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How PCPs are penalized for positive outcomes from lifestyle change
The Centers for Medicare & Medicaid Services 2022 National Quality Strategy is described as an “ambitious long-term initiative that aims to promote the highest quality outcomes and safest care for all individuals.” It is a commendable goal for an overburdened U.S. health care system that spends more than other high-income counties yet experiences poorer outcomes. But whole-person, person-centered care cannot be achieved under current misaligned quality measures that fail to measure what we purport to value: the quintuple aim of improved health outcomes, cost savings, patient satisfaction, clinician well-being, and health equity.
Lifestyle first
Clinical practice guidelines for many chronic diseases recommend lifestyle intervention as the first and optimal treatment. A growing body of evidence supports lifestyle behavior interventions to treat and, when used intensively, even reverse common chronic conditions such as cardiovascular disease, obesity, and type 2 diabetes, while also providing effective prevention for those conditions. However, no current quality measures consider lifestyle interventions. In fact, some quality measures unintentionally penalize physicians for successfully treating or reversing disease through lifestyle behavior interventions while rewarding clinicians for meeting process measures – usually adherence to medication – regardless of whether health outcomes improved.
Rewarding medication adherence for the treatment of diseases in which lifestyle is a primary therapy (such as hypertension), combined with other health care constraints (lack of lifestyle education, time to spend with patients, and infrastructure support) incentivizes physicians to skip the conversation about lifestyle changes and go straight to medication prescription. Meanwhile, the clinician who takes the extra time to guide a patient toward lifestyle interventions that could treat their current disease and prevent future diseases – without side effects – is penalized.
Misaligned quality measures like these can stifle clinical judgment and risk reducing the practice of medicine to mindless box-checking. In many cases, patients are not even informed that lifestyle behavior change may be a treatment option (much less the first recommended option) for their conditions. This delivery of care is not person-centered and, in fact, may raise questions about the adequacy of informed treatment consent.
Reimbursement barriers
Lifestyle medicine is a growing medical specialty that uses therapeutic lifestyle interventions as a primary modality to treat chronic conditions. Since certification began in 2017, almost 2500 US physicians and 1000 nonphysician health professionals have earned certification. Health systems, including the U.S. military, are increasingly integrating lifestyle medicine. There have been advancements since one survey found that more than half of lifestyle medicine clinicians reported receiving no reimbursement for lifestyle behavior interventions. However, barriers, especially in fee-for-service systems, still inhibit many patients from receiving insurance coverage for comprehensive, interdisciplinary, and whole-person treatments called intensive therapeutic lifestyle change (ITLC) programs.
Existing comprehensive lifestyle programs that patients are eligible for (ie, the Diabetes Prevention Program and intensive behavioral therapy) are often so poorly reimbursed that clinicians and health systems decline to offer them. An example of a well-reimbursed ITLC program is intensive cardiac rehabilitation (ICR), which remains underutilized and limited to a narrow segment of patients, despite ICR›s proven benefits for managing comorbid risk factors such as hemoglobin A1c and weight. Even when lifestyle intervention programs are available and patients are eligible to participate (often through shared medical appointments), patient copays for the frequent visits required to achieve and sustain behavior change – or the lack of reimbursement for interdisciplinary team members – discourage engagement.
Penalizing successful outcomes
Despite the fact that lifestyle behaviors are top contributors to health and, conversely, contribute to up to 80% of chronic diseases, few quality measures focus on screening for lifestyle factors or treating diseases with lifestyle interventions. An example of an existing quality measure is screening or treatment for harmful substance use.
Specific quality measures that penalize lifestyle medicine approaches include pharmacotherapy for type 2 diabetes, dyslipidemia, osteoporosis, and gout as well as approaches to rheumatoid arthritis.
Statins offer a useful example of the conundrum faced by clinicians who want to offer lifestyle interventions. A lifestyle medicine primary care physician had a patient covered by Medicare Advantage who was diagnosed with hyperlipidemia. The patient had total cholesterol of 226 and a triglycerides level of 132. Instead of prescribing the routine statin, the physician prescribed lifestyle behavior modifications. Within 3 weeks, the patient›s total cholesterol improved to 171 and triglycerides to 75. This was a great success for the delighted patient. However, the CMS 5-Star Rating System assigned the primary care physician a grade of C rather than A, which put the physician›s 5-star rating at risk. Why? Because the system bases its score largely on medication compliance. The physician was penalized despite achieving the optimal health outcome, and at a lower cost than with medication. This misalignment does not incentivize patient-centered care because it disregards patient preference, shared decision-making, and evidence-based practice.
Risk adjustment
Rather than automatically managing disease with ever-increasing quantities of costly medications and procedures, lifestyle medicine clinicians first pursue a goal of health restoration when appropriate. But Medicare risk adjustment incentivizes physicians to manage rather than reverse disease. How much Medicare pays health plans is determined in part by how sick the patients are; the sicker the patient, the more Medicare pays, because those patients› costs are expected to be higher. This ensures that health plans are not penalized for enrolling sicker patients. But a physician utilizing diet alone to achieve remission in a patient with type 2 diabetes is penalized financially because, when the risk is adjusted, diabetes is no longer listed among the patient›s conditions. So, Medicare pays the physician less money. That misalignment incentivizes clinicians to manage the symptoms of type 2 diabetes rather than achieve remission, despite remission being the ideal clinical outcome.
Realigning quality measures
Quality measures were developed to quantify health care processes and outcomes, and to ensure the delivery of safe care to all patients. However, over time the number of quality measures has swelled to 2500, evolving into a confusing, time-consuming, and even soul-crushing responsibility for the physician.
Instead of relying heavily on process measures, we must incentivize outcome measures that honor patient autonomy and allow clinicians to offer lifestyle intervention as the first line of treatment. Risk-score calculations should be adjusted so that we stop incentivizing disease management and penalizing disease reversal.
CMS’s proposed development of “a universal foundation” of quality measures is an opportunity to begin the realignment of quality measures and values. This foundation is intended to establish more consistent and meaningful measures, reduce clinician burnout by streamlining the reporting process, and advance health equity. For this change to be successful, it is vital that lifestyle behavior interventions – optimal nutrition, physical activity, restorative sleep, social connections, stress management, and avoidance of harmful substances – become the foundation of universal quality measures. This will ensure that every clinician is incentivized to discuss lifestyle behaviors with patients and pursue the first clinical step recommended by clinical practice guidelines for most chronic diseases. Only then can we truly deliver high-value, whole-person, person-centered care and achieve the quintuple aim.
Dr. Patel is president-elect, American College of Lifestyle Medicine; Lifestyle Medicine Medical Director, Wellvana Health, Midland, Tex. She has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The Centers for Medicare & Medicaid Services 2022 National Quality Strategy is described as an “ambitious long-term initiative that aims to promote the highest quality outcomes and safest care for all individuals.” It is a commendable goal for an overburdened U.S. health care system that spends more than other high-income counties yet experiences poorer outcomes. But whole-person, person-centered care cannot be achieved under current misaligned quality measures that fail to measure what we purport to value: the quintuple aim of improved health outcomes, cost savings, patient satisfaction, clinician well-being, and health equity.
Lifestyle first
Clinical practice guidelines for many chronic diseases recommend lifestyle intervention as the first and optimal treatment. A growing body of evidence supports lifestyle behavior interventions to treat and, when used intensively, even reverse common chronic conditions such as cardiovascular disease, obesity, and type 2 diabetes, while also providing effective prevention for those conditions. However, no current quality measures consider lifestyle interventions. In fact, some quality measures unintentionally penalize physicians for successfully treating or reversing disease through lifestyle behavior interventions while rewarding clinicians for meeting process measures – usually adherence to medication – regardless of whether health outcomes improved.
Rewarding medication adherence for the treatment of diseases in which lifestyle is a primary therapy (such as hypertension), combined with other health care constraints (lack of lifestyle education, time to spend with patients, and infrastructure support) incentivizes physicians to skip the conversation about lifestyle changes and go straight to medication prescription. Meanwhile, the clinician who takes the extra time to guide a patient toward lifestyle interventions that could treat their current disease and prevent future diseases – without side effects – is penalized.
Misaligned quality measures like these can stifle clinical judgment and risk reducing the practice of medicine to mindless box-checking. In many cases, patients are not even informed that lifestyle behavior change may be a treatment option (much less the first recommended option) for their conditions. This delivery of care is not person-centered and, in fact, may raise questions about the adequacy of informed treatment consent.
Reimbursement barriers
Lifestyle medicine is a growing medical specialty that uses therapeutic lifestyle interventions as a primary modality to treat chronic conditions. Since certification began in 2017, almost 2500 US physicians and 1000 nonphysician health professionals have earned certification. Health systems, including the U.S. military, are increasingly integrating lifestyle medicine. There have been advancements since one survey found that more than half of lifestyle medicine clinicians reported receiving no reimbursement for lifestyle behavior interventions. However, barriers, especially in fee-for-service systems, still inhibit many patients from receiving insurance coverage for comprehensive, interdisciplinary, and whole-person treatments called intensive therapeutic lifestyle change (ITLC) programs.
Existing comprehensive lifestyle programs that patients are eligible for (ie, the Diabetes Prevention Program and intensive behavioral therapy) are often so poorly reimbursed that clinicians and health systems decline to offer them. An example of a well-reimbursed ITLC program is intensive cardiac rehabilitation (ICR), which remains underutilized and limited to a narrow segment of patients, despite ICR›s proven benefits for managing comorbid risk factors such as hemoglobin A1c and weight. Even when lifestyle intervention programs are available and patients are eligible to participate (often through shared medical appointments), patient copays for the frequent visits required to achieve and sustain behavior change – or the lack of reimbursement for interdisciplinary team members – discourage engagement.
Penalizing successful outcomes
Despite the fact that lifestyle behaviors are top contributors to health and, conversely, contribute to up to 80% of chronic diseases, few quality measures focus on screening for lifestyle factors or treating diseases with lifestyle interventions. An example of an existing quality measure is screening or treatment for harmful substance use.
Specific quality measures that penalize lifestyle medicine approaches include pharmacotherapy for type 2 diabetes, dyslipidemia, osteoporosis, and gout as well as approaches to rheumatoid arthritis.
Statins offer a useful example of the conundrum faced by clinicians who want to offer lifestyle interventions. A lifestyle medicine primary care physician had a patient covered by Medicare Advantage who was diagnosed with hyperlipidemia. The patient had total cholesterol of 226 and a triglycerides level of 132. Instead of prescribing the routine statin, the physician prescribed lifestyle behavior modifications. Within 3 weeks, the patient›s total cholesterol improved to 171 and triglycerides to 75. This was a great success for the delighted patient. However, the CMS 5-Star Rating System assigned the primary care physician a grade of C rather than A, which put the physician›s 5-star rating at risk. Why? Because the system bases its score largely on medication compliance. The physician was penalized despite achieving the optimal health outcome, and at a lower cost than with medication. This misalignment does not incentivize patient-centered care because it disregards patient preference, shared decision-making, and evidence-based practice.
Risk adjustment
Rather than automatically managing disease with ever-increasing quantities of costly medications and procedures, lifestyle medicine clinicians first pursue a goal of health restoration when appropriate. But Medicare risk adjustment incentivizes physicians to manage rather than reverse disease. How much Medicare pays health plans is determined in part by how sick the patients are; the sicker the patient, the more Medicare pays, because those patients› costs are expected to be higher. This ensures that health plans are not penalized for enrolling sicker patients. But a physician utilizing diet alone to achieve remission in a patient with type 2 diabetes is penalized financially because, when the risk is adjusted, diabetes is no longer listed among the patient›s conditions. So, Medicare pays the physician less money. That misalignment incentivizes clinicians to manage the symptoms of type 2 diabetes rather than achieve remission, despite remission being the ideal clinical outcome.
Realigning quality measures
Quality measures were developed to quantify health care processes and outcomes, and to ensure the delivery of safe care to all patients. However, over time the number of quality measures has swelled to 2500, evolving into a confusing, time-consuming, and even soul-crushing responsibility for the physician.
Instead of relying heavily on process measures, we must incentivize outcome measures that honor patient autonomy and allow clinicians to offer lifestyle intervention as the first line of treatment. Risk-score calculations should be adjusted so that we stop incentivizing disease management and penalizing disease reversal.
CMS’s proposed development of “a universal foundation” of quality measures is an opportunity to begin the realignment of quality measures and values. This foundation is intended to establish more consistent and meaningful measures, reduce clinician burnout by streamlining the reporting process, and advance health equity. For this change to be successful, it is vital that lifestyle behavior interventions – optimal nutrition, physical activity, restorative sleep, social connections, stress management, and avoidance of harmful substances – become the foundation of universal quality measures. This will ensure that every clinician is incentivized to discuss lifestyle behaviors with patients and pursue the first clinical step recommended by clinical practice guidelines for most chronic diseases. Only then can we truly deliver high-value, whole-person, person-centered care and achieve the quintuple aim.
Dr. Patel is president-elect, American College of Lifestyle Medicine; Lifestyle Medicine Medical Director, Wellvana Health, Midland, Tex. She has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The Centers for Medicare & Medicaid Services 2022 National Quality Strategy is described as an “ambitious long-term initiative that aims to promote the highest quality outcomes and safest care for all individuals.” It is a commendable goal for an overburdened U.S. health care system that spends more than other high-income counties yet experiences poorer outcomes. But whole-person, person-centered care cannot be achieved under current misaligned quality measures that fail to measure what we purport to value: the quintuple aim of improved health outcomes, cost savings, patient satisfaction, clinician well-being, and health equity.
Lifestyle first
Clinical practice guidelines for many chronic diseases recommend lifestyle intervention as the first and optimal treatment. A growing body of evidence supports lifestyle behavior interventions to treat and, when used intensively, even reverse common chronic conditions such as cardiovascular disease, obesity, and type 2 diabetes, while also providing effective prevention for those conditions. However, no current quality measures consider lifestyle interventions. In fact, some quality measures unintentionally penalize physicians for successfully treating or reversing disease through lifestyle behavior interventions while rewarding clinicians for meeting process measures – usually adherence to medication – regardless of whether health outcomes improved.
Rewarding medication adherence for the treatment of diseases in which lifestyle is a primary therapy (such as hypertension), combined with other health care constraints (lack of lifestyle education, time to spend with patients, and infrastructure support) incentivizes physicians to skip the conversation about lifestyle changes and go straight to medication prescription. Meanwhile, the clinician who takes the extra time to guide a patient toward lifestyle interventions that could treat their current disease and prevent future diseases – without side effects – is penalized.
Misaligned quality measures like these can stifle clinical judgment and risk reducing the practice of medicine to mindless box-checking. In many cases, patients are not even informed that lifestyle behavior change may be a treatment option (much less the first recommended option) for their conditions. This delivery of care is not person-centered and, in fact, may raise questions about the adequacy of informed treatment consent.
Reimbursement barriers
Lifestyle medicine is a growing medical specialty that uses therapeutic lifestyle interventions as a primary modality to treat chronic conditions. Since certification began in 2017, almost 2500 US physicians and 1000 nonphysician health professionals have earned certification. Health systems, including the U.S. military, are increasingly integrating lifestyle medicine. There have been advancements since one survey found that more than half of lifestyle medicine clinicians reported receiving no reimbursement for lifestyle behavior interventions. However, barriers, especially in fee-for-service systems, still inhibit many patients from receiving insurance coverage for comprehensive, interdisciplinary, and whole-person treatments called intensive therapeutic lifestyle change (ITLC) programs.
Existing comprehensive lifestyle programs that patients are eligible for (ie, the Diabetes Prevention Program and intensive behavioral therapy) are often so poorly reimbursed that clinicians and health systems decline to offer them. An example of a well-reimbursed ITLC program is intensive cardiac rehabilitation (ICR), which remains underutilized and limited to a narrow segment of patients, despite ICR›s proven benefits for managing comorbid risk factors such as hemoglobin A1c and weight. Even when lifestyle intervention programs are available and patients are eligible to participate (often through shared medical appointments), patient copays for the frequent visits required to achieve and sustain behavior change – or the lack of reimbursement for interdisciplinary team members – discourage engagement.
Penalizing successful outcomes
Despite the fact that lifestyle behaviors are top contributors to health and, conversely, contribute to up to 80% of chronic diseases, few quality measures focus on screening for lifestyle factors or treating diseases with lifestyle interventions. An example of an existing quality measure is screening or treatment for harmful substance use.
Specific quality measures that penalize lifestyle medicine approaches include pharmacotherapy for type 2 diabetes, dyslipidemia, osteoporosis, and gout as well as approaches to rheumatoid arthritis.
Statins offer a useful example of the conundrum faced by clinicians who want to offer lifestyle interventions. A lifestyle medicine primary care physician had a patient covered by Medicare Advantage who was diagnosed with hyperlipidemia. The patient had total cholesterol of 226 and a triglycerides level of 132. Instead of prescribing the routine statin, the physician prescribed lifestyle behavior modifications. Within 3 weeks, the patient›s total cholesterol improved to 171 and triglycerides to 75. This was a great success for the delighted patient. However, the CMS 5-Star Rating System assigned the primary care physician a grade of C rather than A, which put the physician›s 5-star rating at risk. Why? Because the system bases its score largely on medication compliance. The physician was penalized despite achieving the optimal health outcome, and at a lower cost than with medication. This misalignment does not incentivize patient-centered care because it disregards patient preference, shared decision-making, and evidence-based practice.
Risk adjustment
Rather than automatically managing disease with ever-increasing quantities of costly medications and procedures, lifestyle medicine clinicians first pursue a goal of health restoration when appropriate. But Medicare risk adjustment incentivizes physicians to manage rather than reverse disease. How much Medicare pays health plans is determined in part by how sick the patients are; the sicker the patient, the more Medicare pays, because those patients› costs are expected to be higher. This ensures that health plans are not penalized for enrolling sicker patients. But a physician utilizing diet alone to achieve remission in a patient with type 2 diabetes is penalized financially because, when the risk is adjusted, diabetes is no longer listed among the patient›s conditions. So, Medicare pays the physician less money. That misalignment incentivizes clinicians to manage the symptoms of type 2 diabetes rather than achieve remission, despite remission being the ideal clinical outcome.
Realigning quality measures
Quality measures were developed to quantify health care processes and outcomes, and to ensure the delivery of safe care to all patients. However, over time the number of quality measures has swelled to 2500, evolving into a confusing, time-consuming, and even soul-crushing responsibility for the physician.
Instead of relying heavily on process measures, we must incentivize outcome measures that honor patient autonomy and allow clinicians to offer lifestyle intervention as the first line of treatment. Risk-score calculations should be adjusted so that we stop incentivizing disease management and penalizing disease reversal.
CMS’s proposed development of “a universal foundation” of quality measures is an opportunity to begin the realignment of quality measures and values. This foundation is intended to establish more consistent and meaningful measures, reduce clinician burnout by streamlining the reporting process, and advance health equity. For this change to be successful, it is vital that lifestyle behavior interventions – optimal nutrition, physical activity, restorative sleep, social connections, stress management, and avoidance of harmful substances – become the foundation of universal quality measures. This will ensure that every clinician is incentivized to discuss lifestyle behaviors with patients and pursue the first clinical step recommended by clinical practice guidelines for most chronic diseases. Only then can we truly deliver high-value, whole-person, person-centered care and achieve the quintuple aim.
Dr. Patel is president-elect, American College of Lifestyle Medicine; Lifestyle Medicine Medical Director, Wellvana Health, Midland, Tex. She has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
‘Vaginal dryness’ can be fatal. No, really.
This transcript has been edited for clarity.
What do you mean, Dr. Rubin? How is vaginal dryness killing women? We minimize the term vaginal dryness. When women come to our offices and complain of a little vaginal dryness – or they don’t even come to our office to complain of it because the doctor can’t be bothered with a little vaginal dryness — what they don’t understand is that this “little vaginal dryness” is really something called genitourinary syndrome of menopause (GSM). They don’t know that because they’ve never heard of it, and you may have never heard of it either. In 2014, we changed the terms vaginal dryness and vulvovaginal atrophy or atrophic vaginitis to GSM to make it short and simple.
