Ramy Sedhom, MD, a medical oncologist and a palliative care physician at Penn Medicine Princeton Health in Plainsboro, N.J., will always wonder if prior authorization refusals led to his patient’s death.

The patient had advanced gastric cancer and the insurer initially denied a PET scan to rule out metastatic disease. When the scan was eventually allowed, it revealed that the cancer had spread.

Standard treatment would have been difficult for the patient, an older individual with comorbidities. But Dr. Sedhom knew that a European study had reported equal efficacy and fewer side effects with a reduced chemotherapy regimen, and he thought that was the best approach in this situation.

The insurer disagreed with Dr. Sedhom’s decision and, while the two argued, the patient’s symptoms worsened. He was admitted to the hospital, where he experienced a decline in function, common for older patients. “Long story short, he was never able to seek treatment and then transitioned to hospice,” Dr. Sedhom said. “It was one of those situations where there was a 3- to 4-week delay in what should have been standard care.”

That course of events is not an outlier but everyday life for physicians trying to navigate insurers’ prior authorization rules before they can treat their patients. Nearly 4 years after major organizations — American Hospital Association, America’s Health Insurance Plans, American Medical Association, Blue Cross Blue Shield Association, and others — signed a consensus statement agreeing to improve the prior authorization process, physicians say little progress has been made.

Indeed, 83% of physicians say that the number of prior authorizations required for prescription medications and medical services has increased over the last 5 years, according to survey results released earlier this year.

“It’s decidedly worse — there’s no question about it,” said Andrew R. Spector, MD, a neurologist and sleep medicine specialist at Duke Health in Durham, N.C. “Drugs that I used to get without prior authorizations now require them.”

When Vignesh I. Doraiswamy, MD, an internal medicine hospitalist at the Ohio State University Wexner Medical Center in Columbus, discharged a patient with Clostridioides difficile infection, he followed clinical guidelines to prescribe vancomycin for 10 to 14 days. “And the insurance company said, ‘Well, yeah, we only authorize about 5 days,’ which just makes no sense,” Dr. Doraiswamy said. “There’s nowhere in any literature that says 5 days is sufficient. What worries me is that is the standard of care we are supposed to give and yet we are unable to.”

Yash B. Jobanputra, MD, a cardiology fellow at Saint Vincent Hospital in Worcester, Mass., laments that prior authorization is used in situations that simply do not make common sense. During his residency, a woman who had tested positive for the BRCA gene mutation with a strong family history of breast cancer needed a breast ultrasound and an MRI scan every 6 months to 1 year. Despite the documentation that she was at extremely high risk for developing breast cancer, he had to go through prior authorization every time she was due for new images.

“I had to call the insurance company, they would put me on hold, I would wait to speak to a physician — and the end response would be, ‘Yeah, this is what needs to be done,’” he said. “But having established her positive status once should be enough really. I shouldn’t have to go through the circus all over again.”

Prior authorization is also being used for routine diagnostics, such as a Holter monitor for patients complaining of heart palpitations. “Depending on the insurance, for some patients we can give it to them in the clinic right away,” Dr. Jobanputra said. “Whereas some others we have to wait until we get prior authorization from the insurance company and the patient has to come back again to the hospital to get the monitor. That is a delay in patient care.”

The delays also extend to emergency care, Dr. Doraiswamy said. He cites the example of a heart attack patient who needed an emergency heart catheterization but ran into a prior authorization delay. “I just said, ‘Try your best not to get stressed’ which is not easy for a patient finding out their stay wasn’t covered when they had just been through a heart attack,” he said. “Then I spent 20 to 30 minutes — most of it on hold — to answer the question ‘Why did this patient need to get admitted?’ “

Physicians feel disrespected because that type of prior authorization hassle is just busywork. “Rarely is a valid stay that was initially denied, not eventually accepted,” Dr. Doraiswamy said. “But why couldn’t they have just seen that the guy had a heart attack and he obviously needed to be in the hospital?”

For Dr. Spector, the Duke Health sleep medicine specialist, prior authorization is not just a speed bump, it’s a full stop. Insurers have started mandating a multiple sleep latency test (MSLT) to confirm narcolepsy before covering medication to treat the condition. “We know that the MSLT is very often wrong,” he said. “There are a lot of times we’re dealing with patients with narcolepsy who simply don’t meet the testing criteria that the insurance requires, and payers will not accept our clinical judgment.”

In his view, the prior authorization landscape is worsening — and not only because a “faulty test” is being used to deny treatment. “The appeal process is worse,” Dr. Spector said. “I used to be able to get on the phone and do a peer-to-peer review with a physician who I could reason with… but that doesn’t happen anymore. There is virtually no way to bypass these blanket rules.”

Other survey findings also stand in direct contradiction of the 2018 consensus agreement:

A large majority (87%) of physicians report that prior authorization interferes with continuity of care, even though the industry groups agreed that patients should be protected from treatment disruption when there is a formulary or treatment-coverage change.

Despite a consensus to encourage transparency and easy accessibility of prior authorization requirements, 68% of physicians reported that it is difficult to determine whether a prescription medication requires prior authorization, and 58% report that it’s difficult for medical services.

Phone and fax are the most commonly used methods for completing prior authorizations, despite agreement that electronic prior authorization, using existing national standard transactions, should be accelerated. Fewer than one quarter of physicians said that their electronic health record system supports electronic prior authorization for prescription medications.

Dr. Spector wants to see legislation that forces insurers to live up to some of the tenets of the 2018 consensus statement. In September, a new Texas law went into effect, exempting physicians from prior authorization if, during the previous six months, 90% of their treatments met an insurer›s medical necessity criteria. In January, the recently approved Prior Authorization Reform Act in Illinois will reduce the number of services subject to prior authorization, mandate a prior authorization decision within 5 days, and set disciplinary measures for health plans that do not comply, among other things.

“What gives me hope is that at least somewhere in the country, somebody is doing something,” Dr. Spector said. “And if it goes well, maybe other insurers will adopt it. I’m really hoping they demonstrate that the money they can save on the administration of all the appeals and prior authorization paperwork can actually go into caring for patients.”

In addition to state-level action, reform may also be advancing at the federal level. In October, a bill was introduced in the U.S. Senate that mirrors a prior authorization reform bill introduced in the House of Representatives last May. Both bills have broad bipartisan support; the House bill has more than 235 co-sponsors.

In an interview with this news organization, Rep. Ami Bera, MD, (D-CA) said it is “very realistic” that the bill will become law during this session of Congress. “We do think this bill will get marked up in committee and hopefully we can get it to the floor either as a stand-alone bill where we know we have the votes to pass it or as part of a larger legislative package,” he said.

If approved, the Improving Seniors’ Timely Access to Care Act of 2021 would require that Medicare Advantage plans minimize the use of prior authorization for routinely approved services; require real-time decisions for certain requests; report the extent of their use of prior authorization and their rate of approvals or denials, among other things; and establish an electronic prior authorization system.

Medicare Advantage plans are private insurers that are regulated by the Centers for Medicare & Medicaid Services (CMS), which will create the specific rules and penalties associated with the reforms, if they become law. “One would presume that a condition of being a Medicare Advantage plan is that you’re going to have to comply with these new regulations,” said Katie Orrico, senior vice president of health policy and advocacy for the American Association of Neurological Surgeons and Congress of Neurological Surgeons (AANS/CNS). “So they will have some amount of teeth in the form of a mandate.”

The AANS and CNS are part of the Regulatory Relief Coalition, a group of 14 national physician specialty organizations. Winning prior authorization reform in the Medicare Advantage plans is part of its bigger strategy. “If those commercial plans have to follow a set of rules and processes for Medicare, then why not just expand those same processes to all other parts of their business?” Ms. Orrico said. 

Despite his frustration with their prior authorization processes, Dr. Doraiswamy, the Ohio State hospitalist, agrees that working to improve insurers’ practices is the best way forward. “It’s so easy to make them look like these evil, giant conglomerations that exist solely to suck money and not care about anyone’s health, but I don’t know if that’s necessarily the case,” he said. “We really have to figure out how best to work with insurance companies to make sure that, while they are profit-generating institutions, that [profit] shouldn’t come at the cost of patient care.”

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

Ramy Sedhom, MD, a medical oncologist and a palliative care physician at Penn Medicine Princeton Health in Plainsboro, N.J., will always wonder if prior authorization refusals led to his patient’s death.

The patient had advanced gastric cancer and the insurer initially denied a PET scan to rule out metastatic disease. When the scan was eventually allowed, it revealed that the cancer had spread.

Standard treatment would have been difficult for the patient, an older individual with comorbidities. But Dr. Sedhom knew that a European study had reported equal efficacy and fewer side effects with a reduced chemotherapy regimen, and he thought that was the best approach in this situation.

The insurer disagreed with Dr. Sedhom’s decision and, while the two argued, the patient’s symptoms worsened. He was admitted to the hospital, where he experienced a decline in function, common for older patients. “Long story short, he was never able to seek treatment and then transitioned to hospice,” Dr. Sedhom said. “It was one of those situations where there was a 3- to 4-week delay in what should have been standard care.”

That course of events is not an outlier but everyday life for physicians trying to navigate insurers’ prior authorization rules before they can treat their patients. Nearly 4 years after major organizations — American Hospital Association, America’s Health Insurance Plans, American Medical Association, Blue Cross Blue Shield Association, and others — signed a consensus statement agreeing to improve the prior authorization process, physicians say little progress has been made.

Indeed, 83% of physicians say that the number of prior authorizations required for prescription medications and medical services has increased over the last 5 years, according to survey results released earlier this year.

“It’s decidedly worse — there’s no question about it,” said Andrew R. Spector, MD, a neurologist and sleep medicine specialist at Duke Health in Durham, N.C. “Drugs that I used to get without prior authorizations now require them.”

When Vignesh I. Doraiswamy, MD, an internal medicine hospitalist at the Ohio State University Wexner Medical Center in Columbus, discharged a patient with Clostridioides difficile infection, he followed clinical guidelines to prescribe vancomycin for 10 to 14 days. “And the insurance company said, ‘Well, yeah, we only authorize about 5 days,’ which just makes no sense,” Dr. Doraiswamy said. “There’s nowhere in any literature that says 5 days is sufficient. What worries me is that is the standard of care we are supposed to give and yet we are unable to.”

Yash B. Jobanputra, MD, a cardiology fellow at Saint Vincent Hospital in Worcester, Mass., laments that prior authorization is used in situations that simply do not make common sense. During his residency, a woman who had tested positive for the BRCA gene mutation with a strong family history of breast cancer needed a breast ultrasound and an MRI scan every 6 months to 1 year. Despite the documentation that she was at extremely high risk for developing breast cancer, he had to go through prior authorization every time she was due for new images.

“I had to call the insurance company, they would put me on hold, I would wait to speak to a physician — and the end response would be, ‘Yeah, this is what needs to be done,’” he said. “But having established her positive status once should be enough really. I shouldn’t have to go through the circus all over again.”

