel (liso-cel), a new CAR T-cell therapy for the treatment of adults with relapsed or refractory (nonresponsive) large B-cell lymphoma (LBCL) have been treated with at least 2 prior lines of therapy. These products have design differences, including differences in the costimulatory domain, mechanism of gene/transgene delivery, ability for cryopreservation, and need for T-cell selection.

The CAR T-cell therapy axi-cel demonstrated superior results in the ZUMA-7 clinical trial, which compared CAR T-cell therapy directly to traditional chemotherapy with intended autologous stem cell transplant (ASCT). About 55% of patients were still alive 4 years after receiving axi-cel, compared with 46% of those who initially received the standard treatment for relapsed disease. Based on these results, axi-cel is now the preferred treatment for people whose DLBCL has recurred with 12 months of front-line treatment or who are resistant to standard initial treatment.

Additionally, the BELINDA trial was a randomized phase 3 trial that compared CAR T-cell therapy with liso-cel with second-line chemotherapy with planned ASCT. Like ZUMA-7, this study also demonstrated an improvement in progression-free survival (PFS) compared to standard treatment. As such, CAR T-cell therapy represents the new standard of care for second-line treatment in appropriate patients with refractory or early relapsing LBCL.

There have been several other recent studies on the use of CAR T-cell therapy for B-cell lymphoma. One study, published in Blood Advances (2023), found that receiving a greater number of therapies prior to CAR T-cell therapy is associated with poorer outcomes in patients with aggressive relapsed/refractory B-cell NHL. The study, which included 514 patients from 13 centers treated with CAR-T for aggressive B-cell NHL between 2015 and 2021, found that a greater number of lines of therapy before CAR-T apheresis and bridging therapy were predictive of inferior PFS and overall survival. 

Another study compared 2 CD19-targeting CAR T-cell treatments, axi-cel and tisa-cel, with ASCT in the second line setting for LBCL. The study found that axi-cel was superior to ASCT, with longer median event-free survival and a higher response rate. However, tisa-cel was not found to be superior to ASCT. Further studies will be needed to definitively characterize the relative benefits of CAR-T cell therapies and standard second-line treatments for different subgroups of patients with LBCL. 

An increasing number of effective targeted agents for DLBCL, including novel monoclonal antibodies (tafasitamab) and antibody-drug conjugates (polatuzumab vedotin and loncastuximab teserine), are being used in earlier lines of therapy. Additionally, 2 anti-CD20 bispecific antibodies (epcoritamab and glofitamab) have gained approval for relapsed/refractory DLBCL due to high response rates. Future studies will be needed to determine if treatment with these agents can produce durable remissions like that of CAR-T cell therapy.

There have been several recent developments in the treatment of B-cell lymphoma; however, one of the most significant advances has been the development of chimeric antigen receptor (CAR) T-cell therapy. CAR T-cell therapy is a type of personalized immunotherapy that can help cure some people with aggressive non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), the most common form of aggressive NHL. CAR T-cell therapy has revolutionized the treatment of hematologic malignancies over the past 5 years, with impressive response rates and durable remissions for patients who previously had no viable options. This strategy is highly effective in patients with relapsed/refractory DLBCL, as well as mantle cell lymphoma, follicular lymphoma, acute lymphoblastic leukemia (ALL), and multiple myeloma, as evidenced by recent regulatory approvals. 

The initial products, axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel)— both FDA approved in 2017—involve administration of autologous T-cells programmed to express a CAR targeting the B-cell marker CD19. 

In 2021, the FDA also approved lisocabtagene maraleucel (liso-cel), a new CAR T-cell therapy for the treatment of adults with relapsed or refractory (nonresponsive) large B-cell lymphoma (LBCL) have been treated with at least 2 prior lines of therapy. These products have design differences, including differences in the costimulatory domain, mechanism of gene/transgene delivery, ability for cryopreservation, and need for T-cell selection.

The CAR T-cell therapy axi-cel demonstrated superior results in the ZUMA-7 clinical trial, which compared CAR T-cell therapy directly to traditional chemotherapy with intended autologous stem cell transplant (ASCT). About 55% of patients were still alive 4 years after receiving axi-cel, compared with 46% of those who initially received the standard treatment for relapsed disease. Based on these results, axi-cel is now the preferred treatment for people whose DLBCL has recurred with 12 months of front-line treatment or who are resistant to standard initial treatment.

Additionally, the BELINDA trial was a randomized phase 3 trial that compared CAR T-cell therapy with liso-cel with second-line chemotherapy with planned ASCT. Like ZUMA-7, this study also demonstrated an improvement in progression-free survival (PFS) compared to standard treatment. As such, CAR T-cell therapy represents the new standard of care for second-line treatment in appropriate patients with refractory or early relapsing LBCL.

There have been several other recent studies on the use of CAR T-cell therapy for B-cell lymphoma. One study, published in Blood Advances (2023), found that receiving a greater number of therapies prior to CAR T-cell therapy is associated with poorer outcomes in patients with aggressive relapsed/refractory B-cell NHL. The study, which included 514 patients from 13 centers treated with CAR-T for aggressive B-cell NHL between 2015 and 2021, found that a greater number of lines of therapy before CAR-T apheresis and bridging therapy were predictive of inferior PFS and overall survival. 

Another study compared 2 CD19-targeting CAR T-cell treatments, axi-cel and tisa-cel, with ASCT in the second line setting for LBCL. The study found that axi-cel was superior to ASCT, with longer median event-free survival and a higher response rate. However, tisa-cel was not found to be superior to ASCT. Further studies will be needed to definitively characterize the relative benefits of CAR-T cell therapies and standard second-line treatments for different subgroups of patients with LBCL. 