GSM – what does it mean? It’s not just a little vaginal dryness. It turns out that all of the genital and urinary symptoms from menopause just get worse over time. The bladder, the urethra, and the vagina have lots of hormone receptors, including estrogen and testosterone. When the body no longer makes those hormones, the system doesn’t work very well, and genital and urinary symptoms occur that just get worse over time without treatment. Unlike hot flashes, which tend to go away, GSM does not.
What are the symptoms of GSM? Some are sexual: a little vaginal dryness, pain with sex, and worsening orgasm. But there are also genital and urinary symptoms that get worse: itching, burning irritation, rawness, an awareness of their genitals that the patient has never had before. And as a urologist, we see frequency, urgency, and leakage.
The thing that kills women is recurrent urinary tract infections (UTIs). Did you know that UTIs account for 7 million visits and hospitalizations annually and 25% of all infections in older people? In fact, apparently one-third of the total Medicare expenditure is around UTIs. Not preventing UTIs is costing our health care system an enormous amount of money and resources.
Did you know we’ve had safe and effective treatment options for GSM since the 1970s? Vaginal hormones have existed since the 1970s, but we’re using them only for pain with sex and not for GSM. In fact, data show that by using vaginal hormones, we can prevent UTIs by more than 50%. We can save lives using safe, effective, local, low-dose vaginal hormone strategies. And they are safe and effective for all of our patients in pre- and post menopause.
There are five different treatment options: vaginal estrogen inserts, vaginal estrogen creams, vaginal dehydroepiandrosterone (DHEA), low-dose vaginal estrogen rings, and an oral pill option called ospemifene (Osphena). All are used to treat GSM and will only work if your patient actually uses them and continues to use them.
These treatments are safe. They are effective. They do not increase the level of systemic hormones in the bloodstream. I have many patients with breast cancer who use these products as well. The only patients you may want to talk to your oncology colleagues about is women on active aromatase inhibitors.
We have to understand that UTIs kill people and having GSM is debilitating, often requiring pain medication because it can hurt to sit or to wear pads and our patients’ quality of life is severely affected. So please consider learning how to treat GSM. It turns out you don’t have to do exams. You don’t have to do follow-up. You can give these therapies, and women can use them for life.
Now, if your patient has vaginal bleeding, of course they need to see their gynecologist. But this is something every primary care doctor can and should do. As a urologist, we prescribe a lot of tamsulosin (Flomax) for our male patients to help with urination. Vaginal estrogen or DHEA is basically like Flomax for women, but it prevents UTIs and actually works like sildenafil (Viagra) because it can help orgasm and reduce pain with sex.
You have access to affordable, safe, effective treatment options to treat GSM. So check them out and hopefully change the world.
Dr. Rubin is an assistant clinical professor in the department of urology at Georgetown University, Washington. She reported conflicts of interest with Sprout, Maternal Medical, Absorption Pharmaceuticals, GlaxoSmithKline, and Endo.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
What do you mean, Dr. Rubin? How is vaginal dryness killing women? We minimize the term vaginal dryness. When women come to our offices and complain of a little vaginal dryness – or they don’t even come to our office to complain of it because the doctor can’t be bothered with a little vaginal dryness — what they don’t understand is that this “little vaginal dryness” is really something called genitourinary syndrome of menopause (GSM). They don’t know that because they’ve never heard of it, and you may have never heard of it either. In 2014, we changed the terms vaginal dryness and vulvovaginal atrophy or atrophic vaginitis to GSM to make it short and simple.
GSM – what does it mean? It’s not just a little vaginal dryness. It turns out that all of the genital and urinary symptoms from menopause just get worse over time. The bladder, the urethra, and the vagina have lots of hormone receptors, including estrogen and testosterone. When the body no longer makes those hormones, the system doesn’t work very well, and genital and urinary symptoms occur that just get worse over time without treatment. Unlike hot flashes, which tend to go away, GSM does not.
What are the symptoms of GSM? Some are sexual: a little vaginal dryness, pain with sex, and worsening orgasm. But there are also genital and urinary symptoms that get worse: itching, burning irritation, rawness, an awareness of their genitals that the patient has never had before. And as a urologist, we see frequency, urgency, and leakage.
The thing that kills women is recurrent urinary tract infections (UTIs). Did you know that UTIs account for 7 million visits and hospitalizations annually and 25% of all infections in older people? In fact, apparently one-third of the total Medicare expenditure is around UTIs. Not preventing UTIs is costing our health care system an enormous amount of money and resources.
Did you know we’ve had safe and effective treatment options for GSM since the 1970s? Vaginal hormones have existed since the 1970s, but we’re using them only for pain with sex and not for GSM. In fact, data show that by using vaginal hormones, we can prevent UTIs by more than 50%. We can save lives using safe, effective, local, low-dose vaginal hormone strategies. And they are safe and effective for all of our patients in pre- and post menopause.
There are five different treatment options: vaginal estrogen inserts, vaginal estrogen creams, vaginal dehydroepiandrosterone (DHEA), low-dose vaginal estrogen rings, and an oral pill option called ospemifene (Osphena). All are used to treat GSM and will only work if your patient actually uses them and continues to use them.
These treatments are safe. They are effective. They do not increase the level of systemic hormones in the bloodstream. I have many patients with breast cancer who use these products as well. The only patients you may want to talk to your oncology colleagues about is women on active aromatase inhibitors.
We have to understand that UTIs kill people and having GSM is debilitating, often requiring pain medication because it can hurt to sit or to wear pads and our patients’ quality of life is severely affected. So please consider learning how to treat GSM. It turns out you don’t have to do exams. You don’t have to do follow-up. You can give these therapies, and women can use them for life.
Now, if your patient has vaginal bleeding, of course they need to see their gynecologist. But this is something every primary care doctor can and should do. As a urologist, we prescribe a lot of tamsulosin (Flomax) for our male patients to help with urination. Vaginal estrogen or DHEA is basically like Flomax for women, but it prevents UTIs and actually works like sildenafil (Viagra) because it can help orgasm and reduce pain with sex.
You have access to affordable, safe, effective treatment options to treat GSM. So check them out and hopefully change the world.
Dr. Rubin is an assistant clinical professor in the department of urology at Georgetown University, Washington. She reported conflicts of interest with Sprout, Maternal Medical, Absorption Pharmaceuticals, GlaxoSmithKline, and Endo.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
What do you mean, Dr. Rubin? How is vaginal dryness killing women? We minimize the term vaginal dryness. When women come to our offices and complain of a little vaginal dryness – or they don’t even come to our office to complain of it because the doctor can’t be bothered with a little vaginal dryness — what they don’t understand is that this “little vaginal dryness” is really something called genitourinary syndrome of menopause (GSM). They don’t know that because they’ve never heard of it, and you may have never heard of it either. In 2014, we changed the terms vaginal dryness and vulvovaginal atrophy or atrophic vaginitis to GSM to make it short and simple.
GSM – what does it mean? It’s not just a little vaginal dryness. It turns out that all of the genital and urinary symptoms from menopause just get worse over time. The bladder, the urethra, and the vagina have lots of hormone receptors, including estrogen and testosterone. When the body no longer makes those hormones, the system doesn’t work very well, and genital and urinary symptoms occur that just get worse over time without treatment. Unlike hot flashes, which tend to go away, GSM does not.
What are the symptoms of GSM? Some are sexual: a little vaginal dryness, pain with sex, and worsening orgasm. But there are also genital and urinary symptoms that get worse: itching, burning irritation, rawness, an awareness of their genitals that the patient has never had before. And as a urologist, we see frequency, urgency, and leakage.
The thing that kills women is recurrent urinary tract infections (UTIs). Did you know that UTIs account for 7 million visits and hospitalizations annually and 25% of all infections in older people? In fact, apparently one-third of the total Medicare expenditure is around UTIs. Not preventing UTIs is costing our health care system an enormous amount of money and resources.
Did you know we’ve had safe and effective treatment options for GSM since the 1970s? Vaginal hormones have existed since the 1970s, but we’re using them only for pain with sex and not for GSM. In fact, data show that by using vaginal hormones, we can prevent UTIs by more than 50%. We can save lives using safe, effective, local, low-dose vaginal hormone strategies. And they are safe and effective for all of our patients in pre- and post menopause.
There are five different treatment options: vaginal estrogen inserts, vaginal estrogen creams, vaginal dehydroepiandrosterone (DHEA), low-dose vaginal estrogen rings, and an oral pill option called ospemifene (Osphena). All are used to treat GSM and will only work if your patient actually uses them and continues to use them.
These treatments are safe. They are effective. They do not increase the level of systemic hormones in the bloodstream. I have many patients with breast cancer who use these products as well. The only patients you may want to talk to your oncology colleagues about is women on active aromatase inhibitors.
We have to understand that UTIs kill people and having GSM is debilitating, often requiring pain medication because it can hurt to sit or to wear pads and our patients’ quality of life is severely affected. So please consider learning how to treat GSM. It turns out you don’t have to do exams. You don’t have to do follow-up. You can give these therapies, and women can use them for life.
Now, if your patient has vaginal bleeding, of course they need to see their gynecologist. But this is something every primary care doctor can and should do. As a urologist, we prescribe a lot of tamsulosin (Flomax) for our male patients to help with urination. Vaginal estrogen or DHEA is basically like Flomax for women, but it prevents UTIs and actually works like sildenafil (Viagra) because it can help orgasm and reduce pain with sex.
You have access to affordable, safe, effective treatment options to treat GSM. So check them out and hopefully change the world.
Dr. Rubin is an assistant clinical professor in the department of urology at Georgetown University, Washington. She reported conflicts of interest with Sprout, Maternal Medical, Absorption Pharmaceuticals, GlaxoSmithKline, and Endo.
A version of this article first appeared on Medscape.com.
Zuranolone: FAQs for clinicians and patients
The Food and Drug Administration approval of zuranolone for postpartum depression in August 2023 has raised many important questions (and opinions) about its future use in clinical practice.
At the UNC-Chapel Hill Center for Women’s Mood Disorders, we treat women and pregnant people throughout hormonal transitions, including pregnancy and the postpartum, and have been part of development, research, and now delivery of both brexanolone and zuranolone. While we are excited about new tools in the arsenal for alleviating maternal mental health, we also want to be clear that our work is far from complete and continued efforts to care for pregnant people and their families are imperative.
What is zuranolone?
Zuranolone (brand name Zurzuvae) is an oral medication developed by Sage Therapeutics and Biogen. It is a positive allosteric modulator of the GABAA receptor, the brain’s major inhibitory system. As a positive allosteric modulator, it increases the sensitivity of the GABAA receptor to GABA.
Zuranolone is very similar to brexanolone, a synthetic form of allopregnanolone, a neurosteroid byproduct of progesterone (see below). However, zuranolone is not an oral form of brexanolone – it was slightly modified to ensure good oral stability and bioavailability. It is metabolized by the hepatic enzyme CYP3A4 and has a half-life of 16-23 hours. Zurzuvae is currently produced in capsule form.
What does zuranolone treat?
Zuranolone is the first FDA-approved oral drug for postpartum depression (PPD). It follows brexanolone, an intravenous drug, which was the first FDA-approved medication for PPD. Though these are the first medications with specific approval for PDD, many other treatment options are currently available including therapy, SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), and other treatments used in major depression.
How does zuranolone work?
Zuranolone is a neuroactive steroid, which means that it is a steroid that goes into and acts on the brain. Zuranolone binds to different GABA receptor subunits from those bound by other positive modulators, such as benzodiazepines (for example, lorazepam). As a synthetic form of allopregnanolone, a metabolite of progesterone which rises dramatically in pregnancy then drops during labor and delivery, zuranolone was originally thought to mitigate the response to this drop in patients that are vulnerable to it during the postpartum. An alternative proposed mechanism is that the increased GABAergic, inhibitory signaling with zuranolone may act directly to decrease depression irrespective of the exact mechanism by which the depression occurred.
How was it studied?
Zuranolone was studied in women with severe postpartum depression and had to meet criteria for major depressive disorder (MDD) no earlier than the third trimester of pregnancy (about 28 weeks’ gestation) and no later than 4 weeks post partum. Patients were excluded from these studies if they had a history of bipolar disorder, psychotic disorders, attempted suicide, or if they were at risk for suicide.
The two phase 3 clinical trials that led to FDA approval are ROBIN and SKYLARK. These studies measured the efficacy and safety of zuranolone at 30 mg and 50 mg, respectively, and met their end points of rapid improvement in depressive and anxiety symptoms in postpartum depression.
When will we be able to start using it?
It is anticipated that zuranolone will become commercially available in early 2024.
Who can prescribe it?
Those with medical licenses. Most people will likely receive treatment from their obstetric, family medicine, or psychiatric clinicians.
How much will it cost?
The manufacturers have not released this information as of August 2023.
What sort of doses and duration is recommended?
The current FDA recommended dose is 50 mg for 14 days, taken once per evening with a fatty meal. The dose can be reduced to 40 mg if there are central nervous system (CNS) depressant effects, and to 30 mg if the patient has severe hepatic or moderate-severe renal impairment. There are currently no studies on longer courses of treatment.
What happens if the patient relapses after a 14-day trial?
While there is no clear guidance, an open-label trial (The SHORELINE Study) demonstrated that a repeated 14-day administration can restore clinical response.
What are the side effects?
Common side effects include drowsiness, dizziness, lower energy, diarrhea, and symptoms similar to the common cold. Zuranolone can act like a CNS depressant and can lead to sedation and somnolence.
Are there any boxed warnings?
Because of the CNS depressant effects, zuranolone was given a boxed warning that patients should not drive or operate heavy machinery within 12 hours of taking the medication as it may lead to impairment. Similar to other antidepressants, there is also a warning that zuranolone may increase risk for suicidal thoughts in patients under 24 years old.
Can it be used with other medications?
Yes. In the original trials, women were allowed to remain on medications treating their depressive symptoms (such as SSRIs and SNRIs). According to the FDA, zuranolone can be used alone or with other antidepressants.
Are there any medicines to avoid?
We recommend caution with other medications which may increase sedation, such as benzodiazepines.
Can it be used with birth control?
Yes. In fact, because the outcomes on a fetus are not yet studied, it is recommended that patients be on concurrent birth control during treatment and for a week after cessation. This does not mean that zuranolone is known to cause issues with fetal development, but rather that we do not know at this time.
Can it be used in pregnancy?
As above, the outcomes on fetal development are not known at this time, nor are the effects of zuranolone on labor and delivery. More research will need to be done to understand if there is risk with taking zuranolone during pregnancy. It should be noted that allopregnanolone levels ordinarily reach quite high levels during pregnancy.
Long-term side effects?
Long-term side effects are unknown. The study duration of ROBIN and SKYLARK was 45 days.
Breastfeeding?
Use in lactation has not yet been studied. Continued research is needed.
Can it be used in mood changes related to other reproductive changes or diagnoses like premenstrual dysphoric disorder and perimenopause?
The mechanism by which zuranolone is thought to work – that is, during changes in reproductive hormones – is implicated in other reproductive transitions such as premenstrual dysphoric disorder and perimenopause when reproductive hormones are fluctuating, though at lower levels than in pregnancy. Research will be required to assess efficacy and safety; however, the mechanistic reasons is worth pursuing. Additionally, zuranolone has not been studied in postpartum psychosis.
Can zuranolone be used to treat other affective conditions besides postpartum depression? Bipolar disorder?
Whether it may be beneficial for patients with a depressive episode that is part of an underlying bipolar disorder or other psychiatric illness is not yet known.
Anxiety?
Along with depressive symptoms, women who received zuranolone in the clinical trials also had improvements in anxiety symptoms. These findings provide some hope that zuranolone may eventually be beneficial in patients with anxiety.
However, to date zuranolone has not been directly studied as a treatment for anxiety disorders (such as generalized anxiety disorder, panic disorder, etc.), so its efficacy for these illnesses is currently unknown.
Insomnia?
In a study of 153 postpartum women, randomized to placebo or zuranolone, scale questions for insomnia were improved in the group receiving zuranolone. This provides some hope that, if zuranolone is appropriate, concurrent polypharmacy with a sleep aid can be avoided. Additionally, future evaluation of use in insomnia outside of PPD may be warranted.
How is it different from brexanolone?
The two are slightly different molecules. Brexanolone is synthetically identical to allopregnanolone and zuranolone has been altered to be active and orally bioavailable.
Brexanolone is a 60-hour infusion that requires hospital admission at an approved health care site. Zuranolone is an oral at-home once-daily dosing treatment for 14 days. Zuranolone does not require enrollment in a risk evaluation and mitigation strategy for risk of excessive sedation and sudden loss of consciousness.
When would you consider zuranolone vs. brexanolone vs. other antidepressants?
Zuranolone and brexanolone are rapid-acting antidepressants with a response within 14 days or 60 hours, respectively. Antidepressants such as SSRIs/SNRIs are still available, well studied, and work, although take longer to reach clinical efficacy and are accompanied by potentially troubling side effects (for example, weight gain, sexual dysfunction).
Time to treatment effect should be considered when assessing severity of symptoms and functional impairment of the mother and the overall family unit. Brexanolone requires continuous monitoring which may be beneficial for women who are severely impaired and may benefit from frequent clinical monitoring. Brexanolone does not require a dose reduction with hepatic impairment, however, should be avoided in end-stage renal disease because of the potential accumulation of the solubilizing agent.
Where can I find more information?
Many states have maternal mental health consultation lines (examples include NCMATTERS here in North Carolina and MCPAP for Moms in Massachusetts) for clinicians (mental health, primary care, and obstetricians) that can be utilized for questions about prescribing. Postpartum Support International also has a clinician line for those without state services.
We plan to update this entry upon market release and access to new information.
Dr. Riddle and Dr. Nathan are assistant professors in the department of psychiatry at the University of North Carolina at Chapel Hill. Dr. Richardson is a perinatal psychiatry fellow, department of psychiatry, UNC-Chapel Hill. Dr. Rubinow is Distinguished Professor in the department of psychiatry, UNC-Chapel Hill. Dr. Meltzer-Brody is Assad Meymandi Distinguished Professor and Chair, department of psychiatry, UNC-Chapel Hill.
References
Deligiannidis KM et al. J Clin Psychiatry. 2023 Jan 30;84(1):22m14475. doi: 10.4088/JCP.22m14475.
Deligiannidis KM et al. . Obstetrics & Gynecology. 2023 May;141(5S):64S-65S. doi: 10.1097/01.AOG.0000930588.16136.3f.
Deligiannidis KM et al. Am J Psychiatry. 2023 Sep 1;180(9):668-75. doi: 10.1176/appi.ajp.20220785.
Deligiannidis KM et al. JAMA Psychiatry. 2021 Sep 1;78(9):951-59. doi: 10.1001/jamapsychiatry.2021.1559.
FDA Approves First Oral Treatment for Postpartum Depression. 2023 Aug 4. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-treatment-postpartum-depression
ZURZUVAE – HIGHLIGHTS OF PRESCRIBING INFORMATION. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217369s000lbl.pdf
The Food and Drug Administration approval of zuranolone for postpartum depression in August 2023 has raised many important questions (and opinions) about its future use in clinical practice.
At the UNC-Chapel Hill Center for Women’s Mood Disorders, we treat women and pregnant people throughout hormonal transitions, including pregnancy and the postpartum, and have been part of development, research, and now delivery of both brexanolone and zuranolone. While we are excited about new tools in the arsenal for alleviating maternal mental health, we also want to be clear that our work is far from complete and continued efforts to care for pregnant people and their families are imperative.
What is zuranolone?
Zuranolone (brand name Zurzuvae) is an oral medication developed by Sage Therapeutics and Biogen. It is a positive allosteric modulator of the GABAA receptor, the brain’s major inhibitory system. As a positive allosteric modulator, it increases the sensitivity of the GABAA receptor to GABA.