Prior authorization is also being used for routine diagnostics, such as a Holter monitor for patients complaining of heart palpitations. “Depending on the insurance, for some patients we can give it to them in the clinic right away,” Dr. Jobanputra said. “Whereas some others we have to wait until we get prior authorization from the insurance company and the patient has to come back again to the hospital to get the monitor. That is a delay in patient care.”

The delays also extend to emergency care, Dr. Doraiswamy said. He cites the example of a heart attack patient who needed an emergency heart catheterization but ran into a prior authorization delay. “I just said, ‘Try your best not to get stressed’ which is not easy for a patient finding out their stay wasn’t covered when they had just been through a heart attack,” he said. “Then I spent 20 to 30 minutes — most of it on hold — to answer the question ‘Why did this patient need to get admitted?’ “

Physicians feel disrespected because that type of prior authorization hassle is just busywork. “Rarely is a valid stay that was initially denied, not eventually accepted,” Dr. Doraiswamy said. “But why couldn’t they have just seen that the guy had a heart attack and he obviously needed to be in the hospital?”

For Dr. Spector, the Duke Health sleep medicine specialist, prior authorization is not just a speed bump, it’s a full stop. Insurers have started mandating a multiple sleep latency test (MSLT) to confirm narcolepsy before covering medication to treat the condition. “We know that the MSLT is very often wrong,” he said. “There are a lot of times we’re dealing with patients with narcolepsy who simply don’t meet the testing criteria that the insurance requires, and payers will not accept our clinical judgment.”

In his view, the prior authorization landscape is worsening — and not only because a “faulty test” is being used to deny treatment. “The appeal process is worse,” Dr. Spector said. “I used to be able to get on the phone and do a peer-to-peer review with a physician who I could reason with… but that doesn’t happen anymore. There is virtually no way to bypass these blanket rules.”

Other survey findings also stand in direct contradiction of the 2018 consensus agreement:

A large majority (87%) of physicians report that prior authorization interferes with continuity of care, even though the industry groups agreed that patients should be protected from treatment disruption when there is a formulary or treatment-coverage change.

Despite a consensus to encourage transparency and easy accessibility of prior authorization requirements, 68% of physicians reported that it is difficult to determine whether a prescription medication requires prior authorization, and 58% report that it’s difficult for medical services.

Phone and fax are the most commonly used methods for completing prior authorizations, despite agreement that electronic prior authorization, using existing national standard transactions, should be accelerated. Fewer than one quarter of physicians said that their electronic health record system supports electronic prior authorization for prescription medications.

Dr. Spector wants to see legislation that forces insurers to live up to some of the tenets of the 2018 consensus statement. In September, a new Texas law went into effect, exempting physicians from prior authorization if, during the previous six months, 90% of their treatments met an insurer›s medical necessity criteria. In January, the recently approved Prior Authorization Reform Act in Illinois will reduce the number of services subject to prior authorization, mandate a prior authorization decision within 5 days, and set disciplinary measures for health plans that do not comply, among other things.

“What gives me hope is that at least somewhere in the country, somebody is doing something,” Dr. Spector said. “And if it goes well, maybe other insurers will adopt it. I’m really hoping they demonstrate that the money they can save on the administration of all the appeals and prior authorization paperwork can actually go into caring for patients.”

In addition to state-level action, reform may also be advancing at the federal level. In October, a bill was introduced in the U.S. Senate that mirrors a prior authorization reform bill introduced in the House of Representatives last May. Both bills have broad bipartisan support; the House bill has more than 235 co-sponsors.

In an interview with this news organization, Rep. Ami Bera, MD, (D-CA) said it is “very realistic” that the bill will become law during this session of Congress. “We do think this bill will get marked up in committee and hopefully we can get it to the floor either as a stand-alone bill where we know we have the votes to pass it or as part of a larger legislative package,” he said.

If approved, the Improving Seniors’ Timely Access to Care Act of 2021 would require that Medicare Advantage plans minimize the use of prior authorization for routinely approved services; require real-time decisions for certain requests; report the extent of their use of prior authorization and their rate of approvals or denials, among other things; and establish an electronic prior authorization system.

Medicare Advantage plans are private insurers that are regulated by the Centers for Medicare & Medicaid Services (CMS), which will create the specific rules and penalties associated with the reforms, if they become law. “One would presume that a condition of being a Medicare Advantage plan is that you’re going to have to comply with these new regulations,” said Katie Orrico, senior vice president of health policy and advocacy for the American Association of Neurological Surgeons and Congress of Neurological Surgeons (AANS/CNS). “So they will have some amount of teeth in the form of a mandate.”

The AANS and CNS are part of the Regulatory Relief Coalition, a group of 14 national physician specialty organizations. Winning prior authorization reform in the Medicare Advantage plans is part of its bigger strategy. “If those commercial plans have to follow a set of rules and processes for Medicare, then why not just expand those same processes to all other parts of their business?” Ms. Orrico said. 

Despite his frustration with their prior authorization processes, Dr. Doraiswamy, the Ohio State hospitalist, agrees that working to improve insurers’ practices is the best way forward. “It’s so easy to make them look like these evil, giant conglomerations that exist solely to suck money and not care about anyone’s health, but I don’t know if that’s necessarily the case,” he said. “We really have to figure out how best to work with insurance companies to make sure that, while they are profit-generating institutions, that [profit] shouldn’t come at the cost of patient care.”

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

Ramy Sedhom, MD, a medical oncologist and a palliative care physician at Penn Medicine Princeton Health in Plainsboro, N.J., will always wonder if prior authorization refusals led to his patient’s death.

The patient had advanced gastric cancer and the insurer initially denied a PET scan to rule out metastatic disease. When the scan was eventually allowed, it revealed that the cancer had spread.

Standard treatment would have been difficult for the patient, an older individual with comorbidities. But Dr. Sedhom knew that a European study had reported equal efficacy and fewer side effects with a reduced chemotherapy regimen, and he thought that was the best approach in this situation.

The insurer disagreed with Dr. Sedhom’s decision and, while the two argued, the patient’s symptoms worsened. He was admitted to the hospital, where he experienced a decline in function, common for older patients. “Long story short, he was never able to seek treatment and then transitioned to hospice,” Dr. Sedhom said. “It was one of those situations where there was a 3- to 4-week delay in what should have been standard care.”

That course of events is not an outlier but everyday life for physicians trying to navigate insurers’ prior authorization rules before they can treat their patients. Nearly 4 years after major organizations — American Hospital Association, America’s Health Insurance Plans, American Medical Association, Blue Cross Blue Shield Association, and others — signed a consensus statement agreeing to improve the prior authorization process, physicians say little progress has been made.

Indeed, 83% of physicians say that the number of prior authorizations required for prescription medications and medical services has increased over the last 5 years, according to survey results released earlier this year.

“It’s decidedly worse — there’s no question about it,” said Andrew R. Spector, MD, a neurologist and sleep medicine specialist at Duke Health in Durham, N.C. “Drugs that I used to get without prior authorizations now require them.”

When Vignesh I. Doraiswamy, MD, an internal medicine hospitalist at the Ohio State University Wexner Medical Center in Columbus, discharged a patient with Clostridioides difficile infection, he followed clinical guidelines to prescribe vancomycin for 10 to 14 days. “And the insurance company said, ‘Well, yeah, we only authorize about 5 days,’ which just makes no sense,” Dr. Doraiswamy said. “There’s nowhere in any literature that says 5 days is sufficient. What worries me is that is the standard of care we are supposed to give and yet we are unable to.”

Yash B. Jobanputra, MD, a cardiology fellow at Saint Vincent Hospital in Worcester, Mass., laments that prior authorization is used in situations that simply do not make common sense. During his residency, a woman who had tested positive for the BRCA gene mutation with a strong family history of breast cancer needed a breast ultrasound and an MRI scan every 6 months to 1 year. Despite the documentation that she was at extremely high risk for developing breast cancer, he had to go through prior authorization every time she was due for new images.

“I had to call the insurance company, they would put me on hold, I would wait to speak to a physician — and the end response would be, ‘Yeah, this is what needs to be done,’” he said. “But having established her positive status once should be enough really. I shouldn’t have to go through the circus all over again.”

Prior authorization is also being used for routine diagnostics, such as a Holter monitor for patients complaining of heart palpitations. “Depending on the insurance, for some patients we can give it to them in the clinic right away,” Dr. Jobanputra said. “Whereas some others we have to wait until we get prior authorization from the insurance company and the patient has to come back again to the hospital to get the monitor. That is a delay in patient care.”

The delays also extend to emergency care, Dr. Doraiswamy said. He cites the example of a heart attack patient who needed an emergency heart catheterization but ran into a prior authorization delay. “I just said, ‘Try your best not to get stressed’ which is not easy for a patient finding out their stay wasn’t covered when they had just been through a heart attack,” he said. “Then I spent 20 to 30 minutes — most of it on hold — to answer the question ‘Why did this patient need to get admitted?’ “

Physicians feel disrespected because that type of prior authorization hassle is just busywork. “Rarely is a valid stay that was initially denied, not eventually accepted,” Dr. Doraiswamy said. “But why couldn’t they have just seen that the guy had a heart attack and he obviously needed to be in the hospital?”

For Dr. Spector, the Duke Health sleep medicine specialist, prior authorization is not just a speed bump, it’s a full stop. Insurers have started mandating a multiple sleep latency test (MSLT) to confirm narcolepsy before covering medication to treat the condition. “We know that the MSLT is very often wrong,” he said. “There are a lot of times we’re dealing with patients with narcolepsy who simply don’t meet the testing criteria that the insurance requires, and payers will not accept our clinical judgment.”

In his view, the prior authorization landscape is worsening — and not only because a “faulty test” is being used to deny treatment. “The appeal process is worse,” Dr. Spector said. “I used to be able to get on the phone and do a peer-to-peer review with a physician who I could reason with… but that doesn’t happen anymore. There is virtually no way to bypass these blanket rules.”

Other survey findings also stand in direct contradiction of the 2018 consensus agreement:

A large majority (87%) of physicians report that prior authorization interferes with continuity of care, even though the industry groups agreed that patients should be protected from treatment disruption when there is a formulary or treatment-coverage change.

Despite a consensus to encourage transparency and easy accessibility of prior authorization requirements, 68% of physicians reported that it is difficult to determine whether a prescription medication requires prior authorization, and 58% report that it’s difficult for medical services.

Phone and fax are the most commonly used methods for completing prior authorizations, despite agreement that electronic prior authorization, using existing national standard transactions, should be accelerated. Fewer than one quarter of physicians said that their electronic health record system supports electronic prior authorization for prescription medications.

Dr. Spector wants to see legislation that forces insurers to live up to some of the tenets of the 2018 consensus statement. In September, a new Texas law went into effect, exempting physicians from prior authorization if, during the previous six months, 90% of their treatments met an insurer›s medical necessity criteria. In January, the recently approved Prior Authorization Reform Act in Illinois will reduce the number of services subject to prior authorization, mandate a prior authorization decision within 5 days, and set disciplinary measures for health plans that do not comply, among other things.