An increasing number of effective targeted agents for DLBCL, including novel monoclonal antibodies (tafasitamab) and antibody-drug conjugates (polatuzumab vedotin and loncastuximab teserine), are being used in earlier lines of therapy. Additionally, 2 anti-CD20 bispecific antibodies (epcoritamab and glofitamab) have gained approval for relapsed/refractory DLBCL due to high response rates. Future studies will be needed to determine if treatment with these agents can produce durable remissions like that of CAR-T cell therapy.

There have been several recent developments in the treatment of B-cell lymphoma; however, one of the most significant advances has been the development of chimeric antigen receptor (CAR) T-cell therapy. CAR T-cell therapy is a type of personalized immunotherapy that can help cure some people with aggressive non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), the most common form of aggressive NHL. CAR T-cell therapy has revolutionized the treatment of hematologic malignancies over the past 5 years, with impressive response rates and durable remissions for patients who previously had no viable options. This strategy is highly effective in patients with relapsed/refractory DLBCL, as well as mantle cell lymphoma, follicular lymphoma, acute lymphoblastic leukemia (ALL), and multiple myeloma, as evidenced by recent regulatory approvals. 

The initial products, axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel)— both FDA approved in 2017—involve administration of autologous T-cells programmed to express a CAR targeting the B-cell marker CD19. 

In 2021, the FDA also approved lisocabtagene maraleucel (liso-cel), a new CAR T-cell therapy for the treatment of adults with relapsed or refractory (nonresponsive) large B-cell lymphoma (LBCL) have been treated with at least 2 prior lines of therapy. These products have design differences, including differences in the costimulatory domain, mechanism of gene/transgene delivery, ability for cryopreservation, and need for T-cell selection.

The CAR T-cell therapy axi-cel demonstrated superior results in the ZUMA-7 clinical trial, which compared CAR T-cell therapy directly to traditional chemotherapy with intended autologous stem cell transplant (ASCT). About 55% of patients were still alive 4 years after receiving axi-cel, compared with 46% of those who initially received the standard treatment for relapsed disease. Based on these results, axi-cel is now the preferred treatment for people whose DLBCL has recurred with 12 months of front-line treatment or who are resistant to standard initial treatment.

Additionally, the BELINDA trial was a randomized phase 3 trial that compared CAR T-cell therapy with liso-cel with second-line chemotherapy with planned ASCT. Like ZUMA-7, this study also demonstrated an improvement in progression-free survival (PFS) compared to standard treatment. As such, CAR T-cell therapy represents the new standard of care for second-line treatment in appropriate patients with refractory or early relapsing LBCL.

There have been several other recent studies on the use of CAR T-cell therapy for B-cell lymphoma. One study, published in Blood Advances (2023), found that receiving a greater number of therapies prior to CAR T-cell therapy is associated with poorer outcomes in patients with aggressive relapsed/refractory B-cell NHL. The study, which included 514 patients from 13 centers treated with CAR-T for aggressive B-cell NHL between 2015 and 2021, found that a greater number of lines of therapy before CAR-T apheresis and bridging therapy were predictive of inferior PFS and overall survival. 

Another study compared 2 CD19-targeting CAR T-cell treatments, axi-cel and tisa-cel, with ASCT in the second line setting for LBCL. The study found that axi-cel was superior to ASCT, with longer median event-free survival and a higher response rate. However, tisa-cel was not found to be superior to ASCT. Further studies will be needed to definitively characterize the relative benefits of CAR-T cell therapies and standard second-line treatments for different subgroups of patients with LBCL. 

An increasing number of effective targeted agents for DLBCL, including novel monoclonal antibodies (tafasitamab) and antibody-drug conjugates (polatuzumab vedotin and loncastuximab teserine), are being used in earlier lines of therapy. Additionally, 2 anti-CD20 bispecific antibodies (epcoritamab and glofitamab) have gained approval for relapsed/refractory DLBCL due to high response rates. Future studies will be needed to determine if treatment with these agents can produce durable remissions like that of CAR-T cell therapy.

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

A common, troubling condition

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

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

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

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

Box

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

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

Continue to: Women may be more likely...

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

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

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

Evaluating sleep difficulties

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

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

Treatment options

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

Continue to: Clinicians should understand...

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

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

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

Problems with pharmacotherapy

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

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

Continue to: An alternating medication strategy

 

 

An alternating medication strategy

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

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

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

CASE 1

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

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

Continue to: CASE 2

 

 

CASE 2

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

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

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

CASE 3

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

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

Continue to: Rather than major depressive disorder...

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

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

Bottom Line

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

Related Resources

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

Drug Brand Names

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

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

A common, troubling condition

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

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

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

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

Box

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

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

Continue to: Women may be more likely...

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

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

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

Evaluating sleep difficulties

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

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

Treatment options

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

Continue to: Clinicians should understand...

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

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

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

Problems with pharmacotherapy

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

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

Continue to: An alternating medication strategy

 

 

An alternating medication strategy

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

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

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

CASE 1

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

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

Continue to: CASE 2

 

 

CASE 2

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

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

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

CASE 3

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

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

Continue to: Rather than major depressive disorder...

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

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

Bottom Line

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

Related Resources

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

Drug Brand Names

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

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

A common, troubling condition

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

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

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

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

Box

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

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

Continue to: Women may be more likely...

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

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

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

Evaluating sleep difficulties

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

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

Treatment options

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

Continue to: Clinicians should understand...

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

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

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

Problems with pharmacotherapy

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

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

Continue to: An alternating medication strategy

 

 

An alternating medication strategy

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

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

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

CASE 1

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

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

Continue to: CASE 2

 

 

CASE 2

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

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

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

CASE 3

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

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

Continue to: Rather than major depressive disorder...

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

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

Bottom Line

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

Related Resources

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

Drug Brand Names

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