Zuranolone is very similar to brexanolone, a synthetic form of allopregnanolone, a neurosteroid byproduct of progesterone (see below). However, zuranolone is not an oral form of brexanolone – it was slightly modified to ensure good oral stability and bioavailability. It is metabolized by the hepatic enzyme CYP3A4 and has a half-life of 16-23 hours. Zurzuvae is currently produced in capsule form.
What does zuranolone treat?
Zuranolone is the first FDA-approved oral drug for postpartum depression (PPD). It follows brexanolone, an intravenous drug, which was the first FDA-approved medication for PPD. Though these are the first medications with specific approval for PDD, many other treatment options are currently available including therapy, SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), and other treatments used in major depression.
How does zuranolone work?
Zuranolone is a neuroactive steroid, which means that it is a steroid that goes into and acts on the brain. Zuranolone binds to different GABA receptor subunits from those bound by other positive modulators, such as benzodiazepines (for example, lorazepam). As a synthetic form of allopregnanolone, a metabolite of progesterone which rises dramatically in pregnancy then drops during labor and delivery, zuranolone was originally thought to mitigate the response to this drop in patients that are vulnerable to it during the postpartum. An alternative proposed mechanism is that the increased GABAergic, inhibitory signaling with zuranolone may act directly to decrease depression irrespective of the exact mechanism by which the depression occurred.
How was it studied?
Zuranolone was studied in women with severe postpartum depression and had to meet criteria for major depressive disorder (MDD) no earlier than the third trimester of pregnancy (about 28 weeks’ gestation) and no later than 4 weeks post partum. Patients were excluded from these studies if they had a history of bipolar disorder, psychotic disorders, attempted suicide, or if they were at risk for suicide.
The two phase 3 clinical trials that led to FDA approval are ROBIN and SKYLARK. These studies measured the efficacy and safety of zuranolone at 30 mg and 50 mg, respectively, and met their end points of rapid improvement in depressive and anxiety symptoms in postpartum depression.
When will we be able to start using it?
It is anticipated that zuranolone will become commercially available in early 2024.
Who can prescribe it?
Those with medical licenses. Most people will likely receive treatment from their obstetric, family medicine, or psychiatric clinicians.
How much will it cost?
The manufacturers have not released this information as of August 2023.
What sort of doses and duration is recommended?
The current FDA recommended dose is 50 mg for 14 days, taken once per evening with a fatty meal. The dose can be reduced to 40 mg if there are central nervous system (CNS) depressant effects, and to 30 mg if the patient has severe hepatic or moderate-severe renal impairment. There are currently no studies on longer courses of treatment.
What happens if the patient relapses after a 14-day trial?
While there is no clear guidance, an open-label trial (The SHORELINE Study) demonstrated that a repeated 14-day administration can restore clinical response.
What are the side effects?
Common side effects include drowsiness, dizziness, lower energy, diarrhea, and symptoms similar to the common cold. Zuranolone can act like a CNS depressant and can lead to sedation and somnolence.
Are there any boxed warnings?
Because of the CNS depressant effects, zuranolone was given a boxed warning that patients should not drive or operate heavy machinery within 12 hours of taking the medication as it may lead to impairment. Similar to other antidepressants, there is also a warning that zuranolone may increase risk for suicidal thoughts in patients under 24 years old.
Can it be used with other medications?
Yes. In the original trials, women were allowed to remain on medications treating their depressive symptoms (such as SSRIs and SNRIs). According to the FDA, zuranolone can be used alone or with other antidepressants.
Are there any medicines to avoid?
We recommend caution with other medications which may increase sedation, such as benzodiazepines.
Can it be used with birth control?
Yes. In fact, because the outcomes on a fetus are not yet studied, it is recommended that patients be on concurrent birth control during treatment and for a week after cessation. This does not mean that zuranolone is known to cause issues with fetal development, but rather that we do not know at this time.
Can it be used in pregnancy?
As above, the outcomes on fetal development are not known at this time, nor are the effects of zuranolone on labor and delivery. More research will need to be done to understand if there is risk with taking zuranolone during pregnancy. It should be noted that allopregnanolone levels ordinarily reach quite high levels during pregnancy.
Long-term side effects?
Long-term side effects are unknown. The study duration of ROBIN and SKYLARK was 45 days.
Breastfeeding?
Use in lactation has not yet been studied. Continued research is needed.
Can it be used in mood changes related to other reproductive changes or diagnoses like premenstrual dysphoric disorder and perimenopause?
The mechanism by which zuranolone is thought to work – that is, during changes in reproductive hormones – is implicated in other reproductive transitions such as premenstrual dysphoric disorder and perimenopause when reproductive hormones are fluctuating, though at lower levels than in pregnancy. Research will be required to assess efficacy and safety; however, the mechanistic reasons is worth pursuing. Additionally, zuranolone has not been studied in postpartum psychosis.
Can zuranolone be used to treat other affective conditions besides postpartum depression? Bipolar disorder?
Whether it may be beneficial for patients with a depressive episode that is part of an underlying bipolar disorder or other psychiatric illness is not yet known.
Anxiety?
Along with depressive symptoms, women who received zuranolone in the clinical trials also had improvements in anxiety symptoms. These findings provide some hope that zuranolone may eventually be beneficial in patients with anxiety.
However, to date zuranolone has not been directly studied as a treatment for anxiety disorders (such as generalized anxiety disorder, panic disorder, etc.), so its efficacy for these illnesses is currently unknown.
Insomnia?
In a study of 153 postpartum women, randomized to placebo or zuranolone, scale questions for insomnia were improved in the group receiving zuranolone. This provides some hope that, if zuranolone is appropriate, concurrent polypharmacy with a sleep aid can be avoided. Additionally, future evaluation of use in insomnia outside of PPD may be warranted.
How is it different from brexanolone?
The two are slightly different molecules. Brexanolone is synthetically identical to allopregnanolone and zuranolone has been altered to be active and orally bioavailable.
Brexanolone is a 60-hour infusion that requires hospital admission at an approved health care site. Zuranolone is an oral at-home once-daily dosing treatment for 14 days. Zuranolone does not require enrollment in a risk evaluation and mitigation strategy for risk of excessive sedation and sudden loss of consciousness.
When would you consider zuranolone vs. brexanolone vs. other antidepressants?
Zuranolone and brexanolone are rapid-acting antidepressants with a response within 14 days or 60 hours, respectively. Antidepressants such as SSRIs/SNRIs are still available, well studied, and work, although take longer to reach clinical efficacy and are accompanied by potentially troubling side effects (for example, weight gain, sexual dysfunction).
Time to treatment effect should be considered when assessing severity of symptoms and functional impairment of the mother and the overall family unit. Brexanolone requires continuous monitoring which may be beneficial for women who are severely impaired and may benefit from frequent clinical monitoring. Brexanolone does not require a dose reduction with hepatic impairment, however, should be avoided in end-stage renal disease because of the potential accumulation of the solubilizing agent.
Where can I find more information?
Many states have maternal mental health consultation lines (examples include NCMATTERS here in North Carolina and MCPAP for Moms in Massachusetts) for clinicians (mental health, primary care, and obstetricians) that can be utilized for questions about prescribing. Postpartum Support International also has a clinician line for those without state services.
We plan to update this entry upon market release and access to new information.
Dr. Riddle and Dr. Nathan are assistant professors in the department of psychiatry at the University of North Carolina at Chapel Hill. Dr. Richardson is a perinatal psychiatry fellow, department of psychiatry, UNC-Chapel Hill. Dr. Rubinow is Distinguished Professor in the department of psychiatry, UNC-Chapel Hill. Dr. Meltzer-Brody is Assad Meymandi Distinguished Professor and Chair, department of psychiatry, UNC-Chapel Hill.
References
Deligiannidis KM et al. J Clin Psychiatry. 2023 Jan 30;84(1):22m14475. doi: 10.4088/JCP.22m14475.
Deligiannidis KM et al. . Obstetrics & Gynecology. 2023 May;141(5S):64S-65S. doi: 10.1097/01.AOG.0000930588.16136.3f.
Deligiannidis KM et al. Am J Psychiatry. 2023 Sep 1;180(9):668-75. doi: 10.1176/appi.ajp.20220785.
Deligiannidis KM et al. JAMA Psychiatry. 2021 Sep 1;78(9):951-59. doi: 10.1001/jamapsychiatry.2021.1559.
FDA Approves First Oral Treatment for Postpartum Depression. 2023 Aug 4. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-treatment-postpartum-depression
ZURZUVAE – HIGHLIGHTS OF PRESCRIBING INFORMATION. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217369s000lbl.pdf
The Food and Drug Administration approval of zuranolone for postpartum depression in August 2023 has raised many important questions (and opinions) about its future use in clinical practice.
At the UNC-Chapel Hill Center for Women’s Mood Disorders, we treat women and pregnant people throughout hormonal transitions, including pregnancy and the postpartum, and have been part of development, research, and now delivery of both brexanolone and zuranolone. While we are excited about new tools in the arsenal for alleviating maternal mental health, we also want to be clear that our work is far from complete and continued efforts to care for pregnant people and their families are imperative.
What is zuranolone?
Zuranolone (brand name Zurzuvae) is an oral medication developed by Sage Therapeutics and Biogen. It is a positive allosteric modulator of the GABAA receptor, the brain’s major inhibitory system. As a positive allosteric modulator, it increases the sensitivity of the GABAA receptor to GABA.
Zuranolone is very similar to brexanolone, a synthetic form of allopregnanolone, a neurosteroid byproduct of progesterone (see below). However, zuranolone is not an oral form of brexanolone – it was slightly modified to ensure good oral stability and bioavailability. It is metabolized by the hepatic enzyme CYP3A4 and has a half-life of 16-23 hours. Zurzuvae is currently produced in capsule form.
What does zuranolone treat?
Zuranolone is the first FDA-approved oral drug for postpartum depression (PPD). It follows brexanolone, an intravenous drug, which was the first FDA-approved medication for PPD. Though these are the first medications with specific approval for PDD, many other treatment options are currently available including therapy, SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), and other treatments used in major depression.
How does zuranolone work?
Zuranolone is a neuroactive steroid, which means that it is a steroid that goes into and acts on the brain. Zuranolone binds to different GABA receptor subunits from those bound by other positive modulators, such as benzodiazepines (for example, lorazepam). As a synthetic form of allopregnanolone, a metabolite of progesterone which rises dramatically in pregnancy then drops during labor and delivery, zuranolone was originally thought to mitigate the response to this drop in patients that are vulnerable to it during the postpartum. An alternative proposed mechanism is that the increased GABAergic, inhibitory signaling with zuranolone may act directly to decrease depression irrespective of the exact mechanism by which the depression occurred.
How was it studied?
Zuranolone was studied in women with severe postpartum depression and had to meet criteria for major depressive disorder (MDD) no earlier than the third trimester of pregnancy (about 28 weeks’ gestation) and no later than 4 weeks post partum. Patients were excluded from these studies if they had a history of bipolar disorder, psychotic disorders, attempted suicide, or if they were at risk for suicide.
The two phase 3 clinical trials that led to FDA approval are ROBIN and SKYLARK. These studies measured the efficacy and safety of zuranolone at 30 mg and 50 mg, respectively, and met their end points of rapid improvement in depressive and anxiety symptoms in postpartum depression.
When will we be able to start using it?
It is anticipated that zuranolone will become commercially available in early 2024.
Who can prescribe it?
Those with medical licenses. Most people will likely receive treatment from their obstetric, family medicine, or psychiatric clinicians.
How much will it cost?
The manufacturers have not released this information as of August 2023.
What sort of doses and duration is recommended?
The current FDA recommended dose is 50 mg for 14 days, taken once per evening with a fatty meal. The dose can be reduced to 40 mg if there are central nervous system (CNS) depressant effects, and to 30 mg if the patient has severe hepatic or moderate-severe renal impairment. There are currently no studies on longer courses of treatment.
What happens if the patient relapses after a 14-day trial?
While there is no clear guidance, an open-label trial (The SHORELINE Study) demonstrated that a repeated 14-day administration can restore clinical response.
What are the side effects?
Common side effects include drowsiness, dizziness, lower energy, diarrhea, and symptoms similar to the common cold. Zuranolone can act like a CNS depressant and can lead to sedation and somnolence.
Are there any boxed warnings?
Because of the CNS depressant effects, zuranolone was given a boxed warning that patients should not drive or operate heavy machinery within 12 hours of taking the medication as it may lead to impairment. Similar to other antidepressants, there is also a warning that zuranolone may increase risk for suicidal thoughts in patients under 24 years old.
Can it be used with other medications?
Yes. In the original trials, women were allowed to remain on medications treating their depressive symptoms (such as SSRIs and SNRIs). According to the FDA, zuranolone can be used alone or with other antidepressants.
Are there any medicines to avoid?
We recommend caution with other medications which may increase sedation, such as benzodiazepines.
Can it be used with birth control?
Yes. In fact, because the outcomes on a fetus are not yet studied, it is recommended that patients be on concurrent birth control during treatment and for a week after cessation. This does not mean that zuranolone is known to cause issues with fetal development, but rather that we do not know at this time.
Can it be used in pregnancy?
As above, the outcomes on fetal development are not known at this time, nor are the effects of zuranolone on labor and delivery. More research will need to be done to understand if there is risk with taking zuranolone during pregnancy. It should be noted that allopregnanolone levels ordinarily reach quite high levels during pregnancy.
Long-term side effects?
Long-term side effects are unknown. The study duration of ROBIN and SKYLARK was 45 days.
Breastfeeding?
Use in lactation has not yet been studied. Continued research is needed.
Can it be used in mood changes related to other reproductive changes or diagnoses like premenstrual dysphoric disorder and perimenopause?
The mechanism by which zuranolone is thought to work – that is, during changes in reproductive hormones – is implicated in other reproductive transitions such as premenstrual dysphoric disorder and perimenopause when reproductive hormones are fluctuating, though at lower levels than in pregnancy. Research will be required to assess efficacy and safety; however, the mechanistic reasons is worth pursuing. Additionally, zuranolone has not been studied in postpartum psychosis.
Can zuranolone be used to treat other affective conditions besides postpartum depression? Bipolar disorder?
Whether it may be beneficial for patients with a depressive episode that is part of an underlying bipolar disorder or other psychiatric illness is not yet known.
Anxiety?
Along with depressive symptoms, women who received zuranolone in the clinical trials also had improvements in anxiety symptoms. These findings provide some hope that zuranolone may eventually be beneficial in patients with anxiety.
However, to date zuranolone has not been directly studied as a treatment for anxiety disorders (such as generalized anxiety disorder, panic disorder, etc.), so its efficacy for these illnesses is currently unknown.
Insomnia?
In a study of 153 postpartum women, randomized to placebo or zuranolone, scale questions for insomnia were improved in the group receiving zuranolone. This provides some hope that, if zuranolone is appropriate, concurrent polypharmacy with a sleep aid can be avoided. Additionally, future evaluation of use in insomnia outside of PPD may be warranted.
How is it different from brexanolone?
The two are slightly different molecules. Brexanolone is synthetically identical to allopregnanolone and zuranolone has been altered to be active and orally bioavailable.
Brexanolone is a 60-hour infusion that requires hospital admission at an approved health care site. Zuranolone is an oral at-home once-daily dosing treatment for 14 days. Zuranolone does not require enrollment in a risk evaluation and mitigation strategy for risk of excessive sedation and sudden loss of consciousness.
When would you consider zuranolone vs. brexanolone vs. other antidepressants?
Zuranolone and brexanolone are rapid-acting antidepressants with a response within 14 days or 60 hours, respectively. Antidepressants such as SSRIs/SNRIs are still available, well studied, and work, although take longer to reach clinical efficacy and are accompanied by potentially troubling side effects (for example, weight gain, sexual dysfunction).
Time to treatment effect should be considered when assessing severity of symptoms and functional impairment of the mother and the overall family unit. Brexanolone requires continuous monitoring which may be beneficial for women who are severely impaired and may benefit from frequent clinical monitoring. Brexanolone does not require a dose reduction with hepatic impairment, however, should be avoided in end-stage renal disease because of the potential accumulation of the solubilizing agent.
Where can I find more information?
Many states have maternal mental health consultation lines (examples include NCMATTERS here in North Carolina and MCPAP for Moms in Massachusetts) for clinicians (mental health, primary care, and obstetricians) that can be utilized for questions about prescribing. Postpartum Support International also has a clinician line for those without state services.
We plan to update this entry upon market release and access to new information.
Dr. Riddle and Dr. Nathan are assistant professors in the department of psychiatry at the University of North Carolina at Chapel Hill. Dr. Richardson is a perinatal psychiatry fellow, department of psychiatry, UNC-Chapel Hill. Dr. Rubinow is Distinguished Professor in the department of psychiatry, UNC-Chapel Hill. Dr. Meltzer-Brody is Assad Meymandi Distinguished Professor and Chair, department of psychiatry, UNC-Chapel Hill.
References
Deligiannidis KM et al. J Clin Psychiatry. 2023 Jan 30;84(1):22m14475. doi: 10.4088/JCP.22m14475.
Deligiannidis KM et al. . Obstetrics & Gynecology. 2023 May;141(5S):64S-65S. doi: 10.1097/01.AOG.0000930588.16136.3f.
Deligiannidis KM et al. Am J Psychiatry. 2023 Sep 1;180(9):668-75. doi: 10.1176/appi.ajp.20220785.
Deligiannidis KM et al. JAMA Psychiatry. 2021 Sep 1;78(9):951-59. doi: 10.1001/jamapsychiatry.2021.1559.
FDA Approves First Oral Treatment for Postpartum Depression. 2023 Aug 4. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-treatment-postpartum-depression
ZURZUVAE – HIGHLIGHTS OF PRESCRIBING INFORMATION. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217369s000lbl.pdf
Don’t fear POTS: Tips for diagnosis and treatment
This transcript has been edited for clarity.
Michelle L. O’Donoghue, MD, MPH: I’m here in Amsterdam at the European Society of Cardiology (ESC) Congress 2023. Joining me for a great discussion is my friend Dr. Pam Taub, who is a cardiologist and a professor of medicine at UC San Diego. She has a particular interest in postural orthostatic tachycardia syndrome (POTS), so that’s what we’ll be talking about today.
Thanks for joining me, Pam. When we think about POTS, for those who are not familiar with the term, what does it actually mean and how do you diagnose it?
No tilt table required
Pam R. Taub, MD: That’s typically associated with symptoms such as lightheadedness, dizziness, and cognitive difficulties such as brain fog. The diagnosis can be made by tilt-table testing, but it can also be made in the office with simple orthostats.
In my clinic, I have people lie down for 3-5 minutes. At the end of that period, you get a heart rate and blood pressure. Then you have them stand up for 3-5 minutes and then get heart rate and blood pressure, and you look at the differences. If the heart rate goes up by 30 points – so maybe they’re 80 beats/min when they’re lying down and when they stand up, it goes to 110 beats/min – that’s POTS, so very objective criteria. Typically, these people don’t have what we call orthostatic hypotension, where there is a significant decrease in the blood pressure. It’s more a heart rate issue.
Dr. O’Donoghue: How symptomatically do they usually present?
Dr. Taub: It’s a spectrum. Some people have mild symptoms. After they’re in the upright position for maybe 10 minutes, they get symptoms. There are some people who, when they go from a lying to standing position, they’re extremely symptomatic and can’t really do any activities. There are some people that are even wheelchair-bound because the symptoms are so debilitating. There’s a wide spectrum.
Dr. O’Donoghue: There has been more discussion, I feel like, about the rising prevalence of POTS as a diagnosis, and in particular since the COVID pandemic. What’s our understanding of the relationship between COVID and POTS and what the mechanism might be?
Dr. Taub: We’ve known that POTS can be triggered by a viral infection. Before COVID, we knew that in certain individuals that we think have an underlying genetic predisposition, usually some autoimmune substrate, when they get certain types of infections, whether it’s influenza or mononucleosis, they get POTS.