“What gives me hope is that at least somewhere in the country, somebody is doing something,” Dr. Spector said. “And if it goes well, maybe other insurers will adopt it. I’m really hoping they demonstrate that the money they can save on the administration of all the appeals and prior authorization paperwork can actually go into caring for patients.”

In addition to state-level action, reform may also be advancing at the federal level. In October, a bill was introduced in the U.S. Senate that mirrors a prior authorization reform bill introduced in the House of Representatives last May. Both bills have broad bipartisan support; the House bill has more than 235 co-sponsors.

In an interview with this news organization, Rep. Ami Bera, MD, (D-CA) said it is “very realistic” that the bill will become law during this session of Congress. “We do think this bill will get marked up in committee and hopefully we can get it to the floor either as a stand-alone bill where we know we have the votes to pass it or as part of a larger legislative package,” he said.

If approved, the Improving Seniors’ Timely Access to Care Act of 2021 would require that Medicare Advantage plans minimize the use of prior authorization for routinely approved services; require real-time decisions for certain requests; report the extent of their use of prior authorization and their rate of approvals or denials, among other things; and establish an electronic prior authorization system.

Medicare Advantage plans are private insurers that are regulated by the Centers for Medicare & Medicaid Services (CMS), which will create the specific rules and penalties associated with the reforms, if they become law. “One would presume that a condition of being a Medicare Advantage plan is that you’re going to have to comply with these new regulations,” said Katie Orrico, senior vice president of health policy and advocacy for the American Association of Neurological Surgeons and Congress of Neurological Surgeons (AANS/CNS). “So they will have some amount of teeth in the form of a mandate.”

The AANS and CNS are part of the Regulatory Relief Coalition, a group of 14 national physician specialty organizations. Winning prior authorization reform in the Medicare Advantage plans is part of its bigger strategy. “If those commercial plans have to follow a set of rules and processes for Medicare, then why not just expand those same processes to all other parts of their business?” Ms. Orrico said. 

Despite his frustration with their prior authorization processes, Dr. Doraiswamy, the Ohio State hospitalist, agrees that working to improve insurers’ practices is the best way forward. “It’s so easy to make them look like these evil, giant conglomerations that exist solely to suck money and not care about anyone’s health, but I don’t know if that’s necessarily the case,” he said. “We really have to figure out how best to work with insurance companies to make sure that, while they are profit-generating institutions, that [profit] shouldn’t come at the cost of patient care.”

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

The Crohn’s disease exclusion diet (CDED), with or without partial enteral nutrition (PEN), effectively induced and maintained remission in adults with mild to moderate, biologic-naive CD, a randomized Israeli pilot study found.

The authors, led by Henit Yanai, MD, MBA, chief of the IBD Center at Rabin Medical Center in Petah Tikva, Israel, also suggested that dietary monotherapy might lead to durable endoscopic remission.

European Crohn’s and Colitis Organization

The study, published in The Lancet Gastroenterology & Hepatology, found about 60% of patients on CDED achieved clinical remission by week 6 without adding medications.

Furthermore, 80% of patients in remission at week 6 maintained clinical remission at week 24 on dietary monotherapy alone, allowing more than 50% of the intention-to-treat (ITT) population to achieve sustained remission at 6 months.

Dietary therapy resulted in a significant and progressive reduction in inflammatory markers such as C-reactive protein and fecal calprotectin. The benefit extended to mucosal healing, with 35% of the ITT population achieving endoscopic remission at 24 weeks.

Dr. Yanai explained the clinical context in which her group designed the study. “There were preliminary data regarding the efficacy of the dietary strategy for the induction of remission of mild CD in the pediatric population,” she said in an interview. “Additionally, there was an anecdotal experience in adults who reported benefits. Facing this and the lack of attractive alternatives for mild CD, we decided to examine the effectiveness of this therapeutic strategy in adults.”

Given the costs and side effects of medical treatment, interest in dietary monotherapy for IBD has been growing. As Dr. Yanai said, the CDED, a whole-foods regimen, plus PEN, has been found to help children with CD.

The CDED excludes proinflammatory food components associated with intestinal microbial dysbiosis, altered innate immunity, and impaired gut barrier function.

It involves increased consumption of fruits and vegetables, high-quality lean protein, complex carbohydrates, healthy oils, and fiber, while decreasing intake of inflammation-driving components such as animal and saturated vegetable fats, wheat, and dairy, as well as food additives such as emulsifiers, maltodextrin, and sulfites.

“The realization that exclusive enteral nutrition, which is based on liquid formulas, is effective for inducting remission in children PEN, which is a combination of liquid formulas and food, was less effective, led to the hypothesis that the mechanism might be the exclusion of dietary components that may lead to inflammation,” Dr. Yanai said. This theory, she added, derived from animal models showing that specific dietary components potentially drive inflammation.

The only current guideline-recommended nutritional therapy for remission induction is exclusive enteral nutrition (EEN) in pediatric CD.
 

The study

The open-label pilot trial led by Dr. Yanai, conducted at three medical centers, enrolled biologic-naive adults ages 18-55 with uncomplicated mild to moderate CD, with a disease duration of no more than 5 years. They had active disease on imaging and elevated C-reactive protein or fecal calprotectin.

During the period January 2017 to May 2020, eligible patients were randomly assigned 1 to 1 to CDED plus PEN enteral (n = 20) or CDED alone (n = 24) for 24 weeks. The primary endpoint was clinical remission, defined as a Harvey–Bradshaw Index score of less than 5 at week 6, an outcome was assessed in the ITT population, which consisted of those who used dietary therapy for at least 48 hours.

At week 6, 13 (68%) of 19 remaining patients in the CDED-plus-PEN group and 12 (57%) of 21 patients in the CDED-alone group had achieved clinical remission (P = .4618).

Among the 25 patients in remission 6 weeks out, 20 (80%) remained in sustained remission at week 24: 12 in the CDED-plus-PEN group and 8 in the CDED-alone group.

Moreover, 14 (35%) of 40 patients were in endoscopic remission at week 24: 8 on CDED plus PEN and 6 on CDED alone.

“CDED with or without partial enteral nutrition was effective for induction and maintenance of remission in adults with mild to moderate biologic-naive Crohn’s disease and might lead to endoscopic remission,” the authors wrote, adding that CDED for mild to moderate active disease should be assessed in a powered randomized controlled trial.

Compliance and adherence are obstacles to dietary therapies. Data for adults using exclusive enteral nutrition are conflicting, with poor compliance postulated to drive an inadequate response in some studies.

“Like every dietary treatment, adherence is challenging,” Dr. Yanai said. “However, when patients feel that it helps them, they have more incentive to follow the diet in the long run, and also once they quit and fare worse, they can go back and follow the first stage of CDED.” 

She and her colleagues stressed the need for adequately powered randomized trials and recommended that the personalization of therapeutic diets in the future should take into account the need to deliver energy tailored to the nutritional and therapeutic goals of the patient.
 

Diets alone are not therapy

In an accompanying editorial, Alexa N. Sasson, MD, an IBD fellow at Massachusetts General Hospital and T.H. Chan Harvard School of Public Health, both in Boston, called diet “a promising and potentially modifiable risk factor with mounting evidence supporting its therapeutic benefit.”

Massuchusetts General Hospital

She concurred that the Israeli findings indicate that CDED with or without PEN appears effective for inducing and maintaining remission in this cohort of patients. “Assessment of composite diets such as the CDED is important since they can be incorporated into daily life. The relative efficacy of each of the included and excluded foods, however, is not clear,” she wrote.

She cautioned, however, that dietary therapy does not constitute maintenance therapy and its effects are not sustained after the reintroduction of whole foods. “Identification of sustainable dietary interventions for the prevention and treatment of IBD is increasingly a focus of research,” she wrote.

Dr. Sasson agreed that dietary therapy for CD should be centered on patient interests, goals, and disease states. “Adjunctive dietary measures might be considered in all interested patients as a method of improving gastrointestinal-related symptoms and quality of life, with the potential to achieve a higher and more sustained level of remission,” she wrote.

Both the authors and the commentator agreed on the need for larger randomized trials with long-term follow-up to guide treatment decisions and identify patients who might benefit from dietary intervention.

This study was funded by the Azrieli Foundation and Nestlé Health Science. Dr. Yanai reported financial relationships with Pfizer, AbbVie, Ferring, Janssen, Neopharm, Pfizer, and Takeda. Several coauthors disclosed financial ties to multiple private-sector companies. Dr. Sasson had no competing interests to declare.

This article was updated Dec. 1, 2021.

The Crohn’s disease exclusion diet (CDED), with or without partial enteral nutrition (PEN), effectively induced and maintained remission in adults with mild to moderate, biologic-naive CD, a randomized Israeli pilot study found.

The authors, led by Henit Yanai, MD, MBA, chief of the IBD Center at Rabin Medical Center in Petah Tikva, Israel, also suggested that dietary monotherapy might lead to durable endoscopic remission.

European Crohn’s and Colitis Organization

The study, published in The Lancet Gastroenterology & Hepatology, found about 60% of patients on CDED achieved clinical remission by week 6 without adding medications.

Furthermore, 80% of patients in remission at week 6 maintained clinical remission at week 24 on dietary monotherapy alone, allowing more than 50% of the intention-to-treat (ITT) population to achieve sustained remission at 6 months.

Dietary therapy resulted in a significant and progressive reduction in inflammatory markers such as C-reactive protein and fecal calprotectin. The benefit extended to mucosal healing, with 35% of the ITT population achieving endoscopic remission at 24 weeks.

Dr. Yanai explained the clinical context in which her group designed the study. “There were preliminary data regarding the efficacy of the dietary strategy for the induction of remission of mild CD in the pediatric population,” she said in an interview. “Additionally, there was an anecdotal experience in adults who reported benefits. Facing this and the lack of attractive alternatives for mild CD, we decided to examine the effectiveness of this therapeutic strategy in adults.”

Given the costs and side effects of medical treatment, interest in dietary monotherapy for IBD has been growing. As Dr. Yanai said, the CDED, a whole-foods regimen, plus PEN, has been found to help children with CD.

The CDED excludes proinflammatory food components associated with intestinal microbial dysbiosis, altered innate immunity, and impaired gut barrier function.

It involves increased consumption of fruits and vegetables, high-quality lean protein, complex carbohydrates, healthy oils, and fiber, while decreasing intake of inflammation-driving components such as animal and saturated vegetable fats, wheat, and dairy, as well as food additives such as emulsifiers, maltodextrin, and sulfites.

“The realization that exclusive enteral nutrition, which is based on liquid formulas, is effective for inducting remission in children PEN, which is a combination of liquid formulas and food, was less effective, led to the hypothesis that the mechanism might be the exclusion of dietary components that may lead to inflammation,” Dr. Yanai said. This theory, she added, derived from animal models showing that specific dietary components potentially drive inflammation.

The only current guideline-recommended nutritional therapy for remission induction is exclusive enteral nutrition (EEN) in pediatric CD.
 