Typically, when they get an infection, they start getting deconditioned. They don’t feel well, so they’re on bed rest. When they get long periods of bed rest, when they start to become active, they start to have overactivation of their sympathetic nervous system, and they have a large amount of cardiovascular deconditioning. It’s a cycle that is often triggered after an infection.
A huge increase of POTS has been seen after COVID-19 because we had so many people exposed to this virus. With COVID-19, there is a period where people don’t feel great and they are getting bed rest, so they’re getting deconditioned. We’ve seen so many patients referred for post-COVID POTS and also long COVID or the post-acute sequelae of COVID-19, where POTS is a part of that presentation.
Female sex and autoimmune conditions
Dr. O’Donoghue: We know that POTS seems to disproportionately affect women. Is that understood? Is it thought that that’s related to the perhaps the autoimmune component of that illness?
Dr. Taub: Yes. The theory is because women tend to have more autoimmune conditions, that’s why they’re more predisposed. There’s a large amount of genetic susceptibility. For instance, we know that there’s an association between POTS and conditions like Ehlers-Danlos syndrome and between POTS and mast cell activation. Some of those conditions are more prevalent in women as well.
Dr. O’Donoghue: I feel like many physicians don’t know how to manage POTS, and they’re actually a little fearful perhaps to take it on. Fortunately, there have been a growing number of POTS clinics with specialists that focus on that area. For the average practitioner who maybe can’t refer to a POTS clinic, how should they approach that?
Dr. Taub: The first thing is its diagnosis. When someone tells you that they have symptoms of orthostatic intolerance – so, activities that involve standing – you need to first have that on your differential diagnosis. You can make the diagnosis in the office with orthostats. You don’t need a tilt table. It’s sometimes helpful if you’re unsure about the diagnosis, but you can make the diagnosis.
Many times, you’re finding people that have very mild symptoms. You can treat that with some good lifestyle recommendations, such as increased hydration, increasing salt in their diet, and compression. And the exercise component is really important.
Many people with POTS are told to go exercise, go for a run, or go for a walk. That’s incorrect, because these people have symptoms when they’re in the upright position. The type of exercise they need to do initially is exercise in the lying or seated position – so exercises like rowing or a seated bike, and strength training. As they start to feel better, then they can do upright exercise.
You should never tell a person that has POTS to just initially start with upright exercise, because they’re going to feel so much worse and then they’re never going to want to exercise. It’s really important to give them the right exercise recommendations. I find that for many of these mild cases, if they do the right exercise and engage in the right lifestyle strategies, they get better.
Compression wear and drug therapy
Dr. O’Donoghue: When it comes to compression stockings, do you usually start with a particular length?
Dr. Taub: It’s interesting. There are many different compression stockings, medical grade. Through patients with POTS, I’ve gotten feedback on certain types of athletic wear that have built-in compression, and that’s a little bit easier for people to wear every day because they can do their errands and it doesn’t look like they’re wearing medical-grade compression stockings.
Basically, I’ve collected all the different recommendations that patients say help, and I give them a list. The medical-grade compression stockings sometimes are very challenging to put on, and sometimes people just need light compression or even just socks. Any kind of compression is going to help.
Dr. O’Donoghue: That’s a great tip, because I know there are many patients who refuse to wear the compression stockings. If there’s a fashionable alternative, that’s always good to reach for.
Dr. Taub: Another thing that patients have told me is that abdominal compression is also very helpful. There are many commercially available abdominal compression options, like shapewear. Many patients with POTS use that and that helps, too.
Dr. O’Donoghue: Good. For those patients with POTS that is refractory to the measures you’ve already discussed, what are the next steps after that?
Dr. Taub: Pharmacotherapy is very synergistic with lifestyle, and there are many different pharmacotherapy options. One of the first things that you want to think about is lowering that heart rate. The reason people feel horrible is because their heart rate is usually very high when they’re upright. If they’re upright for long periods of time and they’re having very high heart rates, they’re going to get really tired because it’s like they’re exercising for hours when they’re upright.
Heart rate lowering is the cornerstone of therapy. Traditionally, we’ve used beta-blockers for heart rate lowering. The problem is they also lower blood pressure. They can also cause fatigue, so not the ideal agent for patients with POTS.
One of the clinical trials that I led was with a drug called ivabradine, which selectively works on the SA node and decreases heart rate without affecting blood pressure. What’s really elegant about ivabradine is it has a more potent effect when the heart rate is higher. When the patient is standing, it’s going to have a more potent effect on heart rate lowering. It’s really well tolerated in patients with POTS. In our study, we showed an improvement in quality of life metrics. That’s one of the first-line drugs that I use for patients with POTS.
The other thing is some of them will also have a concomitant lowering of blood pressure. You can think about medications that increase blood pressure, like midodrine, fludrocortisone, and droxidopa. Sometimes that combination of a heart rate-lowering medication and a medication that increases blood pressure really works well.
Dr. O’Donoghue: That’s very helpful. I think that those kinds of practical tips are the ones that practitioners really want to reach for, because they need to have that algorithm in their mind to take on this condition. Thanks again for walking us through that.
I think it’s a very interesting space, and there’s more that we’re going to be learning over the next few years as we further flesh out these post-COVID cases and what we learn from that as well.
Dr. Taub: There are many clinical trials now starting in POTS, so it’s exciting.
Dr. O’Donoghue: Absolutely. Thank you again for joining me today. Signing off, this is Dr Michelle O’Donoghue.
Dr. O’Donoghue is a cardiologist at Brigham and Women’s Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Dr. O’Donoghue loves spending time outdoors with her family but admits with shame that she’s never strapped on hockey skates. She disclosed ties with Amgen, AstraZeneca Pharmaceuticals LP, CVS Minute Clinic, Eisai, GlaxoSmithKline, Janssen Pharmaceuticals, Merck, Novartis, and The Medicines Company. Dr. Taub is professor of Medicine, University of California San Diego Health, La Jolla. She disclosed ties with Amgen, Bayer, Boehringer Ingelheim, Medtronic, Merck, Novartis, Novo Nordisk, and Sanofi.
A version of this article appeared on Medscape.com.
This transcript has been edited for clarity.
Michelle L. O’Donoghue, MD, MPH: I’m here in Amsterdam at the European Society of Cardiology (ESC) Congress 2023. Joining me for a great discussion is my friend Dr. Pam Taub, who is a cardiologist and a professor of medicine at UC San Diego. She has a particular interest in postural orthostatic tachycardia syndrome (POTS), so that’s what we’ll be talking about today.
Thanks for joining me, Pam. When we think about POTS, for those who are not familiar with the term, what does it actually mean and how do you diagnose it?
No tilt table required
Pam R. Taub, MD: That’s typically associated with symptoms such as lightheadedness, dizziness, and cognitive difficulties such as brain fog. The diagnosis can be made by tilt-table testing, but it can also be made in the office with simple orthostats.
In my clinic, I have people lie down for 3-5 minutes. At the end of that period, you get a heart rate and blood pressure. Then you have them stand up for 3-5 minutes and then get heart rate and blood pressure, and you look at the differences. If the heart rate goes up by 30 points – so maybe they’re 80 beats/min when they’re lying down and when they stand up, it goes to 110 beats/min – that’s POTS, so very objective criteria. Typically, these people don’t have what we call orthostatic hypotension, where there is a significant decrease in the blood pressure. It’s more a heart rate issue.
Dr. O’Donoghue: How symptomatically do they usually present?
Dr. Taub: It’s a spectrum. Some people have mild symptoms. After they’re in the upright position for maybe 10 minutes, they get symptoms. There are some people who, when they go from a lying to standing position, they’re extremely symptomatic and can’t really do any activities. There are some people that are even wheelchair-bound because the symptoms are so debilitating. There’s a wide spectrum.
Dr. O’Donoghue: There has been more discussion, I feel like, about the rising prevalence of POTS as a diagnosis, and in particular since the COVID pandemic. What’s our understanding of the relationship between COVID and POTS and what the mechanism might be?
Dr. Taub: We’ve known that POTS can be triggered by a viral infection. Before COVID, we knew that in certain individuals that we think have an underlying genetic predisposition, usually some autoimmune substrate, when they get certain types of infections, whether it’s influenza or mononucleosis, they get POTS.
Typically, when they get an infection, they start getting deconditioned. They don’t feel well, so they’re on bed rest. When they get long periods of bed rest, when they start to become active, they start to have overactivation of their sympathetic nervous system, and they have a large amount of cardiovascular deconditioning. It’s a cycle that is often triggered after an infection.
A huge increase of POTS has been seen after COVID-19 because we had so many people exposed to this virus. With COVID-19, there is a period where people don’t feel great and they are getting bed rest, so they’re getting deconditioned. We’ve seen so many patients referred for post-COVID POTS and also long COVID or the post-acute sequelae of COVID-19, where POTS is a part of that presentation.
Female sex and autoimmune conditions
Dr. O’Donoghue: We know that POTS seems to disproportionately affect women. Is that understood? Is it thought that that’s related to the perhaps the autoimmune component of that illness?
Dr. Taub: Yes. The theory is because women tend to have more autoimmune conditions, that’s why they’re more predisposed. There’s a large amount of genetic susceptibility. For instance, we know that there’s an association between POTS and conditions like Ehlers-Danlos syndrome and between POTS and mast cell activation. Some of those conditions are more prevalent in women as well.
Dr. O’Donoghue: I feel like many physicians don’t know how to manage POTS, and they’re actually a little fearful perhaps to take it on. Fortunately, there have been a growing number of POTS clinics with specialists that focus on that area. For the average practitioner who maybe can’t refer to a POTS clinic, how should they approach that?
Dr. Taub: The first thing is its diagnosis. When someone tells you that they have symptoms of orthostatic intolerance – so, activities that involve standing – you need to first have that on your differential diagnosis. You can make the diagnosis in the office with orthostats. You don’t need a tilt table. It’s sometimes helpful if you’re unsure about the diagnosis, but you can make the diagnosis.
Many times, you’re finding people that have very mild symptoms. You can treat that with some good lifestyle recommendations, such as increased hydration, increasing salt in their diet, and compression. And the exercise component is really important.
Many people with POTS are told to go exercise, go for a run, or go for a walk. That’s incorrect, because these people have symptoms when they’re in the upright position. The type of exercise they need to do initially is exercise in the lying or seated position – so exercises like rowing or a seated bike, and strength training. As they start to feel better, then they can do upright exercise.
You should never tell a person that has POTS to just initially start with upright exercise, because they’re going to feel so much worse and then they’re never going to want to exercise. It’s really important to give them the right exercise recommendations. I find that for many of these mild cases, if they do the right exercise and engage in the right lifestyle strategies, they get better.
Compression wear and drug therapy
Dr. O’Donoghue: When it comes to compression stockings, do you usually start with a particular length?
Dr. Taub: It’s interesting. There are many different compression stockings, medical grade. Through patients with POTS, I’ve gotten feedback on certain types of athletic wear that have built-in compression, and that’s a little bit easier for people to wear every day because they can do their errands and it doesn’t look like they’re wearing medical-grade compression stockings.
Basically, I’ve collected all the different recommendations that patients say help, and I give them a list. The medical-grade compression stockings sometimes are very challenging to put on, and sometimes people just need light compression or even just socks. Any kind of compression is going to help.
Dr. O’Donoghue: That’s a great tip, because I know there are many patients who refuse to wear the compression stockings. If there’s a fashionable alternative, that’s always good to reach for.
Dr. Taub: Another thing that patients have told me is that abdominal compression is also very helpful. There are many commercially available abdominal compression options, like shapewear. Many patients with POTS use that and that helps, too.
Dr. O’Donoghue: Good. For those patients with POTS that is refractory to the measures you’ve already discussed, what are the next steps after that?
Dr. Taub: Pharmacotherapy is very synergistic with lifestyle, and there are many different pharmacotherapy options. One of the first things that you want to think about is lowering that heart rate. The reason people feel horrible is because their heart rate is usually very high when they’re upright. If they’re upright for long periods of time and they’re having very high heart rates, they’re going to get really tired because it’s like they’re exercising for hours when they’re upright.
Heart rate lowering is the cornerstone of therapy. Traditionally, we’ve used beta-blockers for heart rate lowering. The problem is they also lower blood pressure. They can also cause fatigue, so not the ideal agent for patients with POTS.
One of the clinical trials that I led was with a drug called ivabradine, which selectively works on the SA node and decreases heart rate without affecting blood pressure. What’s really elegant about ivabradine is it has a more potent effect when the heart rate is higher. When the patient is standing, it’s going to have a more potent effect on heart rate lowering. It’s really well tolerated in patients with POTS. In our study, we showed an improvement in quality of life metrics. That’s one of the first-line drugs that I use for patients with POTS.
The other thing is some of them will also have a concomitant lowering of blood pressure. You can think about medications that increase blood pressure, like midodrine, fludrocortisone, and droxidopa. Sometimes that combination of a heart rate-lowering medication and a medication that increases blood pressure really works well.
Dr. O’Donoghue: That’s very helpful. I think that those kinds of practical tips are the ones that practitioners really want to reach for, because they need to have that algorithm in their mind to take on this condition. Thanks again for walking us through that.
I think it’s a very interesting space, and there’s more that we’re going to be learning over the next few years as we further flesh out these post-COVID cases and what we learn from that as well.
Dr. Taub: There are many clinical trials now starting in POTS, so it’s exciting.
Dr. O’Donoghue: Absolutely. Thank you again for joining me today. Signing off, this is Dr Michelle O’Donoghue.
Dr. O’Donoghue is a cardiologist at Brigham and Women’s Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Dr. O’Donoghue loves spending time outdoors with her family but admits with shame that she’s never strapped on hockey skates. She disclosed ties with Amgen, AstraZeneca Pharmaceuticals LP, CVS Minute Clinic, Eisai, GlaxoSmithKline, Janssen Pharmaceuticals, Merck, Novartis, and The Medicines Company. Dr. Taub is professor of Medicine, University of California San Diego Health, La Jolla. She disclosed ties with Amgen, Bayer, Boehringer Ingelheim, Medtronic, Merck, Novartis, Novo Nordisk, and Sanofi.
A version of this article appeared on Medscape.com.
This transcript has been edited for clarity.
Michelle L. O’Donoghue, MD, MPH: I’m here in Amsterdam at the European Society of Cardiology (ESC) Congress 2023. Joining me for a great discussion is my friend Dr. Pam Taub, who is a cardiologist and a professor of medicine at UC San Diego. She has a particular interest in postural orthostatic tachycardia syndrome (POTS), so that’s what we’ll be talking about today.
Thanks for joining me, Pam. When we think about POTS, for those who are not familiar with the term, what does it actually mean and how do you diagnose it?
No tilt table required
Pam R. Taub, MD: That’s typically associated with symptoms such as lightheadedness, dizziness, and cognitive difficulties such as brain fog. The diagnosis can be made by tilt-table testing, but it can also be made in the office with simple orthostats.
In my clinic, I have people lie down for 3-5 minutes. At the end of that period, you get a heart rate and blood pressure. Then you have them stand up for 3-5 minutes and then get heart rate and blood pressure, and you look at the differences. If the heart rate goes up by 30 points – so maybe they’re 80 beats/min when they’re lying down and when they stand up, it goes to 110 beats/min – that’s POTS, so very objective criteria. Typically, these people don’t have what we call orthostatic hypotension, where there is a significant decrease in the blood pressure. It’s more a heart rate issue.
Dr. O’Donoghue: How symptomatically do they usually present?
Dr. Taub: It’s a spectrum. Some people have mild symptoms. After they’re in the upright position for maybe 10 minutes, they get symptoms. There are some people who, when they go from a lying to standing position, they’re extremely symptomatic and can’t really do any activities. There are some people that are even wheelchair-bound because the symptoms are so debilitating. There’s a wide spectrum.
Dr. O’Donoghue: There has been more discussion, I feel like, about the rising prevalence of POTS as a diagnosis, and in particular since the COVID pandemic. What’s our understanding of the relationship between COVID and POTS and what the mechanism might be?
Dr. Taub: We’ve known that POTS can be triggered by a viral infection. Before COVID, we knew that in certain individuals that we think have an underlying genetic predisposition, usually some autoimmune substrate, when they get certain types of infections, whether it’s influenza or mononucleosis, they get POTS.
Typically, when they get an infection, they start getting deconditioned. They don’t feel well, so they’re on bed rest. When they get long periods of bed rest, when they start to become active, they start to have overactivation of their sympathetic nervous system, and they have a large amount of cardiovascular deconditioning. It’s a cycle that is often triggered after an infection.
A huge increase of POTS has been seen after COVID-19 because we had so many people exposed to this virus. With COVID-19, there is a period where people don’t feel great and they are getting bed rest, so they’re getting deconditioned. We’ve seen so many patients referred for post-COVID POTS and also long COVID or the post-acute sequelae of COVID-19, where POTS is a part of that presentation.
Female sex and autoimmune conditions
Dr. O’Donoghue: We know that POTS seems to disproportionately affect women. Is that understood? Is it thought that that’s related to the perhaps the autoimmune component of that illness?
Dr. Taub: Yes. The theory is because women tend to have more autoimmune conditions, that’s why they’re more predisposed. There’s a large amount of genetic susceptibility. For instance, we know that there’s an association between POTS and conditions like Ehlers-Danlos syndrome and between POTS and mast cell activation. Some of those conditions are more prevalent in women as well.
Dr. O’Donoghue: I feel like many physicians don’t know how to manage POTS, and they’re actually a little fearful perhaps to take it on. Fortunately, there have been a growing number of POTS clinics with specialists that focus on that area. For the average practitioner who maybe can’t refer to a POTS clinic, how should they approach that?
Dr. Taub: The first thing is its diagnosis. When someone tells you that they have symptoms of orthostatic intolerance – so, activities that involve standing – you need to first have that on your differential diagnosis. You can make the diagnosis in the office with orthostats. You don’t need a tilt table. It’s sometimes helpful if you’re unsure about the diagnosis, but you can make the diagnosis.
Many times, you’re finding people that have very mild symptoms. You can treat that with some good lifestyle recommendations, such as increased hydration, increasing salt in their diet, and compression. And the exercise component is really important.
Many people with POTS are told to go exercise, go for a run, or go for a walk. That’s incorrect, because these people have symptoms when they’re in the upright position. The type of exercise they need to do initially is exercise in the lying or seated position – so exercises like rowing or a seated bike, and strength training. As they start to feel better, then they can do upright exercise.
You should never tell a person that has POTS to just initially start with upright exercise, because they’re going to feel so much worse and then they’re never going to want to exercise. It’s really important to give them the right exercise recommendations. I find that for many of these mild cases, if they do the right exercise and engage in the right lifestyle strategies, they get better.
Compression wear and drug therapy
Dr. O’Donoghue: When it comes to compression stockings, do you usually start with a particular length?
Dr. Taub: It’s interesting. There are many different compression stockings, medical grade. Through patients with POTS, I’ve gotten feedback on certain types of athletic wear that have built-in compression, and that’s a little bit easier for people to wear every day because they can do their errands and it doesn’t look like they’re wearing medical-grade compression stockings.
Basically, I’ve collected all the different recommendations that patients say help, and I give them a list. The medical-grade compression stockings sometimes are very challenging to put on, and sometimes people just need light compression or even just socks. Any kind of compression is going to help.
Dr. O’Donoghue: That’s a great tip, because I know there are many patients who refuse to wear the compression stockings. If there’s a fashionable alternative, that’s always good to reach for.
Dr. Taub: Another thing that patients have told me is that abdominal compression is also very helpful. There are many commercially available abdominal compression options, like shapewear. Many patients with POTS use that and that helps, too.
Dr. O’Donoghue: Good. For those patients with POTS that is refractory to the measures you’ve already discussed, what are the next steps after that?
Dr. Taub: Pharmacotherapy is very synergistic with lifestyle, and there are many different pharmacotherapy options. One of the first things that you want to think about is lowering that heart rate. The reason people feel horrible is because their heart rate is usually very high when they’re upright. If they’re upright for long periods of time and they’re having very high heart rates, they’re going to get really tired because it’s like they’re exercising for hours when they’re upright.
Heart rate lowering is the cornerstone of therapy. Traditionally, we’ve used beta-blockers for heart rate lowering. The problem is they also lower blood pressure. They can also cause fatigue, so not the ideal agent for patients with POTS.
One of the clinical trials that I led was with a drug called ivabradine, which selectively works on the SA node and decreases heart rate without affecting blood pressure. What’s really elegant about ivabradine is it has a more potent effect when the heart rate is higher. When the patient is standing, it’s going to have a more potent effect on heart rate lowering. It’s really well tolerated in patients with POTS. In our study, we showed an improvement in quality of life metrics. That’s one of the first-line drugs that I use for patients with POTS.
The other thing is some of them will also have a concomitant lowering of blood pressure. You can think about medications that increase blood pressure, like midodrine, fludrocortisone, and droxidopa. Sometimes that combination of a heart rate-lowering medication and a medication that increases blood pressure really works well.
Dr. O’Donoghue: That’s very helpful. I think that those kinds of practical tips are the ones that practitioners really want to reach for, because they need to have that algorithm in their mind to take on this condition. Thanks again for walking us through that.
I think it’s a very interesting space, and there’s more that we’re going to be learning over the next few years as we further flesh out these post-COVID cases and what we learn from that as well.
Dr. Taub: There are many clinical trials now starting in POTS, so it’s exciting.
Dr. O’Donoghue: Absolutely. Thank you again for joining me today. Signing off, this is Dr Michelle O’Donoghue.
Dr. O’Donoghue is a cardiologist at Brigham and Women’s Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Dr. O’Donoghue loves spending time outdoors with her family but admits with shame that she’s never strapped on hockey skates. She disclosed ties with Amgen, AstraZeneca Pharmaceuticals LP, CVS Minute Clinic, Eisai, GlaxoSmithKline, Janssen Pharmaceuticals, Merck, Novartis, and The Medicines Company. Dr. Taub is professor of Medicine, University of California San Diego Health, La Jolla. She disclosed ties with Amgen, Bayer, Boehringer Ingelheim, Medtronic, Merck, Novartis, Novo Nordisk, and Sanofi.
A version of this article appeared on Medscape.com.
Take two pills and make a donation
I was a resident, on morning rounds. The attending neurologist was young and ambitious (weren’t we all once?), trying to get the hospital to help him fund a research program in his subspecialty of interest.
One of the patients we saw that morning was a locally known successful businessman who’d been admitted, fortunately not for anything too serious.
My attending took the history, verifying the one I’d presented, and examined the gentleman. He then made some teaching points and explained the care plan to the patient.
Pretty standard up to that point.
After answering questions, however, the attending suddenly went into a sales pitch on his new research program, asking the guy for a financial donation, and giving him the card for the person at his office handling the funding.
I don’t remember anymore if he repeated that with other patients, but even now it still leaves a bad taste in my mouth. As a resident I wasn’t in a position to criticize him, nor did I want to endanger my own standing in the program by talking to someone higher up.
He was, fortunately, the only attending I ever worked with who did that. It still stands out in my mind, perhaps as an example of what not to do, and sometimes I still think about it.
Perhaps I’m naive, but I assumed he was an aberration. Apparently not, as the American College of Physicians recently issued a position paper advising its members not to ask patients for donations to the doctor’s workplace. There’s actually an acronym, GPF (Grateful Patient Fundraising) for this.
I understand a lot of these doctors are in academics and need funding for research and other programs. I know that a lot of good comes from this research, and I fully support it.
But this seems to be a bad way of doing it. Standing at the bedside on that long-ago morning, I remember thinking the patient (who looked kind of surprised) was going to wonder if this was a vague sort of hint: You’ll get better care if you pay up. Or a veiled threat that you may not get decent care if you don’t. I have no idea if he donated.
There must be a better way to get funding than hitting up a patient as part of the care plan. Perhaps discharge materials might include a brochure about how to make a donation, if interested. Or the ubiquitous portal might have a “donate” box in the task bar.
If the patient were to initiate this on his own, I wouldn’t have an issue with it. He gets out of the hospital, is grateful for his care, and calls the physician’s office to say he’d like to make a donation to whatever his program is (or just goes online to do it). That’s fine. I’ve even had the occasional patient call my office to say they’d like to make a donation to my favorite charity, and I give them a list of various neurology research foundations (none of which I’m affiliated with, for the record).
But to actively solicit donations from someone under your care is tasteless and inappropriate. It creates a conflict of interest for both parties.
The patient may believe he’ll get better care, and is obligated to keep giving – or else. The physician may feel like he’s stuck going beyond what’s really needed, ordering unnecessary tests and such to keep the financial VIP happy. And what happens if the big donor patient calls in because he hurt his ankle and needs a Percocet refill that another doctor won’t give him?
The statement by the ACP is appropriate. The only thing that bothers me about it is that it had to be made at all.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
I was a resident, on morning rounds. The attending neurologist was young and ambitious (weren’t we all once?), trying to get the hospital to help him fund a research program in his subspecialty of interest.
One of the patients we saw that morning was a locally known successful businessman who’d been admitted, fortunately not for anything too serious.
My attending took the history, verifying the one I’d presented, and examined the gentleman. He then made some teaching points and explained the care plan to the patient.
Pretty standard up to that point.
After answering questions, however, the attending suddenly went into a sales pitch on his new research program, asking the guy for a financial donation, and giving him the card for the person at his office handling the funding.
I don’t remember anymore if he repeated that with other patients, but even now it still leaves a bad taste in my mouth. As a resident I wasn’t in a position to criticize him, nor did I want to endanger my own standing in the program by talking to someone higher up.
He was, fortunately, the only attending I ever worked with who did that. It still stands out in my mind, perhaps as an example of what not to do, and sometimes I still think about it.
Perhaps I’m naive, but I assumed he was an aberration. Apparently not, as the American College of Physicians recently issued a position paper advising its members not to ask patients for donations to the doctor’s workplace. There’s actually an acronym, GPF (Grateful Patient Fundraising) for this.
I understand a lot of these doctors are in academics and need funding for research and other programs. I know that a lot of good comes from this research, and I fully support it.
But this seems to be a bad way of doing it. Standing at the bedside on that long-ago morning, I remember thinking the patient (who looked kind of surprised) was going to wonder if this was a vague sort of hint: You’ll get better care if you pay up. Or a veiled threat that you may not get decent care if you don’t. I have no idea if he donated.
There must be a better way to get funding than hitting up a patient as part of the care plan. Perhaps discharge materials might include a brochure about how to make a donation, if interested. Or the ubiquitous portal might have a “donate” box in the task bar.
If the patient were to initiate this on his own, I wouldn’t have an issue with it. He gets out of the hospital, is grateful for his care, and calls the physician’s office to say he’d like to make a donation to whatever his program is (or just goes online to do it). That’s fine. I’ve even had the occasional patient call my office to say they’d like to make a donation to my favorite charity, and I give them a list of various neurology research foundations (none of which I’m affiliated with, for the record).
But to actively solicit donations from someone under your care is tasteless and inappropriate. It creates a conflict of interest for both parties.
The patient may believe he’ll get better care, and is obligated to keep giving – or else. The physician may feel like he’s stuck going beyond what’s really needed, ordering unnecessary tests and such to keep the financial VIP happy. And what happens if the big donor patient calls in because he hurt his ankle and needs a Percocet refill that another doctor won’t give him?
The statement by the ACP is appropriate. The only thing that bothers me about it is that it had to be made at all.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
I was a resident, on morning rounds. The attending neurologist was young and ambitious (weren’t we all once?), trying to get the hospital to help him fund a research program in his subspecialty of interest.
One of the patients we saw that morning was a locally known successful businessman who’d been admitted, fortunately not for anything too serious.
My attending took the history, verifying the one I’d presented, and examined the gentleman. He then made some teaching points and explained the care plan to the patient.
Pretty standard up to that point.
After answering questions, however, the attending suddenly went into a sales pitch on his new research program, asking the guy for a financial donation, and giving him the card for the person at his office handling the funding.
I don’t remember anymore if he repeated that with other patients, but even now it still leaves a bad taste in my mouth. As a resident I wasn’t in a position to criticize him, nor did I want to endanger my own standing in the program by talking to someone higher up.
He was, fortunately, the only attending I ever worked with who did that. It still stands out in my mind, perhaps as an example of what not to do, and sometimes I still think about it.
Perhaps I’m naive, but I assumed he was an aberration. Apparently not, as the American College of Physicians recently issued a position paper advising its members not to ask patients for donations to the doctor’s workplace. There’s actually an acronym, GPF (Grateful Patient Fundraising) for this.
I understand a lot of these doctors are in academics and need funding for research and other programs. I know that a lot of good comes from this research, and I fully support it.
But this seems to be a bad way of doing it. Standing at the bedside on that long-ago morning, I remember thinking the patient (who looked kind of surprised) was going to wonder if this was a vague sort of hint: You’ll get better care if you pay up. Or a veiled threat that you may not get decent care if you don’t. I have no idea if he donated.
There must be a better way to get funding than hitting up a patient as part of the care plan. Perhaps discharge materials might include a brochure about how to make a donation, if interested. Or the ubiquitous portal might have a “donate” box in the task bar.
If the patient were to initiate this on his own, I wouldn’t have an issue with it. He gets out of the hospital, is grateful for his care, and calls the physician’s office to say he’d like to make a donation to whatever his program is (or just goes online to do it). That’s fine. I’ve even had the occasional patient call my office to say they’d like to make a donation to my favorite charity, and I give them a list of various neurology research foundations (none of which I’m affiliated with, for the record).
But to actively solicit donations from someone under your care is tasteless and inappropriate. It creates a conflict of interest for both parties.
The patient may believe he’ll get better care, and is obligated to keep giving – or else. The physician may feel like he’s stuck going beyond what’s really needed, ordering unnecessary tests and such to keep the financial VIP happy. And what happens if the big donor patient calls in because he hurt his ankle and needs a Percocet refill that another doctor won’t give him?
The statement by the ACP is appropriate. The only thing that bothers me about it is that it had to be made at all.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
Sleep irregularity
In discussions between health care providers and patients, the words “regularity” and “irregularity” come up primarily in reference to either constipation or menstrual cycles. However, the participants in a recent panel convened by the National Sleep Foundation think we should also be discussing irregularity when we are discussing sleep with our patients.
The sleep experts on the panel began by considering 40,000 papers that directly or tangentially dealt with the topic of irregular sleep patterns. The reviewers uncovered numerous references to an association between sleep irregularity and a wide variety of adverse health outcomes, including obesity and metabolic disorders, hypertension and other cardiovascular disorders, and elevations in several inflammatory markers. Not surprisingly, the investigators also found an abundance of references supporting an association between irregular sleep and a suite of mental health problems, including depression, mood disorders, lower self esteem, poor academic performance, and deficits in attention. For example, several of the studies the panel reviewed found that in college students, GPA was lower when their sleep pattern was irregular. There were some papers that found no significant association between irregular sleep and other adverse health outcomes, but none of the studies demonstrated an association with better or improved health outcomes.
There is currently no universally accepted definition of an irregular sleep pattern. The experts pointed to some papers that used a standard deviation of 1 hour from the patient’s usual bed time determined by averaging over an interval measured in weeks. You and I shouldn’t be surprised that irregular sleep is unhealthy, but the breadth of the panel’s findings is impressive.
Although it has been long in coming, sleep is finally beginning to get some attention by the media. The focus is usually on the optimal number of hours we need each night. This panel’s findings suggest that total sleep time is only part of the story, and may even be less important than the regularity of our sleep patterns.
For those of us in pediatrics, the place where irregularity raises its ugly head is with teenagers and weekends. Although the numbers are far from clear, the question remains of how effective is catch-up sleep after a week of too-early mornings and too-late bedtimes for the chronically under-slept adolescent.
In some studies in which patients had the demonstrable effects of sleep deprivation (e.g., metabolic and cardiovascular) there was some improvement when weekend sleep was extended by 1 or 2 hours, but none beyond 2 hours.
The panel’s findings, while certainly significant, merely add weight and nuance to the existing evidence of importance of sleep and the damage done by sleep deprivation. As one of the panel members has said, “Sleep is the third pillar of health, equally important as diet and exercise, if not more.” However, this message is not getting out, or at least it is not being heeded. Like obesity, our efforts as advisers to our patients isn’t working. Unfortunately, this is because our advice is often whispered and given halfheartedly.
There was some evidence of improvement as a result of the pandemic, when those fortunate enough to be able to work from home were taking advantage of the flexibility in their schedules and getting more sleep. But health care providers certainly can’t take responsibility for what was an accident of nature.
Those of you who have been reading Letters from Maine for the last 3 decades may tire of my beating the tired horse of sleep deprivation. But I will not be deterred. I see very little evidence among health care professionals in taking the importance of sleep seriously. Sure, they may include it buried in the list of potential contributors to their patient’s complaint, but I see very little effort to move it higher on their list of priorities and almost no movement toward making substantive recommendations and then reinforcing them with follow-up.
Like obesity, sleep deprivation is a societal problem. We can lay some of the blame on Thomas Edison, but Until that time you will continue to read columns like this one when I encounter significant studies on the importance of sleep.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].
In discussions between health care providers and patients, the words “regularity” and “irregularity” come up primarily in reference to either constipation or menstrual cycles. However, the participants in a recent panel convened by the National Sleep Foundation think we should also be discussing irregularity when we are discussing sleep with our patients.
The sleep experts on the panel began by considering 40,000 papers that directly or tangentially dealt with the topic of irregular sleep patterns. The reviewers uncovered numerous references to an association between sleep irregularity and a wide variety of adverse health outcomes, including obesity and metabolic disorders, hypertension and other cardiovascular disorders, and elevations in several inflammatory markers. Not surprisingly, the investigators also found an abundance of references supporting an association between irregular sleep and a suite of mental health problems, including depression, mood disorders, lower self esteem, poor academic performance, and deficits in attention. For example, several of the studies the panel reviewed found that in college students, GPA was lower when their sleep pattern was irregular. There were some papers that found no significant association between irregular sleep and other adverse health outcomes, but none of the studies demonstrated an association with better or improved health outcomes.
There is currently no universally accepted definition of an irregular sleep pattern. The experts pointed to some papers that used a standard deviation of 1 hour from the patient’s usual bed time determined by averaging over an interval measured in weeks. You and I shouldn’t be surprised that irregular sleep is unhealthy, but the breadth of the panel’s findings is impressive.
Although it has been long in coming, sleep is finally beginning to get some attention by the media. The focus is usually on the optimal number of hours we need each night. This panel’s findings suggest that total sleep time is only part of the story, and may even be less important than the regularity of our sleep patterns.
For those of us in pediatrics, the place where irregularity raises its ugly head is with teenagers and weekends. Although the numbers are far from clear, the question remains of how effective is catch-up sleep after a week of too-early mornings and too-late bedtimes for the chronically under-slept adolescent.
In some studies in which patients had the demonstrable effects of sleep deprivation (e.g., metabolic and cardiovascular) there was some improvement when weekend sleep was extended by 1 or 2 hours, but none beyond 2 hours.
The panel’s findings, while certainly significant, merely add weight and nuance to the existing evidence of importance of sleep and the damage done by sleep deprivation. As one of the panel members has said, “Sleep is the third pillar of health, equally important as diet and exercise, if not more.” However, this message is not getting out, or at least it is not being heeded. Like obesity, our efforts as advisers to our patients isn’t working. Unfortunately, this is because our advice is often whispered and given halfheartedly.
There was some evidence of improvement as a result of the pandemic, when those fortunate enough to be able to work from home were taking advantage of the flexibility in their schedules and getting more sleep. But health care providers certainly can’t take responsibility for what was an accident of nature.
Those of you who have been reading Letters from Maine for the last 3 decades may tire of my beating the tired horse of sleep deprivation. But I will not be deterred. I see very little evidence among health care professionals in taking the importance of sleep seriously. Sure, they may include it buried in the list of potential contributors to their patient’s complaint, but I see very little effort to move it higher on their list of priorities and almost no movement toward making substantive recommendations and then reinforcing them with follow-up.
Like obesity, sleep deprivation is a societal problem. We can lay some of the blame on Thomas Edison, but Until that time you will continue to read columns like this one when I encounter significant studies on the importance of sleep.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].
In discussions between health care providers and patients, the words “regularity” and “irregularity” come up primarily in reference to either constipation or menstrual cycles. However, the participants in a recent panel convened by the National Sleep Foundation think we should also be discussing irregularity when we are discussing sleep with our patients.
The sleep experts on the panel began by considering 40,000 papers that directly or tangentially dealt with the topic of irregular sleep patterns. The reviewers uncovered numerous references to an association between sleep irregularity and a wide variety of adverse health outcomes, including obesity and metabolic disorders, hypertension and other cardiovascular disorders, and elevations in several inflammatory markers. Not surprisingly, the investigators also found an abundance of references supporting an association between irregular sleep and a suite of mental health problems, including depression, mood disorders, lower self esteem, poor academic performance, and deficits in attention. For example, several of the studies the panel reviewed found that in college students, GPA was lower when their sleep pattern was irregular. There were some papers that found no significant association between irregular sleep and other adverse health outcomes, but none of the studies demonstrated an association with better or improved health outcomes.
There is currently no universally accepted definition of an irregular sleep pattern. The experts pointed to some papers that used a standard deviation of 1 hour from the patient’s usual bed time determined by averaging over an interval measured in weeks. You and I shouldn’t be surprised that irregular sleep is unhealthy, but the breadth of the panel’s findings is impressive.
Although it has been long in coming, sleep is finally beginning to get some attention by the media. The focus is usually on the optimal number of hours we need each night. This panel’s findings suggest that total sleep time is only part of the story, and may even be less important than the regularity of our sleep patterns.
For those of us in pediatrics, the place where irregularity raises its ugly head is with teenagers and weekends. Although the numbers are far from clear, the question remains of how effective is catch-up sleep after a week of too-early mornings and too-late bedtimes for the chronically under-slept adolescent.
In some studies in which patients had the demonstrable effects of sleep deprivation (e.g., metabolic and cardiovascular) there was some improvement when weekend sleep was extended by 1 or 2 hours, but none beyond 2 hours.
The panel’s findings, while certainly significant, merely add weight and nuance to the existing evidence of importance of sleep and the damage done by sleep deprivation. As one of the panel members has said, “Sleep is the third pillar of health, equally important as diet and exercise, if not more.” However, this message is not getting out, or at least it is not being heeded. Like obesity, our efforts as advisers to our patients isn’t working. Unfortunately, this is because our advice is often whispered and given halfheartedly.
There was some evidence of improvement as a result of the pandemic, when those fortunate enough to be able to work from home were taking advantage of the flexibility in their schedules and getting more sleep. But health care providers certainly can’t take responsibility for what was an accident of nature.
Those of you who have been reading Letters from Maine for the last 3 decades may tire of my beating the tired horse of sleep deprivation. But I will not be deterred. I see very little evidence among health care professionals in taking the importance of sleep seriously. Sure, they may include it buried in the list of potential contributors to their patient’s complaint, but I see very little effort to move it higher on their list of priorities and almost no movement toward making substantive recommendations and then reinforcing them with follow-up.
Like obesity, sleep deprivation is a societal problem. We can lay some of the blame on Thomas Edison, but Until that time you will continue to read columns like this one when I encounter significant studies on the importance of sleep.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].
Diversity, equity, and inclusion in reproductive health care
These barriers represent inequality in access to reproductive medical services.