The study

The open-label pilot trial led by Dr. Yanai, conducted at three medical centers, enrolled biologic-naive adults ages 18-55 with uncomplicated mild to moderate CD, with a disease duration of no more than 5 years. They had active disease on imaging and elevated C-reactive protein or fecal calprotectin.

During the period January 2017 to May 2020, eligible patients were randomly assigned 1 to 1 to CDED plus PEN enteral (n = 20) or CDED alone (n = 24) for 24 weeks. The primary endpoint was clinical remission, defined as a Harvey–Bradshaw Index score of less than 5 at week 6, an outcome was assessed in the ITT population, which consisted of those who used dietary therapy for at least 48 hours.

At week 6, 13 (68%) of 19 remaining patients in the CDED-plus-PEN group and 12 (57%) of 21 patients in the CDED-alone group had achieved clinical remission (P = .4618).

Among the 25 patients in remission 6 weeks out, 20 (80%) remained in sustained remission at week 24: 12 in the CDED-plus-PEN group and 8 in the CDED-alone group.

Moreover, 14 (35%) of 40 patients were in endoscopic remission at week 24: 8 on CDED plus PEN and 6 on CDED alone.

“CDED with or without partial enteral nutrition was effective for induction and maintenance of remission in adults with mild to moderate biologic-naive Crohn’s disease and might lead to endoscopic remission,” the authors wrote, adding that CDED for mild to moderate active disease should be assessed in a powered randomized controlled trial.

Compliance and adherence are obstacles to dietary therapies. Data for adults using exclusive enteral nutrition are conflicting, with poor compliance postulated to drive an inadequate response in some studies.

“Like every dietary treatment, adherence is challenging,” Dr. Yanai said. “However, when patients feel that it helps them, they have more incentive to follow the diet in the long run, and also once they quit and fare worse, they can go back and follow the first stage of CDED.” 

She and her colleagues stressed the need for adequately powered randomized trials and recommended that the personalization of therapeutic diets in the future should take into account the need to deliver energy tailored to the nutritional and therapeutic goals of the patient.
 

Diets alone are not therapy

In an accompanying editorial, Alexa N. Sasson, MD, an IBD fellow at Massachusetts General Hospital and T.H. Chan Harvard School of Public Health, both in Boston, called diet “a promising and potentially modifiable risk factor with mounting evidence supporting its therapeutic benefit.”

Massuchusetts General Hospital

She concurred that the Israeli findings indicate that CDED with or without PEN appears effective for inducing and maintaining remission in this cohort of patients. “Assessment of composite diets such as the CDED is important since they can be incorporated into daily life. The relative efficacy of each of the included and excluded foods, however, is not clear,” she wrote.

She cautioned, however, that dietary therapy does not constitute maintenance therapy and its effects are not sustained after the reintroduction of whole foods. “Identification of sustainable dietary interventions for the prevention and treatment of IBD is increasingly a focus of research,” she wrote.

Dr. Sasson agreed that dietary therapy for CD should be centered on patient interests, goals, and disease states. “Adjunctive dietary measures might be considered in all interested patients as a method of improving gastrointestinal-related symptoms and quality of life, with the potential to achieve a higher and more sustained level of remission,” she wrote.

Both the authors and the commentator agreed on the need for larger randomized trials with long-term follow-up to guide treatment decisions and identify patients who might benefit from dietary intervention.

This study was funded by the Azrieli Foundation and Nestlé Health Science. Dr. Yanai reported financial relationships with Pfizer, AbbVie, Ferring, Janssen, Neopharm, Pfizer, and Takeda. Several coauthors disclosed financial ties to multiple private-sector companies. Dr. Sasson had no competing interests to declare.

This article was updated Dec. 1, 2021.

The Crohn’s disease exclusion diet (CDED), with or without partial enteral nutrition (PEN), effectively induced and maintained remission in adults with mild to moderate, biologic-naive CD, a randomized Israeli pilot study found.

The authors, led by Henit Yanai, MD, MBA, chief of the IBD Center at Rabin Medical Center in Petah Tikva, Israel, also suggested that dietary monotherapy might lead to durable endoscopic remission.

European Crohn’s and Colitis Organization

The study, published in The Lancet Gastroenterology & Hepatology, found about 60% of patients on CDED achieved clinical remission by week 6 without adding medications.

Furthermore, 80% of patients in remission at week 6 maintained clinical remission at week 24 on dietary monotherapy alone, allowing more than 50% of the intention-to-treat (ITT) population to achieve sustained remission at 6 months.

Dietary therapy resulted in a significant and progressive reduction in inflammatory markers such as C-reactive protein and fecal calprotectin. The benefit extended to mucosal healing, with 35% of the ITT population achieving endoscopic remission at 24 weeks.

Dr. Yanai explained the clinical context in which her group designed the study. “There were preliminary data regarding the efficacy of the dietary strategy for the induction of remission of mild CD in the pediatric population,” she said in an interview. “Additionally, there was an anecdotal experience in adults who reported benefits. Facing this and the lack of attractive alternatives for mild CD, we decided to examine the effectiveness of this therapeutic strategy in adults.”

Given the costs and side effects of medical treatment, interest in dietary monotherapy for IBD has been growing. As Dr. Yanai said, the CDED, a whole-foods regimen, plus PEN, has been found to help children with CD.

The CDED excludes proinflammatory food components associated with intestinal microbial dysbiosis, altered innate immunity, and impaired gut barrier function.

It involves increased consumption of fruits and vegetables, high-quality lean protein, complex carbohydrates, healthy oils, and fiber, while decreasing intake of inflammation-driving components such as animal and saturated vegetable fats, wheat, and dairy, as well as food additives such as emulsifiers, maltodextrin, and sulfites.

“The realization that exclusive enteral nutrition, which is based on liquid formulas, is effective for inducting remission in children PEN, which is a combination of liquid formulas and food, was less effective, led to the hypothesis that the mechanism might be the exclusion of dietary components that may lead to inflammation,” Dr. Yanai said. This theory, she added, derived from animal models showing that specific dietary components potentially drive inflammation.

The only current guideline-recommended nutritional therapy for remission induction is exclusive enteral nutrition (EEN) in pediatric CD.
 

The study

The open-label pilot trial led by Dr. Yanai, conducted at three medical centers, enrolled biologic-naive adults ages 18-55 with uncomplicated mild to moderate CD, with a disease duration of no more than 5 years. They had active disease on imaging and elevated C-reactive protein or fecal calprotectin.

During the period January 2017 to May 2020, eligible patients were randomly assigned 1 to 1 to CDED plus PEN enteral (n = 20) or CDED alone (n = 24) for 24 weeks. The primary endpoint was clinical remission, defined as a Harvey–Bradshaw Index score of less than 5 at week 6, an outcome was assessed in the ITT population, which consisted of those who used dietary therapy for at least 48 hours.

At week 6, 13 (68%) of 19 remaining patients in the CDED-plus-PEN group and 12 (57%) of 21 patients in the CDED-alone group had achieved clinical remission (P = .4618).

Among the 25 patients in remission 6 weeks out, 20 (80%) remained in sustained remission at week 24: 12 in the CDED-plus-PEN group and 8 in the CDED-alone group.

Moreover, 14 (35%) of 40 patients were in endoscopic remission at week 24: 8 on CDED plus PEN and 6 on CDED alone.

“CDED with or without partial enteral nutrition was effective for induction and maintenance of remission in adults with mild to moderate biologic-naive Crohn’s disease and might lead to endoscopic remission,” the authors wrote, adding that CDED for mild to moderate active disease should be assessed in a powered randomized controlled trial.

Compliance and adherence are obstacles to dietary therapies. Data for adults using exclusive enteral nutrition are conflicting, with poor compliance postulated to drive an inadequate response in some studies.

“Like every dietary treatment, adherence is challenging,” Dr. Yanai said. “However, when patients feel that it helps them, they have more incentive to follow the diet in the long run, and also once they quit and fare worse, they can go back and follow the first stage of CDED.” 

She and her colleagues stressed the need for adequately powered randomized trials and recommended that the personalization of therapeutic diets in the future should take into account the need to deliver energy tailored to the nutritional and therapeutic goals of the patient.
 

Diets alone are not therapy

In an accompanying editorial, Alexa N. Sasson, MD, an IBD fellow at Massachusetts General Hospital and T.H. Chan Harvard School of Public Health, both in Boston, called diet “a promising and potentially modifiable risk factor with mounting evidence supporting its therapeutic benefit.”

Massuchusetts General Hospital

She concurred that the Israeli findings indicate that CDED with or without PEN appears effective for inducing and maintaining remission in this cohort of patients. “Assessment of composite diets such as the CDED is important since they can be incorporated into daily life. The relative efficacy of each of the included and excluded foods, however, is not clear,” she wrote.

She cautioned, however, that dietary therapy does not constitute maintenance therapy and its effects are not sustained after the reintroduction of whole foods. “Identification of sustainable dietary interventions for the prevention and treatment of IBD is increasingly a focus of research,” she wrote.

Dr. Sasson agreed that dietary therapy for CD should be centered on patient interests, goals, and disease states. “Adjunctive dietary measures might be considered in all interested patients as a method of improving gastrointestinal-related symptoms and quality of life, with the potential to achieve a higher and more sustained level of remission,” she wrote.

Both the authors and the commentator agreed on the need for larger randomized trials with long-term follow-up to guide treatment decisions and identify patients who might benefit from dietary intervention.

This study was funded by the Azrieli Foundation and Nestlé Health Science. Dr. Yanai reported financial relationships with Pfizer, AbbVie, Ferring, Janssen, Neopharm, Pfizer, and Takeda. Several coauthors disclosed financial ties to multiple private-sector companies. Dr. Sasson had no competing interests to declare.

This article was updated Dec. 1, 2021.

There is a significant inverse relationship between concentrations of circulating 25-hydroxy-vitamin D (25[OH]D) and all-cause mortality, but only in people with vitamin D deficiency, suggests a new large-scale analysis.

Data on more than 380,000 participants gathered from 35 studies showed that, overall, there is no significant relationship between 25(OH)D concentrations, a clinical indicator of vitamin D status, and the incidence of coronary heart disease (CHD), stroke, or all-cause death, in a Mendelian randomization analysis.

However, Stephen Burgess, PhD, and colleagues showed that, in vitamin D–deficient individuals, each 10 nmol/L increase in 25(OH)D concentrations reduced the risk of all-cause mortality by 31%.

The research, published in The Lancet Diabetes & Endocrinology, also suggests there was a nonsignificant link between 25(OH)D concentrations and stroke and CHD, but again, only in vitamin D deficient individuals.

In an accompanying editorial, Guillaume Butler-Laporte, MD, and J. Brent Richards, MD, praise the researchers on their study methodology.

They add that the results “could have important public health and clinical consequences” and will “allow clinicians to better weigh the potential benefits of supplementation against its risk,” such as financial cost, “for better patient care – particularly among those with frank vitamin D deficiency.”