These challenges are also seen in other reproductive disorders such as polycystic ovary syndrome (PCOS), fibroids, and endometriosis. It is estimated that < 25% of individuals with infertility in the United States access the resources required to have their treatment needs met (Fertil Steril. 2015 Nov;104(5):1104-10. doi: 10.1016/j.fertnstert.2015.07.113)
In 2020, the American Society for Reproductive Medicine (ASRM) created a task force on Diversity, Equity, and Inclusion (DEI) chaired by Board Member Michael A. Thomas, MD. Two years later, the ASRM elevated this task force to a committee that is now chaired by Gloria Richard-Davis, MD. As health care systems and societies increasingly recognize these obstacles to care, I invited Dr. Thomas, the current president of the ASRM, to address this vital concern. Dr. Thomas is professor and chair, department of obstetrics and gynecology, at the University of Cincinnati.
While not limited to reproductive health care, how prevalent is the lack of DEI and what factors contribute to this problem?
When we established the initial ASRM DEI task force, we wanted to look at DEI issues within our profession and as an access-to-care initiative. We found that ASRM and ABOG (American Board of Obstetrics and Gynecology) were not asking questions about the makeup of our REI (Reproductive Endocrinology & Infertility) providers, nursing staff, and lab personnel. We had some older data from 2018 about the REI fellowships. Since that time, there appears to be an upward trend of people of color in REI fellowships.
We still need more data about academic, hybrid, and private REI practices when it comes to all employees. The goal would be to increase the number of people of color in all aspects of our field.
As far as access to care, we know that people of color do not have the ability to undergo ART (assisted reproductive technology) procedures at the same rate. This could be due to affordability, slower and/or later referral patterns, and personal stigma issues. Even in mandated states, people of color are seen by IVF providers in lower numbers. There is a need for a better understanding of the access-to-care issues, especially when affordability is not a problem, and the barriers to our LGBTQ+ patients.
Can you provide information about actions by the ASRM DEI task force and any plans for the future?
The DEI task force is now an ASRM committee. This committee is chaired by Dr. Gloria Richard-Davis and continues to work on increasing people of color in the REI workforce and understanding and decreasing access to care issues faced by people of color and members of the LGBTQ+ community.
What can physicians do at the local, state, and national level to support DEI?
All REI and ob.gyn. physicians can work with insurance companies to work on the current barriers that stand in the way of patients who want to have a family. For example, physicians can work with insurance companies to remove their definition of infertility as exposure to sperm for 1 year before fertility coverage can take effect. Also, mandated insurance coverage in all 50 states would allow even smaller companies to require this benefit to patients.
Many people of color work in smaller companies that, unfortunately, are not required to offer IVF coverage in states where mandated insurance coverage is available. As potential encouraging news, ASRM, RESOLVE (The National Infertility Association) and other patient advocacy groups are working with each state to help enact fertility mandates.
Which group, if any, has been most negatively affected by a lack of DEI?
People of color, LGBTQ+ communities, people with disabilities, single individuals, and those with income challenges are the most likely to be affected by adverse DEI policies.
While it is long overdue, why do you believe DEI has become such a touchstone and pervasive movement at this time?
This is the million-dollar question. After the George Floyd death, there was a global re-examination of how people of color were treated in every aspect of society. ASRM was the first to start this DEI initiative in women’s health.
ASRM and its patient advocacy partners are working with every nonmandated state toward the goal of passing infertility legislation to dramatically reduce the financial burden on all patients. We are starting to see more states either coming on board with mandates or at least discussing the possibilities. ASRM and RESOLVE have seen some recent positive outcomes with improved insurance for military families and government workers.
We can all agree that access to infertility treatment, particularly IVF, is not equivalent among different racial/ethnic populations. Part of the ASRM DEI task force is to evaluate research on IVF outcomes and race/ethnicity. Can you share why pregnancy outcomes would be included to potentially improve DEI?
More research needs to be done on pregnancy outcomes in women of color. We know that women of color have a decreased pregnancy rate in ART cycles even when controlling for age and other factors. We also know that birth outcomes are worse in these women. More understanding of this problem for women of color, especially African American women needs to be done.
Estimates are that more than one in eight LGBTQ+ patients live in states where physicians can refuse to treat them. Consequently, how can we improve DEI in these regions?
As someone with a number of family members in the LGBTQ+ community, this is a problem that is close to my heart. There appear to be many barriers that are being built to disenfranchise our LGBTQ+ community members. It is up to ASRM and patient advocacy groups to work with legislators to pass more inclusive laws and for insurance companies to update their definitions of infertility to be more inclusive for all.
Any final comments?
Everyone should have the right to become a parent whether they want to now or in the future!
Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
These barriers represent inequality in access to reproductive medical services.
These challenges are also seen in other reproductive disorders such as polycystic ovary syndrome (PCOS), fibroids, and endometriosis. It is estimated that < 25% of individuals with infertility in the United States access the resources required to have their treatment needs met (Fertil Steril. 2015 Nov;104(5):1104-10. doi: 10.1016/j.fertnstert.2015.07.113)
In 2020, the American Society for Reproductive Medicine (ASRM) created a task force on Diversity, Equity, and Inclusion (DEI) chaired by Board Member Michael A. Thomas, MD. Two years later, the ASRM elevated this task force to a committee that is now chaired by Gloria Richard-Davis, MD. As health care systems and societies increasingly recognize these obstacles to care, I invited Dr. Thomas, the current president of the ASRM, to address this vital concern. Dr. Thomas is professor and chair, department of obstetrics and gynecology, at the University of Cincinnati.
While not limited to reproductive health care, how prevalent is the lack of DEI and what factors contribute to this problem?
When we established the initial ASRM DEI task force, we wanted to look at DEI issues within our profession and as an access-to-care initiative. We found that ASRM and ABOG (American Board of Obstetrics and Gynecology) were not asking questions about the makeup of our REI (Reproductive Endocrinology & Infertility) providers, nursing staff, and lab personnel. We had some older data from 2018 about the REI fellowships. Since that time, there appears to be an upward trend of people of color in REI fellowships.
We still need more data about academic, hybrid, and private REI practices when it comes to all employees. The goal would be to increase the number of people of color in all aspects of our field.
As far as access to care, we know that people of color do not have the ability to undergo ART (assisted reproductive technology) procedures at the same rate. This could be due to affordability, slower and/or later referral patterns, and personal stigma issues. Even in mandated states, people of color are seen by IVF providers in lower numbers. There is a need for a better understanding of the access-to-care issues, especially when affordability is not a problem, and the barriers to our LGBTQ+ patients.
Can you provide information about actions by the ASRM DEI task force and any plans for the future?
The DEI task force is now an ASRM committee. This committee is chaired by Dr. Gloria Richard-Davis and continues to work on increasing people of color in the REI workforce and understanding and decreasing access to care issues faced by people of color and members of the LGBTQ+ community.
What can physicians do at the local, state, and national level to support DEI?
All REI and ob.gyn. physicians can work with insurance companies to work on the current barriers that stand in the way of patients who want to have a family. For example, physicians can work with insurance companies to remove their definition of infertility as exposure to sperm for 1 year before fertility coverage can take effect. Also, mandated insurance coverage in all 50 states would allow even smaller companies to require this benefit to patients.
Many people of color work in smaller companies that, unfortunately, are not required to offer IVF coverage in states where mandated insurance coverage is available. As potential encouraging news, ASRM, RESOLVE (The National Infertility Association) and other patient advocacy groups are working with each state to help enact fertility mandates.
Which group, if any, has been most negatively affected by a lack of DEI?
People of color, LGBTQ+ communities, people with disabilities, single individuals, and those with income challenges are the most likely to be affected by adverse DEI policies.
While it is long overdue, why do you believe DEI has become such a touchstone and pervasive movement at this time?
This is the million-dollar question. After the George Floyd death, there was a global re-examination of how people of color were treated in every aspect of society. ASRM was the first to start this DEI initiative in women’s health.
ASRM and its patient advocacy partners are working with every nonmandated state toward the goal of passing infertility legislation to dramatically reduce the financial burden on all patients. We are starting to see more states either coming on board with mandates or at least discussing the possibilities. ASRM and RESOLVE have seen some recent positive outcomes with improved insurance for military families and government workers.
We can all agree that access to infertility treatment, particularly IVF, is not equivalent among different racial/ethnic populations. Part of the ASRM DEI task force is to evaluate research on IVF outcomes and race/ethnicity. Can you share why pregnancy outcomes would be included to potentially improve DEI?
More research needs to be done on pregnancy outcomes in women of color. We know that women of color have a decreased pregnancy rate in ART cycles even when controlling for age and other factors. We also know that birth outcomes are worse in these women. More understanding of this problem for women of color, especially African American women needs to be done.
Estimates are that more than one in eight LGBTQ+ patients live in states where physicians can refuse to treat them. Consequently, how can we improve DEI in these regions?
As someone with a number of family members in the LGBTQ+ community, this is a problem that is close to my heart. There appear to be many barriers that are being built to disenfranchise our LGBTQ+ community members. It is up to ASRM and patient advocacy groups to work with legislators to pass more inclusive laws and for insurance companies to update their definitions of infertility to be more inclusive for all.
Any final comments?
Everyone should have the right to become a parent whether they want to now or in the future!
Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
These barriers represent inequality in access to reproductive medical services.
These challenges are also seen in other reproductive disorders such as polycystic ovary syndrome (PCOS), fibroids, and endometriosis. It is estimated that < 25% of individuals with infertility in the United States access the resources required to have their treatment needs met (Fertil Steril. 2015 Nov;104(5):1104-10. doi: 10.1016/j.fertnstert.2015.07.113)
In 2020, the American Society for Reproductive Medicine (ASRM) created a task force on Diversity, Equity, and Inclusion (DEI) chaired by Board Member Michael A. Thomas, MD. Two years later, the ASRM elevated this task force to a committee that is now chaired by Gloria Richard-Davis, MD. As health care systems and societies increasingly recognize these obstacles to care, I invited Dr. Thomas, the current president of the ASRM, to address this vital concern. Dr. Thomas is professor and chair, department of obstetrics and gynecology, at the University of Cincinnati.
While not limited to reproductive health care, how prevalent is the lack of DEI and what factors contribute to this problem?
When we established the initial ASRM DEI task force, we wanted to look at DEI issues within our profession and as an access-to-care initiative. We found that ASRM and ABOG (American Board of Obstetrics and Gynecology) were not asking questions about the makeup of our REI (Reproductive Endocrinology & Infertility) providers, nursing staff, and lab personnel. We had some older data from 2018 about the REI fellowships. Since that time, there appears to be an upward trend of people of color in REI fellowships.
We still need more data about academic, hybrid, and private REI practices when it comes to all employees. The goal would be to increase the number of people of color in all aspects of our field.
As far as access to care, we know that people of color do not have the ability to undergo ART (assisted reproductive technology) procedures at the same rate. This could be due to affordability, slower and/or later referral patterns, and personal stigma issues. Even in mandated states, people of color are seen by IVF providers in lower numbers. There is a need for a better understanding of the access-to-care issues, especially when affordability is not a problem, and the barriers to our LGBTQ+ patients.
Can you provide information about actions by the ASRM DEI task force and any plans for the future?
The DEI task force is now an ASRM committee. This committee is chaired by Dr. Gloria Richard-Davis and continues to work on increasing people of color in the REI workforce and understanding and decreasing access to care issues faced by people of color and members of the LGBTQ+ community.
What can physicians do at the local, state, and national level to support DEI?
All REI and ob.gyn. physicians can work with insurance companies to work on the current barriers that stand in the way of patients who want to have a family. For example, physicians can work with insurance companies to remove their definition of infertility as exposure to sperm for 1 year before fertility coverage can take effect. Also, mandated insurance coverage in all 50 states would allow even smaller companies to require this benefit to patients.
Many people of color work in smaller companies that, unfortunately, are not required to offer IVF coverage in states where mandated insurance coverage is available. As potential encouraging news, ASRM, RESOLVE (The National Infertility Association) and other patient advocacy groups are working with each state to help enact fertility mandates.
Which group, if any, has been most negatively affected by a lack of DEI?
People of color, LGBTQ+ communities, people with disabilities, single individuals, and those with income challenges are the most likely to be affected by adverse DEI policies.
While it is long overdue, why do you believe DEI has become such a touchstone and pervasive movement at this time?
This is the million-dollar question. After the George Floyd death, there was a global re-examination of how people of color were treated in every aspect of society. ASRM was the first to start this DEI initiative in women’s health.
ASRM and its patient advocacy partners are working with every nonmandated state toward the goal of passing infertility legislation to dramatically reduce the financial burden on all patients. We are starting to see more states either coming on board with mandates or at least discussing the possibilities. ASRM and RESOLVE have seen some recent positive outcomes with improved insurance for military families and government workers.
We can all agree that access to infertility treatment, particularly IVF, is not equivalent among different racial/ethnic populations. Part of the ASRM DEI task force is to evaluate research on IVF outcomes and race/ethnicity. Can you share why pregnancy outcomes would be included to potentially improve DEI?
More research needs to be done on pregnancy outcomes in women of color. We know that women of color have a decreased pregnancy rate in ART cycles even when controlling for age and other factors. We also know that birth outcomes are worse in these women. More understanding of this problem for women of color, especially African American women needs to be done.
Estimates are that more than one in eight LGBTQ+ patients live in states where physicians can refuse to treat them. Consequently, how can we improve DEI in these regions?
As someone with a number of family members in the LGBTQ+ community, this is a problem that is close to my heart. There appear to be many barriers that are being built to disenfranchise our LGBTQ+ community members. It is up to ASRM and patient advocacy groups to work with legislators to pass more inclusive laws and for insurance companies to update their definitions of infertility to be more inclusive for all.
Any final comments?
Everyone should have the right to become a parent whether they want to now or in the future!
Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
Hyperbaric oxygen therapy for traumatic brain injury: Promising or wishful thinking?
A recent review by Hadanny and colleagues recommends hyperbaric oxygen therapy (HBOT) for acute moderate to severe traumatic brain injury (TBI) and selected patients with prolonged postconcussive syndrome.
This article piqued my curiosity because I trained in HBOT more than 20 years ago. As a passionate scuba diver, my motivation was to master treatment for air embolism and decompression illness. Thankfully, these diving accidents are rare. However, I used HBOT for nonhealing wounds, and its efficacy was sometimes remarkable.
Paradoxical results with oxygen therapy
Although it may seem self-evident that “more oxygen is better” for medical illness, this is not necessarily true. I recently interviewed Ola Didrik Saugstad, MD, who demonstrated that the traditional practice of resuscitating newborns with 100% oxygen was more toxic than resuscitation with air (which contains 21% oxygen). His counterintuitive discovery led to a lifesaving change in the international newborn resuscitation guidelines.
The Food and Drug Administration has approved HBOT for a wide variety of conditions, but some practitioners enthusiastically promote it for off-label indications. These include antiaging, autism, multiple sclerosis, and the aforementioned TBI.
More than 50 years ago, HBOT was proposed for stroke, another disorder where the brain has been deprived of oxygen. Despite obvious logic, clinical trials have been unconvincing. The FDA has not approved HBOT for stroke.
HBOT in practice
During HBOT, the patient breathes 100% oxygen while the whole body is pressurized within a hyperbaric chamber. The chamber’s construction allows pressures above normal sea level of 1.0 atmosphere absolute (ATA). For example, The U.S. Navy Treatment Table for decompression sickness recommends 100% oxygen at 2.8 ATA. Chambers may hold one or more patients at a time.
The frequency of therapy varies but often consists of 20-60 sessions lasting 90-120 minutes. For off-label use like TBI, patients usually pay out of pocket. Given the multiple treatments, costs can add up.
Inconsistent evidence and sham controls
The unwieldy 33-page evidence review by Hadanny and colleagues cites multiple studies supporting HBOT for TBI. However, many, if not all, suffer from methodological flaws. These include vague inclusion criteria, lack of a control group, small patient numbers, treatment at different times since injury, poorly defined or varying HBOT protocols, varying outcome measures, and superficial results analysis.
A sham or control arm is essential for HBOT research trials, given the potential placebo effect of placing a human being inside a large, high-tech, sealed tube for an hour or more. In some sham-controlled studies, which consisted of low-pressure oxygen (that is, 1.3 ATA as sham vs. 2.4 ATA as treatment), all groups experienced symptom improvement. The review authors argue that the low-dose HBOT sham arms were biologically active and that the improvements seen mean that both high- and low-dose HBOT is therapeutic. The alternative explanation is that the placebo effect accounted for improvement in both groups.
The late Michael Bennett, a world authority on hyperbaric and underwater medicine, doubted that conventional HBOT sham controls could genuinely have a therapeutic effect, and I agree. The upcoming HOT-POCS trial (discussed below) should answer the question more definitively.
Mechanisms of action and safety
Mechanisms of benefit for HBOT include increased oxygen availability and angiogenesis. Animal research suggests that it may reduce secondary cell death from TBI, through stabilization of the blood-brain barrier and inflammation reduction.
HBOT is generally safe and well tolerated. A retrospective analysis of 1.5 million outpatient hyperbaric treatments revealed that less than 1% were associated with adverse events. The most common were ear and sinus barotrauma. Because HBOT uses increased air pressure, patients must equalize their ears and sinuses. Those who cannot because of altered consciousness, anatomical defects, or congestion must undergo myringotomy or terminate therapy. Claustrophobia was the second most common adverse effect. Convulsions and tension pneumocephalus were rare.
Perhaps the most concerning risk of HBOT for patients with TBI is the potential waste of human and financial resources.
Desperate physicians and patients
As a neurologist who regularly treats patients with TBI, I share the review authors’ frustration regarding the limited efficacy of available treatments. However, the suboptimal efficacy of currently available therapy is insufficient justification to recommend HBOT.
With respect to chronic TBI, it is difficult to imagine how HBOT could reverse brain injury that has been present for months or years. No other therapy exists that reliably encourages neuronal regeneration or prevents the development of posttraumatic epilepsy.
Frank Conidi, MD, a board-certified sports neurologist and headache specialist, shared his thoughts via email. He agrees that HBOT may have a role in TBI, but after reviewing Hadanny and colleagues’ paper, he concluded that there is insufficient evidence for the use of HBOT in all forms of TBI. He would like to see large multicenter, well-designed studies with standardized pressures and duration and a standard definition of the various types of head injury.
Ongoing research
There are at least five ongoing trials on HBOT for TBI or postconcussive syndrome, including the well-designed placebo-controlled HOT-POCS study. The latter has a novel placebo gas system that addresses Hadanny and colleagues’ contention that even low-dose HBOT might be effective.
The placebo arm in HOT-POCS mimics the HBO environment but provides only 0.21 ATA of oxygen, the same as room air. The active arm provides 100% oxygen at 2.0 ATA. If patients in both arms improve, the benefit will be caused by a placebo response, not HBOT.
Conflict of interest
Another concern with the review is that all three authors are affiliated with Aviv Scientific. This company has an exclusive partnership with the world’s largest hyperbaric medicine and research facility, the Sagol Center at Shamir Medical Center in Be’er Ya’akov, Israel.
This conflict of interest does not a priori invalidate their conclusions. However, official HBOT guidelines from a leading organization like the Undersea and Hyperbaric Medicine Society or the American Academy of Neurology would be preferable.
Conclusion
There is an urgent unmet need for more effective treatments for postconcussive syndrome and chronic TBI.
The review authors’ recommendations for HBOT seem premature. They are arguably a disservice to the many desperate patients and their families who will be tempted to expend valuable resources of time and money for an appealing but unproven therapy. Appropriately designed placebo-controlled studies such as HOT-POCS will help separate fact from wishful thinking.
Dr. Wilner is associate professor of neurology at University of Tennessee Health Science Center, Memphis. He reported a conflict of interest with Accordant Health Services.
A version of this article first appeared on Medscape.com.
A recent review by Hadanny and colleagues recommends hyperbaric oxygen therapy (HBOT) for acute moderate to severe traumatic brain injury (TBI) and selected patients with prolonged postconcussive syndrome.
This article piqued my curiosity because I trained in HBOT more than 20 years ago. As a passionate scuba diver, my motivation was to master treatment for air embolism and decompression illness. Thankfully, these diving accidents are rare. However, I used HBOT for nonhealing wounds, and its efficacy was sometimes remarkable.
Paradoxical results with oxygen therapy
Although it may seem self-evident that “more oxygen is better” for medical illness, this is not necessarily true. I recently interviewed Ola Didrik Saugstad, MD, who demonstrated that the traditional practice of resuscitating newborns with 100% oxygen was more toxic than resuscitation with air (which contains 21% oxygen). His counterintuitive discovery led to a lifesaving change in the international newborn resuscitation guidelines.
The Food and Drug Administration has approved HBOT for a wide variety of conditions, but some practitioners enthusiastically promote it for off-label indications. These include antiaging, autism, multiple sclerosis, and the aforementioned TBI.
More than 50 years ago, HBOT was proposed for stroke, another disorder where the brain has been deprived of oxygen. Despite obvious logic, clinical trials have been unconvincing. The FDA has not approved HBOT for stroke.
HBOT in practice
During HBOT, the patient breathes 100% oxygen while the whole body is pressurized within a hyperbaric chamber. The chamber’s construction allows pressures above normal sea level of 1.0 atmosphere absolute (ATA). For example, The U.S. Navy Treatment Table for decompression sickness recommends 100% oxygen at 2.8 ATA. Chambers may hold one or more patients at a time.
The frequency of therapy varies but often consists of 20-60 sessions lasting 90-120 minutes. For off-label use like TBI, patients usually pay out of pocket. Given the multiple treatments, costs can add up.
Inconsistent evidence and sham controls
The unwieldy 33-page evidence review by Hadanny and colleagues cites multiple studies supporting HBOT for TBI. However, many, if not all, suffer from methodological flaws. These include vague inclusion criteria, lack of a control group, small patient numbers, treatment at different times since injury, poorly defined or varying HBOT protocols, varying outcome measures, and superficial results analysis.
A sham or control arm is essential for HBOT research trials, given the potential placebo effect of placing a human being inside a large, high-tech, sealed tube for an hour or more. In some sham-controlled studies, which consisted of low-pressure oxygen (that is, 1.3 ATA as sham vs. 2.4 ATA as treatment), all groups experienced symptom improvement. The review authors argue that the low-dose HBOT sham arms were biologically active and that the improvements seen mean that both high- and low-dose HBOT is therapeutic. The alternative explanation is that the placebo effect accounted for improvement in both groups.
The late Michael Bennett, a world authority on hyperbaric and underwater medicine, doubted that conventional HBOT sham controls could genuinely have a therapeutic effect, and I agree. The upcoming HOT-POCS trial (discussed below) should answer the question more definitively.
Mechanisms of action and safety
Mechanisms of benefit for HBOT include increased oxygen availability and angiogenesis. Animal research suggests that it may reduce secondary cell death from TBI, through stabilization of the blood-brain barrier and inflammation reduction.
HBOT is generally safe and well tolerated. A retrospective analysis of 1.5 million outpatient hyperbaric treatments revealed that less than 1% were associated with adverse events. The most common were ear and sinus barotrauma. Because HBOT uses increased air pressure, patients must equalize their ears and sinuses. Those who cannot because of altered consciousness, anatomical defects, or congestion must undergo myringotomy or terminate therapy. Claustrophobia was the second most common adverse effect. Convulsions and tension pneumocephalus were rare.
Perhaps the most concerning risk of HBOT for patients with TBI is the potential waste of human and financial resources.
Desperate physicians and patients
As a neurologist who regularly treats patients with TBI, I share the review authors’ frustration regarding the limited efficacy of available treatments. However, the suboptimal efficacy of currently available therapy is insufficient justification to recommend HBOT.
With respect to chronic TBI, it is difficult to imagine how HBOT could reverse brain injury that has been present for months or years. No other therapy exists that reliably encourages neuronal regeneration or prevents the development of posttraumatic epilepsy.
Frank Conidi, MD, a board-certified sports neurologist and headache specialist, shared his thoughts via email. He agrees that HBOT may have a role in TBI, but after reviewing Hadanny and colleagues’ paper, he concluded that there is insufficient evidence for the use of HBOT in all forms of TBI. He would like to see large multicenter, well-designed studies with standardized pressures and duration and a standard definition of the various types of head injury.
Ongoing research
There are at least five ongoing trials on HBOT for TBI or postconcussive syndrome, including the well-designed placebo-controlled HOT-POCS study. The latter has a novel placebo gas system that addresses Hadanny and colleagues’ contention that even low-dose HBOT might be effective.
The placebo arm in HOT-POCS mimics the HBO environment but provides only 0.21 ATA of oxygen, the same as room air. The active arm provides 100% oxygen at 2.0 ATA. If patients in both arms improve, the benefit will be caused by a placebo response, not HBOT.
Conflict of interest
Another concern with the review is that all three authors are affiliated with Aviv Scientific. This company has an exclusive partnership with the world’s largest hyperbaric medicine and research facility, the Sagol Center at Shamir Medical Center in Be’er Ya’akov, Israel.
This conflict of interest does not a priori invalidate their conclusions. However, official HBOT guidelines from a leading organization like the Undersea and Hyperbaric Medicine Society or the American Academy of Neurology would be preferable.
Conclusion
There is an urgent unmet need for more effective treatments for postconcussive syndrome and chronic TBI.
The review authors’ recommendations for HBOT seem premature. They are arguably a disservice to the many desperate patients and their families who will be tempted to expend valuable resources of time and money for an appealing but unproven therapy. Appropriately designed placebo-controlled studies such as HOT-POCS will help separate fact from wishful thinking.
Dr. Wilner is associate professor of neurology at University of Tennessee Health Science Center, Memphis. He reported a conflict of interest with Accordant Health Services.
A version of this article first appeared on Medscape.com.
A recent review by Hadanny and colleagues recommends hyperbaric oxygen therapy (HBOT) for acute moderate to severe traumatic brain injury (TBI) and selected patients with prolonged postconcussive syndrome.
This article piqued my curiosity because I trained in HBOT more than 20 years ago. As a passionate scuba diver, my motivation was to master treatment for air embolism and decompression illness. Thankfully, these diving accidents are rare. However, I used HBOT for nonhealing wounds, and its efficacy was sometimes remarkable.
Paradoxical results with oxygen therapy
Although it may seem self-evident that “more oxygen is better” for medical illness, this is not necessarily true. I recently interviewed Ola Didrik Saugstad, MD, who demonstrated that the traditional practice of resuscitating newborns with 100% oxygen was more toxic than resuscitation with air (which contains 21% oxygen). His counterintuitive discovery led to a lifesaving change in the international newborn resuscitation guidelines.
The Food and Drug Administration has approved HBOT for a wide variety of conditions, but some practitioners enthusiastically promote it for off-label indications. These include antiaging, autism, multiple sclerosis, and the aforementioned TBI.
More than 50 years ago, HBOT was proposed for stroke, another disorder where the brain has been deprived of oxygen. Despite obvious logic, clinical trials have been unconvincing. The FDA has not approved HBOT for stroke.
HBOT in practice
During HBOT, the patient breathes 100% oxygen while the whole body is pressurized within a hyperbaric chamber. The chamber’s construction allows pressures above normal sea level of 1.0 atmosphere absolute (ATA). For example, The U.S. Navy Treatment Table for decompression sickness recommends 100% oxygen at 2.8 ATA. Chambers may hold one or more patients at a time.
The frequency of therapy varies but often consists of 20-60 sessions lasting 90-120 minutes. For off-label use like TBI, patients usually pay out of pocket. Given the multiple treatments, costs can add up.
Inconsistent evidence and sham controls
The unwieldy 33-page evidence review by Hadanny and colleagues cites multiple studies supporting HBOT for TBI. However, many, if not all, suffer from methodological flaws. These include vague inclusion criteria, lack of a control group, small patient numbers, treatment at different times since injury, poorly defined or varying HBOT protocols, varying outcome measures, and superficial results analysis.
A sham or control arm is essential for HBOT research trials, given the potential placebo effect of placing a human being inside a large, high-tech, sealed tube for an hour or more. In some sham-controlled studies, which consisted of low-pressure oxygen (that is, 1.3 ATA as sham vs. 2.4 ATA as treatment), all groups experienced symptom improvement. The review authors argue that the low-dose HBOT sham arms were biologically active and that the improvements seen mean that both high- and low-dose HBOT is therapeutic. The alternative explanation is that the placebo effect accounted for improvement in both groups.
The late Michael Bennett, a world authority on hyperbaric and underwater medicine, doubted that conventional HBOT sham controls could genuinely have a therapeutic effect, and I agree. The upcoming HOT-POCS trial (discussed below) should answer the question more definitively.
Mechanisms of action and safety
Mechanisms of benefit for HBOT include increased oxygen availability and angiogenesis. Animal research suggests that it may reduce secondary cell death from TBI, through stabilization of the blood-brain barrier and inflammation reduction.
HBOT is generally safe and well tolerated. A retrospective analysis of 1.5 million outpatient hyperbaric treatments revealed that less than 1% were associated with adverse events. The most common were ear and sinus barotrauma. Because HBOT uses increased air pressure, patients must equalize their ears and sinuses. Those who cannot because of altered consciousness, anatomical defects, or congestion must undergo myringotomy or terminate therapy. Claustrophobia was the second most common adverse effect. Convulsions and tension pneumocephalus were rare.
Perhaps the most concerning risk of HBOT for patients with TBI is the potential waste of human and financial resources.
Desperate physicians and patients
As a neurologist who regularly treats patients with TBI, I share the review authors’ frustration regarding the limited efficacy of available treatments. However, the suboptimal efficacy of currently available therapy is insufficient justification to recommend HBOT.
With respect to chronic TBI, it is difficult to imagine how HBOT could reverse brain injury that has been present for months or years. No other therapy exists that reliably encourages neuronal regeneration or prevents the development of posttraumatic epilepsy.
Frank Conidi, MD, a board-certified sports neurologist and headache specialist, shared his thoughts via email. He agrees that HBOT may have a role in TBI, but after reviewing Hadanny and colleagues’ paper, he concluded that there is insufficient evidence for the use of HBOT in all forms of TBI. He would like to see large multicenter, well-designed studies with standardized pressures and duration and a standard definition of the various types of head injury.
Ongoing research
There are at least five ongoing trials on HBOT for TBI or postconcussive syndrome, including the well-designed placebo-controlled HOT-POCS study. The latter has a novel placebo gas system that addresses Hadanny and colleagues’ contention that even low-dose HBOT might be effective.
The placebo arm in HOT-POCS mimics the HBO environment but provides only 0.21 ATA of oxygen, the same as room air. The active arm provides 100% oxygen at 2.0 ATA. If patients in both arms improve, the benefit will be caused by a placebo response, not HBOT.
Conflict of interest
Another concern with the review is that all three authors are affiliated with Aviv Scientific. This company has an exclusive partnership with the world’s largest hyperbaric medicine and research facility, the Sagol Center at Shamir Medical Center in Be’er Ya’akov, Israel.
This conflict of interest does not a priori invalidate their conclusions. However, official HBOT guidelines from a leading organization like the Undersea and Hyperbaric Medicine Society or the American Academy of Neurology would be preferable.
Conclusion
There is an urgent unmet need for more effective treatments for postconcussive syndrome and chronic TBI.
The review authors’ recommendations for HBOT seem premature. They are arguably a disservice to the many desperate patients and their families who will be tempted to expend valuable resources of time and money for an appealing but unproven therapy. Appropriately designed placebo-controlled studies such as HOT-POCS will help separate fact from wishful thinking.
Dr. Wilner is associate professor of neurology at University of Tennessee Health Science Center, Memphis. He reported a conflict of interest with Accordant Health Services.
A version of this article first appeared on Medscape.com.
Hormone replacement therapy for postmenopausal osteoporosis
The actress Sally Field recently described her struggles with postmenopausal osteoporosis – she was given the diagnosis when she was 60 years old despite being physically active and engaging in activities such as biking, hiking, and yoga. As a slim, White woman in her sixth decade of life, she certainly had several risk factors for osteoporosis.
Osteoporosis, a condition associated with weak bones and an increased risk for fracture, is common in women after menopause. It’s defined as a bone mineral density (BMD) T-score of less than or equal to –2.5 on dual-energy x-ray absorptiometry (DXA) scan, occurrence of a spine or hip fracture regardless of BMD, or a BMD T-score between –1 and –2.5, along with a history of certain kinds of fractures or increased fracture risk based on the Fracture Risk Assessment Tool (FRAX).
The National Health and Nutrition Examination Survey from 2013 to 2014 reported that 16.5 % of women aged 50 years or older in the U.S. have osteoporosis (vs. only 5% of men of a similar age), with an increasing prevalence with increasing age. For example, the risk for osteoporosis of the hip increases from about 7% in women 50-59 years of age to about 35% in those aged 80 years or older. The risk for postmenopausal osteoporosis is reported to be highest in Asian women (40%), followed by Hispanic (20.5%), non-Hispanic White (17%), and non-Hispanic Black women (8.2%).
Why increased fracture risk in postmenopausal women?
The primary cause of postmenopausal osteoporosis is the cessation of estrogen production by the ovaries around the menopausal transition. Estrogen is very important for bone health. It reduces bone loss by reducing levels of receptor activator of NF-kappa B ligand (RANKL) and sclerostin, and it probably also increases bone formation through its effects on sclerostin.
Around menopause, the decrease in estrogen levels results in an increase in RANKL and sclerostin, with a consequent increase in bone loss at a pace that exceeds the rate of bone formation, thereby leading to osteoporosis.
Many factors further increase the risk for osteoporosis and fracture in postmenopausal women. These include a sedentary lifestyle, lower body weight, family history of osteoporosis, smoking, and certain medications and diseases. Medications that adversely affect bone health at this age include (but are not limited to) glucocorticoids such as hydrocortisone, prednisone, and dexamethasone; letrozole; excess thyroid hormone; certain drugs used to treat cancer; immunosuppressive drugs; certain antiseizure medications; proton pump inhibitors (such as omeprazole); sodium-glucose cotransporter 2 inhibitors and certain other drugs used to treat type 2 diabetes; and selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors (used to treat anxiety and depression).
Diseases associated with increased osteoporosis risk include certain genetic conditions affecting bone, a history of early ovarian insufficiency, hyperthyroidism, high levels of cortisol, diabetes, hyperparathyroidism, eating disorders, obesity, calcium and vitamin D deficiency, excess urinary excretion of calcium, malabsorption and certain gastrointestinal surgeries, chronic kidney disease, rheumatoid arthritis, certain types of cancer, and frailty.
Furthermore, older age, low bone density, a previous history of fracture, a family history of hip fracture, smoking, and excessive alcohol intake increase the risk for an osteoporotic fracture in a postmenopausal woman.
Bone density assessment using DXA is recommended in postmenopausal women who are at increased risk for low bone density and fracture. Monitoring of bone density is typically initiated about 5 years after the menopausal transition but should be considered earlier in those at high risk for osteoporosis. Women who are aged 70 or older, and those who have had significant height loss, should also get radiography of the spine to look for vertebral fractures.
Optimal nutrition is important for all postmenopausal women. Weight extremes are to be avoided. Although the use of calcium and vitamin D supplementation in postmenopausal women is still debated, the Institute of Medicine recommends that women 51-70 years of age take 1,000-1,200 mg of calcium and 400-600 IU of vitamin D daily, and that those older than 70 years take 1,000-1,200 mg of calcium and 400-800 IU of vitamin D daily.
Women with low vitamin D levels often require higher doses of vitamin D. It’s very important to avoid smoking and excessive alcohol consumption. Optimizing protein intake and exercises that improve muscle strength and improve balance can reduce the risk for falls, a key contributor to osteoporotic fractures.
Estrogen to prevent fracture risk
Because estrogen deficiency is a key cause of postmenopausal osteoporosis, estrogen replacement therapy has been used to prevent this condition, particularly early in the menopausal transition (51-60 years). Different formulations of estrogen given via oral or transdermal routes have been demonstrated to prevent osteoporosis; transdermal estrogen is often preferred because of a lower risk for blood clots and stroke. Women who have an intact uterus should also receive a progestin preparation either daily or cyclically, because estrogen alone can increase the risk for uterine cancer in the long run. Estrogen replacement has been associated with a 34% reduction in vertebral, hip, and total fractures in women of this age group.
Sally Field did receive hormone replacement therapy, which was helpful for her bones. However, as typically happens, her bone density dropped again when she discontinued hormone replacement. She also had low vitamin D levels, but vitamin D supplementation was not helpful. She received other medical intervention, with recovery back to good bone health.
Raloxifene is a medication that acts on the estrogen receptor, with beneficial effects on bone, and is approved for prevention and treatment of postmenopausal osteoporosis.
Medications that reduce bone loss (antiresorptive drugs), such as bisphosphonates and denosumab, and those that increase bone formation (osteoanabolic drugs), such as teriparatide, abaloparatide, and romosozumab, are used alone or in combination in women whose osteoporosis doesn’t respond to lifestyle and preventive strategies. The osteoanabolic drugs are typically reserved for women at very high risk for fractures, such as those with a BMD T-score ≤ less than or equal to –3, older women with recent fractures, and those with other risk factors. Treatment is typically lifelong.
(such as fractures of the spine and hip). It’s important to recognize those at greatest risk for this condition; implement bone health monitoring in a timely fashion; and ensure optimal nutrition, calcium and vitamin D supplementation, and exercises that optimize muscle strength and balance. Hormone replacement therapy is a consideration in many women. Some women will require antiresorptive or osteoanabolic drugs to manage this condition. With optimal treatment, older women can live long and productive lives.
Dr. Misra is Chief, Division of Pediatric Endocrinology, Mass General for Children; Associate Director, Harvard Catalyst Translation and Clinical Research Center; Director, Pediatric Endocrine-Sports Endocrine-Neuroendocrine Lab, Mass General Hospital; Professor, department of pediatrics, Harvard Medical School, Boston. She has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AbbVie; Sanofi; Ipsen.
A version of this article first appeared on Medscape.com.
The actress Sally Field recently described her struggles with postmenopausal osteoporosis – she was given the diagnosis when she was 60 years old despite being physically active and engaging in activities such as biking, hiking, and yoga. As a slim, White woman in her sixth decade of life, she certainly had several risk factors for osteoporosis.
Osteoporosis, a condition associated with weak bones and an increased risk for fracture, is common in women after menopause. It’s defined as a bone mineral density (BMD) T-score of less than or equal to –2.5 on dual-energy x-ray absorptiometry (DXA) scan, occurrence of a spine or hip fracture regardless of BMD, or a BMD T-score between –1 and –2.5, along with a history of certain kinds of fractures or increased fracture risk based on the Fracture Risk Assessment Tool (FRAX).
The National Health and Nutrition Examination Survey from 2013 to 2014 reported that 16.5 % of women aged 50 years or older in the U.S. have osteoporosis (vs. only 5% of men of a similar age), with an increasing prevalence with increasing age. For example, the risk for osteoporosis of the hip increases from about 7% in women 50-59 years of age to about 35% in those aged 80 years or older. The risk for postmenopausal osteoporosis is reported to be highest in Asian women (40%), followed by Hispanic (20.5%), non-Hispanic White (17%), and non-Hispanic Black women (8.2%).
Why increased fracture risk in postmenopausal women?
The primary cause of postmenopausal osteoporosis is the cessation of estrogen production by the ovaries around the menopausal transition. Estrogen is very important for bone health. It reduces bone loss by reducing levels of receptor activator of NF-kappa B ligand (RANKL) and sclerostin, and it probably also increases bone formation through its effects on sclerostin.
Around menopause, the decrease in estrogen levels results in an increase in RANKL and sclerostin, with a consequent increase in bone loss at a pace that exceeds the rate of bone formation, thereby leading to osteoporosis.