They continue: “Given that vitamin D deficiency is relatively common and vitamin D supplementation is safe, the rationale exists to test the effect of vitamin D supplementation in those with deficiency in large-scale randomized controlled trials.”

However, Dr. Butler-Laporte and Dr. Richards, of the Lady Davis Institute, Jewish General Hospital, Montreal, also note the study has several limitations, including the fact that the lifetime exposure to lower vitamin D levels captured by Mendelian randomization may result in larger effect sizes than in conventional trials.
 

Prior RCTS underpowered to detect effects of vitamin D supplements

“There are several potential mechanisms by which vitamin D could be protective for cardiovascular mortality, including mechanisms linking low vitamin D status with hyperparathyroidism and low serum calcium and phosphate,” write Dr. Burgess of the MRC Biostatistics Unit, University of Cambridge (England), and coauthors.

They also highlight that vitamin D is “further implicated in endothelial cell function” and affects the transcription of genes linked to cell division and apoptosis, providing “potential mechanisms implicating vitamin D for cancer.”

The researchers note that, while epidemiologic studies have “consistently” found a link between 25(OH)D levels and increased risk of cardiovascular disease, all-cause mortality, and other chronic diseases, several large trials of vitamin D supplementation have reported “null results.”

They argue, however, that many of these trials have recruited individuals “irrespective of baseline 25(OH)D concentration” and have been underpowered to detect the effects of supplementation.

To overcome these limitations, the team gathered data from the UK Biobank, the European Prospective Investigation Into Cancer and Nutrition Cardiovascular Disease (EPIC-CVD) study, 31 studies from the Vitamin D Studies Collaboration (VitDSC), and two Copenhagen population-based studies.

They first performed an observational study that included 384,721 individuals from the UK Biobank and 26,336 from EPIC-CVD who had a valid 25(OH)D measurement and no previously known cardiovascular disease at baseline.

Researchers also included 67,992 participants from the VitDSC studies who did not have previously known cardiovascular disease. They analyzed 25(OH)D concentrations, conventional cardiovascular risk factors, and major incident cardiovascular morbidity and mortality using individual participant data.

The results showed that, at low 25(OH)D concentrations, there was an inverse association between 25(OH)D and incident CHD, stroke, and all-cause mortality.

Next, the team conducted a Mendelian randomization analysis on 333,002 individuals from the UK Biobank and 26,336 from EPIC-CVD who were of European ancestry and had both a valid 25(OH)D measurement and genetic data that passed quality-control steps.

Information on 31,362 participants in the Copenhagen population-based studies was also included, giving a total of 386,406 individuals, of whom 33,546 had CHD, 18,166 had a stroke, and 27,885 died.

The mean age of participants ranged from 54.8 to 57.5 years, and between 53.4% and 55.4% were female.
 

Up to 7% of study participants were vitamin D deficient

The 25(OH)D analysis indicated that 3.9% of UK Biobank and 3.7% of Copenhagen study participants were deficient, compared with 6.9% in EPIC-CVD.

Across the full range of 25(OH)D concentrations, there was no significant association between genetically predicted 25(OH)D levels and CHD, stroke, or all-cause mortality.

However, restricting the analysis to individuals deemed vitamin D deficient (25[OH]D concentration < 25 nmol/L) revealed there was “strong evidence” for an inverse association with all-cause mortality, at an odds ratio per 10 nmol/L increase in genetically predicted 25(OH)D concentration of 0.69 (P < .0001), the team notes.

There were also nonsignificant associations between being in the deficient stratum and CHD, at an odds ratio of 0.89 (P = .14), and stroke, at an odds ratio of 0.85 (P = .09).

Further analysis suggests the association between 25(OH)D concentrations and all-cause mortality has a “clear threshold shape,” the researchers say, with evidence of an inverse association at concentrations below 40 nmol/L and null associations above that threshold.

They acknowledge, however, that their study has several potential limitations, including the assumption in their Mendelian randomization that the “only causal pathway from the genetic variants to the outcome is via 25(OH)D concentrations.”

Moreover, the genetic variants may affect 25(OH)D concentrations in a different way from “dietary supplementation or other clinical interventions.”

They also concede that their study was limited to middle-aged participants of European ancestries, which means the findings “might not be applicable to other populations.”

The study was funded by the British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer. Dr. Burgess has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.

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

There is a significant inverse relationship between concentrations of circulating 25-hydroxy-vitamin D (25[OH]D) and all-cause mortality, but only in people with vitamin D deficiency, suggests a new large-scale analysis.

Data on more than 380,000 participants gathered from 35 studies showed that, overall, there is no significant relationship between 25(OH)D concentrations, a clinical indicator of vitamin D status, and the incidence of coronary heart disease (CHD), stroke, or all-cause death, in a Mendelian randomization analysis.

However, Stephen Burgess, PhD, and colleagues showed that, in vitamin D–deficient individuals, each 10 nmol/L increase in 25(OH)D concentrations reduced the risk of all-cause mortality by 31%.

The research, published in The Lancet Diabetes & Endocrinology, also suggests there was a nonsignificant link between 25(OH)D concentrations and stroke and CHD, but again, only in vitamin D deficient individuals.

In an accompanying editorial, Guillaume Butler-Laporte, MD, and J. Brent Richards, MD, praise the researchers on their study methodology.

They add that the results “could have important public health and clinical consequences” and will “allow clinicians to better weigh the potential benefits of supplementation against its risk,” such as financial cost, “for better patient care – particularly among those with frank vitamin D deficiency.”

They continue: “Given that vitamin D deficiency is relatively common and vitamin D supplementation is safe, the rationale exists to test the effect of vitamin D supplementation in those with deficiency in large-scale randomized controlled trials.”

However, Dr. Butler-Laporte and Dr. Richards, of the Lady Davis Institute, Jewish General Hospital, Montreal, also note the study has several limitations, including the fact that the lifetime exposure to lower vitamin D levels captured by Mendelian randomization may result in larger effect sizes than in conventional trials.
 

Prior RCTS underpowered to detect effects of vitamin D supplements

“There are several potential mechanisms by which vitamin D could be protective for cardiovascular mortality, including mechanisms linking low vitamin D status with hyperparathyroidism and low serum calcium and phosphate,” write Dr. Burgess of the MRC Biostatistics Unit, University of Cambridge (England), and coauthors.

They also highlight that vitamin D is “further implicated in endothelial cell function” and affects the transcription of genes linked to cell division and apoptosis, providing “potential mechanisms implicating vitamin D for cancer.”

The researchers note that, while epidemiologic studies have “consistently” found a link between 25(OH)D levels and increased risk of cardiovascular disease, all-cause mortality, and other chronic diseases, several large trials of vitamin D supplementation have reported “null results.”

They argue, however, that many of these trials have recruited individuals “irrespective of baseline 25(OH)D concentration” and have been underpowered to detect the effects of supplementation.

To overcome these limitations, the team gathered data from the UK Biobank, the European Prospective Investigation Into Cancer and Nutrition Cardiovascular Disease (EPIC-CVD) study, 31 studies from the Vitamin D Studies Collaboration (VitDSC), and two Copenhagen population-based studies.

They first performed an observational study that included 384,721 individuals from the UK Biobank and 26,336 from EPIC-CVD who had a valid 25(OH)D measurement and no previously known cardiovascular disease at baseline.

Researchers also included 67,992 participants from the VitDSC studies who did not have previously known cardiovascular disease. They analyzed 25(OH)D concentrations, conventional cardiovascular risk factors, and major incident cardiovascular morbidity and mortality using individual participant data.

The results showed that, at low 25(OH)D concentrations, there was an inverse association between 25(OH)D and incident CHD, stroke, and all-cause mortality.

Next, the team conducted a Mendelian randomization analysis on 333,002 individuals from the UK Biobank and 26,336 from EPIC-CVD who were of European ancestry and had both a valid 25(OH)D measurement and genetic data that passed quality-control steps.

Information on 31,362 participants in the Copenhagen population-based studies was also included, giving a total of 386,406 individuals, of whom 33,546 had CHD, 18,166 had a stroke, and 27,885 died.

The mean age of participants ranged from 54.8 to 57.5 years, and between 53.4% and 55.4% were female.
 

Up to 7% of study participants were vitamin D deficient

The 25(OH)D analysis indicated that 3.9% of UK Biobank and 3.7% of Copenhagen study participants were deficient, compared with 6.9% in EPIC-CVD.

Across the full range of 25(OH)D concentrations, there was no significant association between genetically predicted 25(OH)D levels and CHD, stroke, or all-cause mortality.

However, restricting the analysis to individuals deemed vitamin D deficient (25[OH]D concentration < 25 nmol/L) revealed there was “strong evidence” for an inverse association with all-cause mortality, at an odds ratio per 10 nmol/L increase in genetically predicted 25(OH)D concentration of 0.69 (P < .0001), the team notes.

There were also nonsignificant associations between being in the deficient stratum and CHD, at an odds ratio of 0.89 (P = .14), and stroke, at an odds ratio of 0.85 (P = .09).

Further analysis suggests the association between 25(OH)D concentrations and all-cause mortality has a “clear threshold shape,” the researchers say, with evidence of an inverse association at concentrations below 40 nmol/L and null associations above that threshold.

They acknowledge, however, that their study has several potential limitations, including the assumption in their Mendelian randomization that the “only causal pathway from the genetic variants to the outcome is via 25(OH)D concentrations.”

Moreover, the genetic variants may affect 25(OH)D concentrations in a different way from “dietary supplementation or other clinical interventions.”

They also concede that their study was limited to middle-aged participants of European ancestries, which means the findings “might not be applicable to other populations.”

The study was funded by the British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer. Dr. Burgess has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.

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

There is a significant inverse relationship between concentrations of circulating 25-hydroxy-vitamin D (25[OH]D) and all-cause mortality, but only in people with vitamin D deficiency, suggests a new large-scale analysis.

Data on more than 380,000 participants gathered from 35 studies showed that, overall, there is no significant relationship between 25(OH)D concentrations, a clinical indicator of vitamin D status, and the incidence of coronary heart disease (CHD), stroke, or all-cause death, in a Mendelian randomization analysis.

However, Stephen Burgess, PhD, and colleagues showed that, in vitamin D–deficient individuals, each 10 nmol/L increase in 25(OH)D concentrations reduced the risk of all-cause mortality by 31%.

The research, published in The Lancet Diabetes & Endocrinology, also suggests there was a nonsignificant link between 25(OH)D concentrations and stroke and CHD, but again, only in vitamin D deficient individuals.

In an accompanying editorial, Guillaume Butler-Laporte, MD, and J. Brent Richards, MD, praise the researchers on their study methodology.

They add that the results “could have important public health and clinical consequences” and will “allow clinicians to better weigh the potential benefits of supplementation against its risk,” such as financial cost, “for better patient care – particularly among those with frank vitamin D deficiency.”

They continue: “Given that vitamin D deficiency is relatively common and vitamin D supplementation is safe, the rationale exists to test the effect of vitamin D supplementation in those with deficiency in large-scale randomized controlled trials.”