Many factors further increase the risk for osteoporosis and fracture in postmenopausal women. These include a sedentary lifestyle, lower body weight, family history of osteoporosis, smoking, and certain medications and diseases. Medications that adversely affect bone health at this age include (but are not limited to) glucocorticoids such as hydrocortisone, prednisone, and dexamethasone; letrozole; excess thyroid hormone; certain drugs used to treat cancer; immunosuppressive drugs; certain antiseizure medications; proton pump inhibitors (such as omeprazole); sodium-glucose cotransporter 2 inhibitors and certain other drugs used to treat type 2 diabetes; and selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors (used to treat anxiety and depression).
Diseases associated with increased osteoporosis risk include certain genetic conditions affecting bone, a history of early ovarian insufficiency, hyperthyroidism, high levels of cortisol, diabetes, hyperparathyroidism, eating disorders, obesity, calcium and vitamin D deficiency, excess urinary excretion of calcium, malabsorption and certain gastrointestinal surgeries, chronic kidney disease, rheumatoid arthritis, certain types of cancer, and frailty.
Furthermore, older age, low bone density, a previous history of fracture, a family history of hip fracture, smoking, and excessive alcohol intake increase the risk for an osteoporotic fracture in a postmenopausal woman.
Bone density assessment using DXA is recommended in postmenopausal women who are at increased risk for low bone density and fracture. Monitoring of bone density is typically initiated about 5 years after the menopausal transition but should be considered earlier in those at high risk for osteoporosis. Women who are aged 70 or older, and those who have had significant height loss, should also get radiography of the spine to look for vertebral fractures.
Optimal nutrition is important for all postmenopausal women. Weight extremes are to be avoided. Although the use of calcium and vitamin D supplementation in postmenopausal women is still debated, the Institute of Medicine recommends that women 51-70 years of age take 1,000-1,200 mg of calcium and 400-600 IU of vitamin D daily, and that those older than 70 years take 1,000-1,200 mg of calcium and 400-800 IU of vitamin D daily.
Women with low vitamin D levels often require higher doses of vitamin D. It’s very important to avoid smoking and excessive alcohol consumption. Optimizing protein intake and exercises that improve muscle strength and improve balance can reduce the risk for falls, a key contributor to osteoporotic fractures.
Estrogen to prevent fracture risk
Because estrogen deficiency is a key cause of postmenopausal osteoporosis, estrogen replacement therapy has been used to prevent this condition, particularly early in the menopausal transition (51-60 years). Different formulations of estrogen given via oral or transdermal routes have been demonstrated to prevent osteoporosis; transdermal estrogen is often preferred because of a lower risk for blood clots and stroke. Women who have an intact uterus should also receive a progestin preparation either daily or cyclically, because estrogen alone can increase the risk for uterine cancer in the long run. Estrogen replacement has been associated with a 34% reduction in vertebral, hip, and total fractures in women of this age group.
Sally Field did receive hormone replacement therapy, which was helpful for her bones. However, as typically happens, her bone density dropped again when she discontinued hormone replacement. She also had low vitamin D levels, but vitamin D supplementation was not helpful. She received other medical intervention, with recovery back to good bone health.
Raloxifene is a medication that acts on the estrogen receptor, with beneficial effects on bone, and is approved for prevention and treatment of postmenopausal osteoporosis.
Medications that reduce bone loss (antiresorptive drugs), such as bisphosphonates and denosumab, and those that increase bone formation (osteoanabolic drugs), such as teriparatide, abaloparatide, and romosozumab, are used alone or in combination in women whose osteoporosis doesn’t respond to lifestyle and preventive strategies. The osteoanabolic drugs are typically reserved for women at very high risk for fractures, such as those with a BMD T-score ≤ less than or equal to –3, older women with recent fractures, and those with other risk factors. Treatment is typically lifelong.
(such as fractures of the spine and hip). It’s important to recognize those at greatest risk for this condition; implement bone health monitoring in a timely fashion; and ensure optimal nutrition, calcium and vitamin D supplementation, and exercises that optimize muscle strength and balance. Hormone replacement therapy is a consideration in many women. Some women will require antiresorptive or osteoanabolic drugs to manage this condition. With optimal treatment, older women can live long and productive lives.
Dr. Misra is Chief, Division of Pediatric Endocrinology, Mass General for Children; Associate Director, Harvard Catalyst Translation and Clinical Research Center; Director, Pediatric Endocrine-Sports Endocrine-Neuroendocrine Lab, Mass General Hospital; Professor, department of pediatrics, Harvard Medical School, Boston. She has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AbbVie; Sanofi; Ipsen.
A version of this article first appeared on Medscape.com.
The actress Sally Field recently described her struggles with postmenopausal osteoporosis – she was given the diagnosis when she was 60 years old despite being physically active and engaging in activities such as biking, hiking, and yoga. As a slim, White woman in her sixth decade of life, she certainly had several risk factors for osteoporosis.
Osteoporosis, a condition associated with weak bones and an increased risk for fracture, is common in women after menopause. It’s defined as a bone mineral density (BMD) T-score of less than or equal to –2.5 on dual-energy x-ray absorptiometry (DXA) scan, occurrence of a spine or hip fracture regardless of BMD, or a BMD T-score between –1 and –2.5, along with a history of certain kinds of fractures or increased fracture risk based on the Fracture Risk Assessment Tool (FRAX).
The National Health and Nutrition Examination Survey from 2013 to 2014 reported that 16.5 % of women aged 50 years or older in the U.S. have osteoporosis (vs. only 5% of men of a similar age), with an increasing prevalence with increasing age. For example, the risk for osteoporosis of the hip increases from about 7% in women 50-59 years of age to about 35% in those aged 80 years or older. The risk for postmenopausal osteoporosis is reported to be highest in Asian women (40%), followed by Hispanic (20.5%), non-Hispanic White (17%), and non-Hispanic Black women (8.2%).
Why increased fracture risk in postmenopausal women?
The primary cause of postmenopausal osteoporosis is the cessation of estrogen production by the ovaries around the menopausal transition. Estrogen is very important for bone health. It reduces bone loss by reducing levels of receptor activator of NF-kappa B ligand (RANKL) and sclerostin, and it probably also increases bone formation through its effects on sclerostin.
Around menopause, the decrease in estrogen levels results in an increase in RANKL and sclerostin, with a consequent increase in bone loss at a pace that exceeds the rate of bone formation, thereby leading to osteoporosis.
Many factors further increase the risk for osteoporosis and fracture in postmenopausal women. These include a sedentary lifestyle, lower body weight, family history of osteoporosis, smoking, and certain medications and diseases. Medications that adversely affect bone health at this age include (but are not limited to) glucocorticoids such as hydrocortisone, prednisone, and dexamethasone; letrozole; excess thyroid hormone; certain drugs used to treat cancer; immunosuppressive drugs; certain antiseizure medications; proton pump inhibitors (such as omeprazole); sodium-glucose cotransporter 2 inhibitors and certain other drugs used to treat type 2 diabetes; and selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors (used to treat anxiety and depression).
Diseases associated with increased osteoporosis risk include certain genetic conditions affecting bone, a history of early ovarian insufficiency, hyperthyroidism, high levels of cortisol, diabetes, hyperparathyroidism, eating disorders, obesity, calcium and vitamin D deficiency, excess urinary excretion of calcium, malabsorption and certain gastrointestinal surgeries, chronic kidney disease, rheumatoid arthritis, certain types of cancer, and frailty.
Furthermore, older age, low bone density, a previous history of fracture, a family history of hip fracture, smoking, and excessive alcohol intake increase the risk for an osteoporotic fracture in a postmenopausal woman.
Bone density assessment using DXA is recommended in postmenopausal women who are at increased risk for low bone density and fracture. Monitoring of bone density is typically initiated about 5 years after the menopausal transition but should be considered earlier in those at high risk for osteoporosis. Women who are aged 70 or older, and those who have had significant height loss, should also get radiography of the spine to look for vertebral fractures.
Optimal nutrition is important for all postmenopausal women. Weight extremes are to be avoided. Although the use of calcium and vitamin D supplementation in postmenopausal women is still debated, the Institute of Medicine recommends that women 51-70 years of age take 1,000-1,200 mg of calcium and 400-600 IU of vitamin D daily, and that those older than 70 years take 1,000-1,200 mg of calcium and 400-800 IU of vitamin D daily.
Women with low vitamin D levels often require higher doses of vitamin D. It’s very important to avoid smoking and excessive alcohol consumption. Optimizing protein intake and exercises that improve muscle strength and improve balance can reduce the risk for falls, a key contributor to osteoporotic fractures.
Estrogen to prevent fracture risk
Because estrogen deficiency is a key cause of postmenopausal osteoporosis, estrogen replacement therapy has been used to prevent this condition, particularly early in the menopausal transition (51-60 years). Different formulations of estrogen given via oral or transdermal routes have been demonstrated to prevent osteoporosis; transdermal estrogen is often preferred because of a lower risk for blood clots and stroke. Women who have an intact uterus should also receive a progestin preparation either daily or cyclically, because estrogen alone can increase the risk for uterine cancer in the long run. Estrogen replacement has been associated with a 34% reduction in vertebral, hip, and total fractures in women of this age group.
Sally Field did receive hormone replacement therapy, which was helpful for her bones. However, as typically happens, her bone density dropped again when she discontinued hormone replacement. She also had low vitamin D levels, but vitamin D supplementation was not helpful. She received other medical intervention, with recovery back to good bone health.
Raloxifene is a medication that acts on the estrogen receptor, with beneficial effects on bone, and is approved for prevention and treatment of postmenopausal osteoporosis.
Medications that reduce bone loss (antiresorptive drugs), such as bisphosphonates and denosumab, and those that increase bone formation (osteoanabolic drugs), such as teriparatide, abaloparatide, and romosozumab, are used alone or in combination in women whose osteoporosis doesn’t respond to lifestyle and preventive strategies. The osteoanabolic drugs are typically reserved for women at very high risk for fractures, such as those with a BMD T-score ≤ less than or equal to –3, older women with recent fractures, and those with other risk factors. Treatment is typically lifelong.
(such as fractures of the spine and hip). It’s important to recognize those at greatest risk for this condition; implement bone health monitoring in a timely fashion; and ensure optimal nutrition, calcium and vitamin D supplementation, and exercises that optimize muscle strength and balance. Hormone replacement therapy is a consideration in many women. Some women will require antiresorptive or osteoanabolic drugs to manage this condition. With optimal treatment, older women can live long and productive lives.
Dr. Misra is Chief, Division of Pediatric Endocrinology, Mass General for Children; Associate Director, Harvard Catalyst Translation and Clinical Research Center; Director, Pediatric Endocrine-Sports Endocrine-Neuroendocrine Lab, Mass General Hospital; Professor, department of pediatrics, Harvard Medical School, Boston. She has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AbbVie; Sanofi; Ipsen.
A version of this article first appeared on Medscape.com.
New ‘C word’: Cure should be the goal for patients with lung cancer
This transcript has been edited for clarity.
Hello. It’s Mark Kris from Memorial Sloan-Kettering, still musing on things I learned at ASCO 2023.
I learned that there is a new C word.
People used to be afraid to use the word “cancer,” so they would call it the C word. Hopefully we’ve gotten over that stigma, that cancer is an illness that can be fought like any other illness.
There’s a new C word now that people seem, again, afraid to use, and that word is “cure.” It’s almost a true rarity that – again, I’m talking about the lung cancer world in particular – folks use the word “cure.” I didn’t hear it at ASCO, but the truth of the matter is that’s a word we should be using and be using more.
What do our patients want? I think if you truly ask a patient what their goal of care should be, it would be to cure the illness. What I mean by “cure” is to eradicate the cancer that is in their body, keep the cancer and its effects from interfering with their ability to continue their lives, and to do it for the length of their natural life. That’s what our patients want. Yes, overall survival is important, but not as much as a life free of cancer and the burden that it puts on people having cancer in the body.
When you start thinking about cure and how to make it a goal of care, a number of issues immediately crop up. The first one is defining what is meant by “cure.” We don’t have a strict definition of cure. Again, I would probably go to the patients and ask them what they mean by it. There may be some landmark part of the definition that needs to be discussed and addressed, but again, to me it’s having your life not disturbed by cancer, and that generally comes by eradicating cancer. Living with cancer is harder than the living after cancer has been cured. But we don’t have a good definition.
We also don’t have a good way of designing clinical trials to assess whether the regimen is curative. I don’t think I’ve ever seen a trial in lung cancer that looked at the ability of any given treatment to cure patients. We need to come up with ways to design trials to do that. Now, in addition to clinical trials, we don’t have a good body of evidence to design our preclinical experiments to look for those treatments that can lead to cures, or total eradication of cancer in whatever model system might be used. If we make cure the goal, then we need to find ways preclinically to identify those strategies that could lead to that.
Also in the realm of clinical trials, we need a very clear statistical underpinning to show that one or another treatment has a better chance of cure and to show with scientific rigor that one treatment is better than the other when it comes to cure. I think there needs to be more attention to this, and as we think about revamping the clinical trial process, we need to focus more on cure.
I’m saving the most important step for last. None of this can happen unless we try to make it happen and we say cure is possible. My mentor, George Boswell, always taught us that we would, in every single patient with cancer, try to develop a curative strategy. Is there a curative strategy for this patient? If so, pursue it with all the tools and vigor that we have. We really need to think that way.
Obviously, not every patient with cancer can be cured with our current armamentarium of anticancer treatments, but we need to make sure we put it on the table. We need to [confirm] that a strategy does not currently exist that could lead to cure. And of course, if we do find that strategy, we need to pursue it with all the energy and resources that we have.
Please don’t be afraid to use the word “cure.” Our patients want that. They deserve it. We should work hard to try to provide it and work toward developing strategies that we can propose and cure more patients.
Mark G. Kris, MD, is chief of the thoracic oncology service and the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan Kettering Cancer Center in New York. His research interests include targeted therapies for lung cancer, multimodality therapy, the development of new anticancer drugs, and symptom management with a focus on preventing emesis.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Hello. It’s Mark Kris from Memorial Sloan-Kettering, still musing on things I learned at ASCO 2023.
I learned that there is a new C word.
People used to be afraid to use the word “cancer,” so they would call it the C word. Hopefully we’ve gotten over that stigma, that cancer is an illness that can be fought like any other illness.
There’s a new C word now that people seem, again, afraid to use, and that word is “cure.” It’s almost a true rarity that – again, I’m talking about the lung cancer world in particular – folks use the word “cure.” I didn’t hear it at ASCO, but the truth of the matter is that’s a word we should be using and be using more.
What do our patients want? I think if you truly ask a patient what their goal of care should be, it would be to cure the illness. What I mean by “cure” is to eradicate the cancer that is in their body, keep the cancer and its effects from interfering with their ability to continue their lives, and to do it for the length of their natural life. That’s what our patients want. Yes, overall survival is important, but not as much as a life free of cancer and the burden that it puts on people having cancer in the body.
When you start thinking about cure and how to make it a goal of care, a number of issues immediately crop up. The first one is defining what is meant by “cure.” We don’t have a strict definition of cure. Again, I would probably go to the patients and ask them what they mean by it. There may be some landmark part of the definition that needs to be discussed and addressed, but again, to me it’s having your life not disturbed by cancer, and that generally comes by eradicating cancer. Living with cancer is harder than the living after cancer has been cured. But we don’t have a good definition.
We also don’t have a good way of designing clinical trials to assess whether the regimen is curative. I don’t think I’ve ever seen a trial in lung cancer that looked at the ability of any given treatment to cure patients. We need to come up with ways to design trials to do that. Now, in addition to clinical trials, we don’t have a good body of evidence to design our preclinical experiments to look for those treatments that can lead to cures, or total eradication of cancer in whatever model system might be used. If we make cure the goal, then we need to find ways preclinically to identify those strategies that could lead to that.
Also in the realm of clinical trials, we need a very clear statistical underpinning to show that one or another treatment has a better chance of cure and to show with scientific rigor that one treatment is better than the other when it comes to cure. I think there needs to be more attention to this, and as we think about revamping the clinical trial process, we need to focus more on cure.
I’m saving the most important step for last. None of this can happen unless we try to make it happen and we say cure is possible. My mentor, George Boswell, always taught us that we would, in every single patient with cancer, try to develop a curative strategy. Is there a curative strategy for this patient? If so, pursue it with all the tools and vigor that we have. We really need to think that way.
Obviously, not every patient with cancer can be cured with our current armamentarium of anticancer treatments, but we need to make sure we put it on the table. We need to [confirm] that a strategy does not currently exist that could lead to cure. And of course, if we do find that strategy, we need to pursue it with all the energy and resources that we have.
Please don’t be afraid to use the word “cure.” Our patients want that. They deserve it. We should work hard to try to provide it and work toward developing strategies that we can propose and cure more patients.
Mark G. Kris, MD, is chief of the thoracic oncology service and the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan Kettering Cancer Center in New York. His research interests include targeted therapies for lung cancer, multimodality therapy, the development of new anticancer drugs, and symptom management with a focus on preventing emesis.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Hello. It’s Mark Kris from Memorial Sloan-Kettering, still musing on things I learned at ASCO 2023.
I learned that there is a new C word.
People used to be afraid to use the word “cancer,” so they would call it the C word. Hopefully we’ve gotten over that stigma, that cancer is an illness that can be fought like any other illness.
There’s a new C word now that people seem, again, afraid to use, and that word is “cure.” It’s almost a true rarity that – again, I’m talking about the lung cancer world in particular – folks use the word “cure.” I didn’t hear it at ASCO, but the truth of the matter is that’s a word we should be using and be using more.
What do our patients want? I think if you truly ask a patient what their goal of care should be, it would be to cure the illness. What I mean by “cure” is to eradicate the cancer that is in their body, keep the cancer and its effects from interfering with their ability to continue their lives, and to do it for the length of their natural life. That’s what our patients want. Yes, overall survival is important, but not as much as a life free of cancer and the burden that it puts on people having cancer in the body.
When you start thinking about cure and how to make it a goal of care, a number of issues immediately crop up. The first one is defining what is meant by “cure.” We don’t have a strict definition of cure. Again, I would probably go to the patients and ask them what they mean by it. There may be some landmark part of the definition that needs to be discussed and addressed, but again, to me it’s having your life not disturbed by cancer, and that generally comes by eradicating cancer. Living with cancer is harder than the living after cancer has been cured. But we don’t have a good definition.
We also don’t have a good way of designing clinical trials to assess whether the regimen is curative. I don’t think I’ve ever seen a trial in lung cancer that looked at the ability of any given treatment to cure patients. We need to come up with ways to design trials to do that. Now, in addition to clinical trials, we don’t have a good body of evidence to design our preclinical experiments to look for those treatments that can lead to cures, or total eradication of cancer in whatever model system might be used. If we make cure the goal, then we need to find ways preclinically to identify those strategies that could lead to that.
Also in the realm of clinical trials, we need a very clear statistical underpinning to show that one or another treatment has a better chance of cure and to show with scientific rigor that one treatment is better than the other when it comes to cure. I think there needs to be more attention to this, and as we think about revamping the clinical trial process, we need to focus more on cure.
I’m saving the most important step for last. None of this can happen unless we try to make it happen and we say cure is possible. My mentor, George Boswell, always taught us that we would, in every single patient with cancer, try to develop a curative strategy. Is there a curative strategy for this patient? If so, pursue it with all the tools and vigor that we have. We really need to think that way.
Obviously, not every patient with cancer can be cured with our current armamentarium of anticancer treatments, but we need to make sure we put it on the table. We need to [confirm] that a strategy does not currently exist that could lead to cure. And of course, if we do find that strategy, we need to pursue it with all the energy and resources that we have.
Please don’t be afraid to use the word “cure.” Our patients want that. They deserve it. We should work hard to try to provide it and work toward developing strategies that we can propose and cure more patients.
Mark G. Kris, MD, is chief of the thoracic oncology service and the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan Kettering Cancer Center in New York. His research interests include targeted therapies for lung cancer, multimodality therapy, the development of new anticancer drugs, and symptom management with a focus on preventing emesis.
A version of this article first appeared on Medscape.com.