However, Dr. Butler-Laporte and Dr. Richards, of the Lady Davis Institute, Jewish General Hospital, Montreal, also note the study has several limitations, including the fact that the lifetime exposure to lower vitamin D levels captured by Mendelian randomization may result in larger effect sizes than in conventional trials.
 

Prior RCTS underpowered to detect effects of vitamin D supplements

“There are several potential mechanisms by which vitamin D could be protective for cardiovascular mortality, including mechanisms linking low vitamin D status with hyperparathyroidism and low serum calcium and phosphate,” write Dr. Burgess of the MRC Biostatistics Unit, University of Cambridge (England), and coauthors.

They also highlight that vitamin D is “further implicated in endothelial cell function” and affects the transcription of genes linked to cell division and apoptosis, providing “potential mechanisms implicating vitamin D for cancer.”

The researchers note that, while epidemiologic studies have “consistently” found a link between 25(OH)D levels and increased risk of cardiovascular disease, all-cause mortality, and other chronic diseases, several large trials of vitamin D supplementation have reported “null results.”

They argue, however, that many of these trials have recruited individuals “irrespective of baseline 25(OH)D concentration” and have been underpowered to detect the effects of supplementation.

To overcome these limitations, the team gathered data from the UK Biobank, the European Prospective Investigation Into Cancer and Nutrition Cardiovascular Disease (EPIC-CVD) study, 31 studies from the Vitamin D Studies Collaboration (VitDSC), and two Copenhagen population-based studies.

They first performed an observational study that included 384,721 individuals from the UK Biobank and 26,336 from EPIC-CVD who had a valid 25(OH)D measurement and no previously known cardiovascular disease at baseline.

Researchers also included 67,992 participants from the VitDSC studies who did not have previously known cardiovascular disease. They analyzed 25(OH)D concentrations, conventional cardiovascular risk factors, and major incident cardiovascular morbidity and mortality using individual participant data.

The results showed that, at low 25(OH)D concentrations, there was an inverse association between 25(OH)D and incident CHD, stroke, and all-cause mortality.

Next, the team conducted a Mendelian randomization analysis on 333,002 individuals from the UK Biobank and 26,336 from EPIC-CVD who were of European ancestry and had both a valid 25(OH)D measurement and genetic data that passed quality-control steps.

Information on 31,362 participants in the Copenhagen population-based studies was also included, giving a total of 386,406 individuals, of whom 33,546 had CHD, 18,166 had a stroke, and 27,885 died.

The mean age of participants ranged from 54.8 to 57.5 years, and between 53.4% and 55.4% were female.
 

Up to 7% of study participants were vitamin D deficient

The 25(OH)D analysis indicated that 3.9% of UK Biobank and 3.7% of Copenhagen study participants were deficient, compared with 6.9% in EPIC-CVD.

Across the full range of 25(OH)D concentrations, there was no significant association between genetically predicted 25(OH)D levels and CHD, stroke, or all-cause mortality.

However, restricting the analysis to individuals deemed vitamin D deficient (25[OH]D concentration < 25 nmol/L) revealed there was “strong evidence” for an inverse association with all-cause mortality, at an odds ratio per 10 nmol/L increase in genetically predicted 25(OH)D concentration of 0.69 (P < .0001), the team notes.

There were also nonsignificant associations between being in the deficient stratum and CHD, at an odds ratio of 0.89 (P = .14), and stroke, at an odds ratio of 0.85 (P = .09).

Further analysis suggests the association between 25(OH)D concentrations and all-cause mortality has a “clear threshold shape,” the researchers say, with evidence of an inverse association at concentrations below 40 nmol/L and null associations above that threshold.

They acknowledge, however, that their study has several potential limitations, including the assumption in their Mendelian randomization that the “only causal pathway from the genetic variants to the outcome is via 25(OH)D concentrations.”

Moreover, the genetic variants may affect 25(OH)D concentrations in a different way from “dietary supplementation or other clinical interventions.”

They also concede that their study was limited to middle-aged participants of European ancestries, which means the findings “might not be applicable to other populations.”

The study was funded by the British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer. Dr. Burgess has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.

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

The Food and Drug Administration has approved the first treatment for posttransplant cytomegalovirus (CMV) that is resistant to other drugs. The treatment, maribavir (Livtencity), is approved for adults and children 12 years and older who weigh at least 35 kg (77 pounds).

There are an estimated 200,000 adult transplants every year globally. CMV, a type of herpes virus, is one of the most common infections in transplant patients, occurring in 16%-56% of solid organ transplant recipients and 30%-70% of hematopoietic stem cell transplant recipients, according to Takeda Pharmaceutical Company Limited, the company that manufactures Livtencity. For immunosuppressed transplant patients, CMV infection can lead to complications that include loss of the transplanted or organ or even death.

“Cytomegalovirus infections that are resistant or do not respond to available drugs are of even greater concern,” John Farley, MD, MPH, the director of the Office of Infectious Diseases in the FDA’s Center for Drug Evaluation and Research, said in a statement. “Today’s approval helps meet a significant unmet medical need by providing a treatment option for this patient population.”

Livtencity, which is taken orally, works by preventing the activity of the enzyme responsible for virus replication. The approval, announced Nov. 23, was based on a phase 3 clinical trial that compared Livtencity with conventional antiviral treatments in the achievement of CMV DNA concentration levels below what is measurable in transplant patients with CMV infection that is refractory or treatment-resistant. After 8 weeks, of the 235 patients who received Livtencity, 56% achieved this primary endpoint, compared with 24% of the 117 patients who received conventional antiviral treatments, the press release says.

The most reported adverse reactions of Livtencity were taste disturbance, nausea, diarrhea, vomiting, and fatigue.

“We are grateful for the contributions of the patients and clinicians who participated in our clinical trials, as well as the dedication of our scientists and researchers,” Ramona Sequeira, president of the Takeda’s U.S. Business Unit and Global Portfolio Commercialization, said in a statement. “People undergoing transplants have a lengthy and complex health care journey; with the approval of this treatment, we’re proud to offer these individuals a new oral antiviral to fight CMV infection and disease.”

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

The Food and Drug Administration has approved the first treatment for posttransplant cytomegalovirus (CMV) that is resistant to other drugs. The treatment, maribavir (Livtencity), is approved for adults and children 12 years and older who weigh at least 35 kg (77 pounds).

There are an estimated 200,000 adult transplants every year globally. CMV, a type of herpes virus, is one of the most common infections in transplant patients, occurring in 16%-56% of solid organ transplant recipients and 30%-70% of hematopoietic stem cell transplant recipients, according to Takeda Pharmaceutical Company Limited, the company that manufactures Livtencity. For immunosuppressed transplant patients, CMV infection can lead to complications that include loss of the transplanted or organ or even death.

“Cytomegalovirus infections that are resistant or do not respond to available drugs are of even greater concern,” John Farley, MD, MPH, the director of the Office of Infectious Diseases in the FDA’s Center for Drug Evaluation and Research, said in a statement. “Today’s approval helps meet a significant unmet medical need by providing a treatment option for this patient population.”

Livtencity, which is taken orally, works by preventing the activity of the enzyme responsible for virus replication. The approval, announced Nov. 23, was based on a phase 3 clinical trial that compared Livtencity with conventional antiviral treatments in the achievement of CMV DNA concentration levels below what is measurable in transplant patients with CMV infection that is refractory or treatment-resistant. After 8 weeks, of the 235 patients who received Livtencity, 56% achieved this primary endpoint, compared with 24% of the 117 patients who received conventional antiviral treatments, the press release says.

The most reported adverse reactions of Livtencity were taste disturbance, nausea, diarrhea, vomiting, and fatigue.

“We are grateful for the contributions of the patients and clinicians who participated in our clinical trials, as well as the dedication of our scientists and researchers,” Ramona Sequeira, president of the Takeda’s U.S. Business Unit and Global Portfolio Commercialization, said in a statement. “People undergoing transplants have a lengthy and complex health care journey; with the approval of this treatment, we’re proud to offer these individuals a new oral antiviral to fight CMV infection and disease.”

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

The Food and Drug Administration has approved the first treatment for posttransplant cytomegalovirus (CMV) that is resistant to other drugs. The treatment, maribavir (Livtencity), is approved for adults and children 12 years and older who weigh at least 35 kg (77 pounds).

There are an estimated 200,000 adult transplants every year globally. CMV, a type of herpes virus, is one of the most common infections in transplant patients, occurring in 16%-56% of solid organ transplant recipients and 30%-70% of hematopoietic stem cell transplant recipients, according to Takeda Pharmaceutical Company Limited, the company that manufactures Livtencity. For immunosuppressed transplant patients, CMV infection can lead to complications that include loss of the transplanted or organ or even death.

“Cytomegalovirus infections that are resistant or do not respond to available drugs are of even greater concern,” John Farley, MD, MPH, the director of the Office of Infectious Diseases in the FDA’s Center for Drug Evaluation and Research, said in a statement. “Today’s approval helps meet a significant unmet medical need by providing a treatment option for this patient population.”

Livtencity, which is taken orally, works by preventing the activity of the enzyme responsible for virus replication. The approval, announced Nov. 23, was based on a phase 3 clinical trial that compared Livtencity with conventional antiviral treatments in the achievement of CMV DNA concentration levels below what is measurable in transplant patients with CMV infection that is refractory or treatment-resistant. After 8 weeks, of the 235 patients who received Livtencity, 56% achieved this primary endpoint, compared with 24% of the 117 patients who received conventional antiviral treatments, the press release says.

The most reported adverse reactions of Livtencity were taste disturbance, nausea, diarrhea, vomiting, and fatigue.

“We are grateful for the contributions of the patients and clinicians who participated in our clinical trials, as well as the dedication of our scientists and researchers,” Ramona Sequeira, president of the Takeda’s U.S. Business Unit and Global Portfolio Commercialization, said in a statement. “People undergoing transplants have a lengthy and complex health care journey; with the approval of this treatment, we’re proud to offer these individuals a new oral antiviral to fight CMV infection and disease.”

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

The Diagnosis: Nevoid Basal Cell Carcinoma Syndrome

Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is a rare autosomal-dominant disorder that increases the risk for developing various carcinomas and affects multiple organ systems. Nevoid basal cell carcinoma syndrome is estimated at 1 per 40,000 to 60,000 individuals with no sexual predilection.^1,2 Pathogenesis of NBCCS occurs through molecular alterations in the dormant hedgehog signaling pathway, causing constitutive signaling activity and a loss of function in the tumor suppressor patched 1 gene, PTCH1. As a result, the inhibition of smoothened oncogenes is released, Gli proteins are activated, and the hedgehog signaling pathway is no longer quiescent.² Additional loss of function in the suppressor of fused homolog protein, a negative regulator of the hedgehog pathway, allows for further tumor proliferation. The crucial role these genes play in the hedgehog signaling pathway and their mutation association with NBCCS allows for molecular confirmation in the diagnosis of NBCCS. Allelic losses at the PTCH1 gene site are thought to occur in approximately 70% of NBCCS patients.²

Diagnosis of NBCCS is based on genetic testing to examine pathogenic gene variants, notably in the PTCH1 gene, and identification of characteristic clinical findings.² Diagnosis of NBCCS requires either 2 minor suggestive criteria and 1 major suggestive criterion, 2 major suggestive criteria and 1 minor suggestive criterion, or 1 major suggestive criterion with molecular confirmation. The presence of basal cell carcinomas (BCCs) before 20 years of age or an excessive numbers of BCCs, keratocystic odontogenic tumors (KOTs), palmar or plantar pitting, and first-degree relatives with NBCCS are classified as major suggestive criteria.² Nevoid basal cell carcinoma syndrome patients typically have BCCs that crust, ulcerate, or bleed. Minor suggestive criteria for NBCCS are rib abnormalities, skeletal malformations, macrocephaly, cleft lip or palate, and desmoplastic medulloblastoma.^2-4 Suppressor of fused homolog protein mutations may increase the risk for desmoplastic medulloblastoma in NBCCS patients. Our patient had 4 of the major suggestive criteria, including a history of KOTs, multiple BCCs, first-degree relatives with NBCCS, and palmar or plantar pitting (bottom quiz image), while having 1 minor suggestive criterion of frontal bossing.

Patients with NBCCS have high phenotypic variability, as their skin carcinomas do not have the classic features of pearly surfaces or corkscrew telangiectasia that typically are associated with BCCs.¹ Basal cell carcinomas in NBCCS-affected individuals usually are indistinguishable from sporadic lesions that arise in sun-exposed areas, making NBCCS difficult to diagnose. These sporadic lesions often are misdiagnosed as psoriatic or eczematous lesions, and additional subsequent examination is required. The findings of multiple papules and plaques spanning the body as well as lesions with rolled borders and ulcerated bases, indicative of BCCs, aid dermatologists in distinguishing benign lesions from those of NBCCS.¹

Additional differential diagnoses are required to distinguish NBCCS from other similar inherited skin disorders that are characterized by BCCs. The presence of multiple incidental BCCs early in life remains a histopathologic clue for NBCCS diagnosis, as opposed to Rombo syndrome, in which BCCs often develop in adulthood.^2,4 In addition, although both Bazex syndrome and Muir-Torre syndrome are characterized by the early onset of BCCs, the lack of skeletal abnormalities and palmar and plantar pitting distinguish these entities from NBCCS.^2,4 Furthermore, though psoriasis also can present on the scalp, clinical presentation often includes well-demarcated and symmetric plaques that are erythematous and silvery, all of which were not present in our patient and typically are not seen in NBCCS.⁵

The recommended treatment of NBCCS is vismodegib, a specific oncogene inhibitor. This medication suppresses the hedgehog signaling pathway by inhibiting smoothened oncogenes and downstream target molecules, thereby decreasing tumor proliferation.⁶ In doing so, vismodegib inhibits the development of new BCCs while reducing the burden of present ones. Additionally, vismodegib appears to effectively treat KOTs. If successful, this medication may be able to suppress KOTs in patients with NBCCS and thus facilitate surgery.⁶ Additional hedgehog inhibitors include patidegib, sonidegib, and itraconazole. Patidegib gel 2% currently is in phase 3 clinical trials for evaluation of efficacy and safety in treatment of NBCCS. Sonidegib is approved for the treatment of locally advanced BCCs in the United States and the European Union and for both locally advanced BCCs and metastatic BCCs in Switzerland and Australia.⁷ Further research is needed before recommending antifungal itraconazole for NBCCS clinical use.8 Other medications for localized areas include topical application of 5-fluorouracil and imiquimod.²

The Diagnosis: Nevoid Basal Cell Carcinoma Syndrome

Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is a rare autosomal-dominant disorder that increases the risk for developing various carcinomas and affects multiple organ systems. Nevoid basal cell carcinoma syndrome is estimated at 1 per 40,000 to 60,000 individuals with no sexual predilection.^1,2 Pathogenesis of NBCCS occurs through molecular alterations in the dormant hedgehog signaling pathway, causing constitutive signaling activity and a loss of function in the tumor suppressor patched 1 gene, PTCH1. As a result, the inhibition of smoothened oncogenes is released, Gli proteins are activated, and the hedgehog signaling pathway is no longer quiescent.² Additional loss of function in the suppressor of fused homolog protein, a negative regulator of the hedgehog pathway, allows for further tumor proliferation. The crucial role these genes play in the hedgehog signaling pathway and their mutation association with NBCCS allows for molecular confirmation in the diagnosis of NBCCS. Allelic losses at the PTCH1 gene site are thought to occur in approximately 70% of NBCCS patients.²

Diagnosis of NBCCS is based on genetic testing to examine pathogenic gene variants, notably in the PTCH1 gene, and identification of characteristic clinical findings.² Diagnosis of NBCCS requires either 2 minor suggestive criteria and 1 major suggestive criterion, 2 major suggestive criteria and 1 minor suggestive criterion, or 1 major suggestive criterion with molecular confirmation. The presence of basal cell carcinomas (BCCs) before 20 years of age or an excessive numbers of BCCs, keratocystic odontogenic tumors (KOTs), palmar or plantar pitting, and first-degree relatives with NBCCS are classified as major suggestive criteria.² Nevoid basal cell carcinoma syndrome patients typically have BCCs that crust, ulcerate, or bleed. Minor suggestive criteria for NBCCS are rib abnormalities, skeletal malformations, macrocephaly, cleft lip or palate, and desmoplastic medulloblastoma.^2-4 Suppressor of fused homolog protein mutations may increase the risk for desmoplastic medulloblastoma in NBCCS patients. Our patient had 4 of the major suggestive criteria, including a history of KOTs, multiple BCCs, first-degree relatives with NBCCS, and palmar or plantar pitting (bottom quiz image), while having 1 minor suggestive criterion of frontal bossing.

Patients with NBCCS have high phenotypic variability, as their skin carcinomas do not have the classic features of pearly surfaces or corkscrew telangiectasia that typically are associated with BCCs.¹ Basal cell carcinomas in NBCCS-affected individuals usually are indistinguishable from sporadic lesions that arise in sun-exposed areas, making NBCCS difficult to diagnose. These sporadic lesions often are misdiagnosed as psoriatic or eczematous lesions, and additional subsequent examination is required. The findings of multiple papules and plaques spanning the body as well as lesions with rolled borders and ulcerated bases, indicative of BCCs, aid dermatologists in distinguishing benign lesions from those of NBCCS.¹

Additional differential diagnoses are required to distinguish NBCCS from other similar inherited skin disorders that are characterized by BCCs. The presence of multiple incidental BCCs early in life remains a histopathologic clue for NBCCS diagnosis, as opposed to Rombo syndrome, in which BCCs often develop in adulthood.^2,4 In addition, although both Bazex syndrome and Muir-Torre syndrome are characterized by the early onset of BCCs, the lack of skeletal abnormalities and palmar and plantar pitting distinguish these entities from NBCCS.^2,4 Furthermore, though psoriasis also can present on the scalp, clinical presentation often includes well-demarcated and symmetric plaques that are erythematous and silvery, all of which were not present in our patient and typically are not seen in NBCCS.⁵

The recommended treatment of NBCCS is vismodegib, a specific oncogene inhibitor. This medication suppresses the hedgehog signaling pathway by inhibiting smoothened oncogenes and downstream target molecules, thereby decreasing tumor proliferation.⁶ In doing so, vismodegib inhibits the development of new BCCs while reducing the burden of present ones. Additionally, vismodegib appears to effectively treat KOTs. If successful, this medication may be able to suppress KOTs in patients with NBCCS and thus facilitate surgery.⁶ Additional hedgehog inhibitors include patidegib, sonidegib, and itraconazole. Patidegib gel 2% currently is in phase 3 clinical trials for evaluation of efficacy and safety in treatment of NBCCS. Sonidegib is approved for the treatment of locally advanced BCCs in the United States and the European Union and for both locally advanced BCCs and metastatic BCCs in Switzerland and Australia.⁷ Further research is needed before recommending antifungal itraconazole for NBCCS clinical use.8 Other medications for localized areas include topical application of 5-fluorouracil and imiquimod.²

The Diagnosis: Nevoid Basal Cell Carcinoma Syndrome

Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is a rare autosomal-dominant disorder that increases the risk for developing various carcinomas and affects multiple organ systems. Nevoid basal cell carcinoma syndrome is estimated at 1 per 40,000 to 60,000 individuals with no sexual predilection.^1,2 Pathogenesis of NBCCS occurs through molecular alterations in the dormant hedgehog signaling pathway, causing constitutive signaling activity and a loss of function in the tumor suppressor patched 1 gene, PTCH1. As a result, the inhibition of smoothened oncogenes is released, Gli proteins are activated, and the hedgehog signaling pathway is no longer quiescent.² Additional loss of function in the suppressor of fused homolog protein, a negative regulator of the hedgehog pathway, allows for further tumor proliferation. The crucial role these genes play in the hedgehog signaling pathway and their mutation association with NBCCS allows for molecular confirmation in the diagnosis of NBCCS. Allelic losses at the PTCH1 gene site are thought to occur in approximately 70% of NBCCS patients.²

Diagnosis of NBCCS is based on genetic testing to examine pathogenic gene variants, notably in the PTCH1 gene, and identification of characteristic clinical findings.² Diagnosis of NBCCS requires either 2 minor suggestive criteria and 1 major suggestive criterion, 2 major suggestive criteria and 1 minor suggestive criterion, or 1 major suggestive criterion with molecular confirmation. The presence of basal cell carcinomas (BCCs) before 20 years of age or an excessive numbers of BCCs, keratocystic odontogenic tumors (KOTs), palmar or plantar pitting, and first-degree relatives with NBCCS are classified as major suggestive criteria.² Nevoid basal cell carcinoma syndrome patients typically have BCCs that crust, ulcerate, or bleed. Minor suggestive criteria for NBCCS are rib abnormalities, skeletal malformations, macrocephaly, cleft lip or palate, and desmoplastic medulloblastoma.^2-4 Suppressor of fused homolog protein mutations may increase the risk for desmoplastic medulloblastoma in NBCCS patients. Our patient had 4 of the major suggestive criteria, including a history of KOTs, multiple BCCs, first-degree relatives with NBCCS, and palmar or plantar pitting (bottom quiz image), while having 1 minor suggestive criterion of frontal bossing.

Patients with NBCCS have high phenotypic variability, as their skin carcinomas do not have the classic features of pearly surfaces or corkscrew telangiectasia that typically are associated with BCCs.¹ Basal cell carcinomas in NBCCS-affected individuals usually are indistinguishable from sporadic lesions that arise in sun-exposed areas, making NBCCS difficult to diagnose. These sporadic lesions often are misdiagnosed as psoriatic or eczematous lesions, and additional subsequent examination is required. The findings of multiple papules and plaques spanning the body as well as lesions with rolled borders and ulcerated bases, indicative of BCCs, aid dermatologists in distinguishing benign lesions from those of NBCCS.¹

Additional differential diagnoses are required to distinguish NBCCS from other similar inherited skin disorders that are characterized by BCCs. The presence of multiple incidental BCCs early in life remains a histopathologic clue for NBCCS diagnosis, as opposed to Rombo syndrome, in which BCCs often develop in adulthood.^2,4 In addition, although both Bazex syndrome and Muir-Torre syndrome are characterized by the early onset of BCCs, the lack of skeletal abnormalities and palmar and plantar pitting distinguish these entities from NBCCS.^2,4 Furthermore, though psoriasis also can present on the scalp, clinical presentation often includes well-demarcated and symmetric plaques that are erythematous and silvery, all of which were not present in our patient and typically are not seen in NBCCS.⁵

The recommended treatment of NBCCS is vismodegib, a specific oncogene inhibitor. This medication suppresses the hedgehog signaling pathway by inhibiting smoothened oncogenes and downstream target molecules, thereby decreasing tumor proliferation.⁶ In doing so, vismodegib inhibits the development of new BCCs while reducing the burden of present ones. Additionally, vismodegib appears to effectively treat KOTs. If successful, this medication may be able to suppress KOTs in patients with NBCCS and thus facilitate surgery.⁶ Additional hedgehog inhibitors include patidegib, sonidegib, and itraconazole. Patidegib gel 2% currently is in phase 3 clinical trials for evaluation of efficacy and safety in treatment of NBCCS. Sonidegib is approved for the treatment of locally advanced BCCs in the United States and the European Union and for both locally advanced BCCs and metastatic BCCs in Switzerland and Australia.⁷ Further research is needed before recommending antifungal itraconazole for NBCCS clinical use.8 Other medications for localized areas include topical application of 5-fluorouracil and imiquimod.²

Obesity rates among “emerging adults” aged 18-25 have soared in the United States in recent decades with the mean body mass index (BMI) for these young adults now in the overweight category, according to research highlighting troubling trends in an often-overlooked age group.

While similar patterns have been observed in other age groups, including adolescents (ages 12-19) and young adults (ages 20-39) across recent decades, emerging adulthood tends to get less attention in the evaluation of obesity trends.

“Emerging adulthood may be a key period for preventing and treating obesity given that habits formed during this period often persist through the remainder of the life course,” write the authors of the study, which was published online Nov. 23 in JAMA.  

“There is an urgent need for research on risk factors contributing to obesity during this developmental stage to inform the design of interventions as well as policies aimed at prevention,” they add.

They found that by 2018 a third of all young adults had obesity, compared with just 6% at the beginning of the study periods in 1976.

Studying the ages of transition

The findings are from an analysis of 8,015 emerging adults aged 18-25 in the cross-sectional National Health and Nutrition Examination Survey (NHANES), including NHANES II (1976-1980), NHANES III (1988-1994), and the continuous NHANES cycles from 1999 through 2018.

About half (3,965) of participants were female, 3,037 were non-Hispanic Black, and 2,386 met the criteria for household poverty.

The results showed substantial increases in mean BMI among emerging adults from a level in the normal range, at 23.1 kg/m2, in 1976-1980, increasing to 27.7 kg/m2 (overweight) in 2017-2018 (P = .006).

The prevalence of obesity (BMI 30.0 kg/m2 or higher) in the emerging adult age group soared from 6.2% between 1976-1980 to 32.7% in 2017-2018 (P = .007).

Meanwhile, the rate of those with normal/healthy weight (BMI 18.5-24.9 kg/m2) dropped from 68.7% to 37.5% (P = .005) over the same period.

Sensitivity analyses that were limited to continuous NHANES cycles showed similar results.

First author Alejandra Ellison-Barnes, MD, MPH, said the trends are consistent with rising obesity rates in the population as a whole – other studies have shown increases in obesity among children, adolescents, and adults over the same period – but are nevertheless striking, she stressed.
 

Young adults now fall into overweight category

“While we were not surprised by the general trend, given what is known about the increasing prevalence of obesity in both children and adults, we were surprised by the magnitude of the increase in prevalence and that the mean BMI in this age group now falls in the overweight range,” Dr. Ellison-Barnes, of the Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, told this news organization.

She said she is not aware of other studies that have looked at obesity trends specifically among emerging adults.

However, considering the substantial life changes and growing independence, the life stage is important to understand in terms of dietary/lifestyle patterns.

“We theorize that emerging adulthood is a critical period for obesity development given that it is a time when individuals are often undergoing major life transitions such as leaving home, attending higher education, entering the workforce, and developing new relationships,” she emphasized.

As far as causes are concerned, “societal and cultural trends in these areas over the past several decades may have played a role in the observed changes,” she speculated.

The study population was limited to non-Hispanic Black and non-Hispanic White individuals due to changes in how NHANES assessed race and ethnicity over time. Therefore, a study limitation is that the patterns observed may not be generalizable to other races and ethnicities, the authors note.

However, considering the influence lifestyle changes can have, early adulthood “may be an ideal time to intervene in the clinical setting to prevent, manage, or reverse obesity to prevent adverse health outcomes in the future,” Dr. Ellison-Barnes said.

Dr. Ellison-Barnes has reported no relevant financial relationships.

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

Obesity rates among “emerging adults” aged 18-25 have soared in the United States in recent decades with the mean body mass index (BMI) for these young adults now in the overweight category, according to research highlighting troubling trends in an often-overlooked age group.

While similar patterns have been observed in other age groups, including adolescents (ages 12-19) and young adults (ages 20-39) across recent decades, emerging adulthood tends to get less attention in the evaluation of obesity trends.

“Emerging adulthood may be a key period for preventing and treating obesity given that habits formed during this period often persist through the remainder of the life course,” write the authors of the study, which was published online Nov. 23 in JAMA.  

“There is an urgent need for research on risk factors contributing to obesity during this developmental stage to inform the design of interventions as well as policies aimed at prevention,” they add.

They found that by 2018 a third of all young adults had obesity, compared with just 6% at the beginning of the study periods in 1976.

Studying the ages of transition

The findings are from an analysis of 8,015 emerging adults aged 18-25 in the cross-sectional National Health and Nutrition Examination Survey (NHANES), including NHANES II (1976-1980), NHANES III (1988-1994), and the continuous NHANES cycles from 1999 through 2018.

About half (3,965) of participants were female, 3,037 were non-Hispanic Black, and 2,386 met the criteria for household poverty.

The results showed substantial increases in mean BMI among emerging adults from a level in the normal range, at 23.1 kg/m2, in 1976-1980, increasing to 27.7 kg/m2 (overweight) in 2017-2018 (P = .006).

The prevalence of obesity (BMI 30.0 kg/m2 or higher) in the emerging adult age group soared from 6.2% between 1976-1980 to 32.7% in 2017-2018 (P = .007).

Meanwhile, the rate of those with normal/healthy weight (BMI 18.5-24.9 kg/m2) dropped from 68.7% to 37.5% (P = .005) over the same period.

Sensitivity analyses that were limited to continuous NHANES cycles showed similar results.

First author Alejandra Ellison-Barnes, MD, MPH, said the trends are consistent with rising obesity rates in the population as a whole – other studies have shown increases in obesity among children, adolescents, and adults over the same period – but are nevertheless striking, she stressed.
 

Young adults now fall into overweight category

“While we were not surprised by the general trend, given what is known about the increasing prevalence of obesity in both children and adults, we were surprised by the magnitude of the increase in prevalence and that the mean BMI in this age group now falls in the overweight range,” Dr. Ellison-Barnes, of the Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, told this news organization.

She said she is not aware of other studies that have looked at obesity trends specifically among emerging adults.

However, considering the substantial life changes and growing independence, the life stage is important to understand in terms of dietary/lifestyle patterns.

“We theorize that emerging adulthood is a critical period for obesity development given that it is a time when individuals are often undergoing major life transitions such as leaving home, attending higher education, entering the workforce, and developing new relationships,” she emphasized.

As far as causes are concerned, “societal and cultural trends in these areas over the past several decades may have played a role in the observed changes,” she speculated.

The study population was limited to non-Hispanic Black and non-Hispanic White individuals due to changes in how NHANES assessed race and ethnicity over time. Therefore, a study limitation is that the patterns observed may not be generalizable to other races and ethnicities, the authors note.

However, considering the influence lifestyle changes can have, early adulthood “may be an ideal time to intervene in the clinical setting to prevent, manage, or reverse obesity to prevent adverse health outcomes in the future,” Dr. Ellison-Barnes said.

Dr. Ellison-Barnes has reported no relevant financial relationships.

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

Obesity rates among “emerging adults” aged 18-25 have soared in the United States in recent decades with the mean body mass index (BMI) for these young adults now in the overweight category, according to research highlighting troubling trends in an often-overlooked age group.

While similar patterns have been observed in other age groups, including adolescents (ages 12-19) and young adults (ages 20-39) across recent decades, emerging adulthood tends to get less attention in the evaluation of obesity trends.

“Emerging adulthood may be a key period for preventing and treating obesity given that habits formed during this period often persist through the remainder of the life course,” write the authors of the study, which was published online Nov. 23 in JAMA.  

“There is an urgent need for research on risk factors contributing to obesity during this developmental stage to inform the design of interventions as well as policies aimed at prevention,” they add.

They found that by 2018 a third of all young adults had obesity, compared with just 6% at the beginning of the study periods in 1976.

Studying the ages of transition

The findings are from an analysis of 8,015 emerging adults aged 18-25 in the cross-sectional National Health and Nutrition Examination Survey (NHANES), including NHANES II (1976-1980), NHANES III (1988-1994), and the continuous NHANES cycles from 1999 through 2018.

About half (3,965) of participants were female, 3,037 were non-Hispanic Black, and 2,386 met the criteria for household poverty.

The results showed substantial increases in mean BMI among emerging adults from a level in the normal range, at 23.1 kg/m2, in 1976-1980, increasing to 27.7 kg/m2 (overweight) in 2017-2018 (P = .006).

The prevalence of obesity (BMI 30.0 kg/m2 or higher) in the emerging adult age group soared from 6.2% between 1976-1980 to 32.7% in 2017-2018 (P = .007).

Meanwhile, the rate of those with normal/healthy weight (BMI 18.5-24.9 kg/m2) dropped from 68.7% to 37.5% (P = .005) over the same period.

Sensitivity analyses that were limited to continuous NHANES cycles showed similar results.

First author Alejandra Ellison-Barnes, MD, MPH, said the trends are consistent with rising obesity rates in the population as a whole – other studies have shown increases in obesity among children, adolescents, and adults over the same period – but are nevertheless striking, she stressed.
 

Young adults now fall into overweight category

“While we were not surprised by the general trend, given what is known about the increasing prevalence of obesity in both children and adults, we were surprised by the magnitude of the increase in prevalence and that the mean BMI in this age group now falls in the overweight range,” Dr. Ellison-Barnes, of the Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, told this news organization.

She said she is not aware of other studies that have looked at obesity trends specifically among emerging adults.

However, considering the substantial life changes and growing independence, the life stage is important to understand in terms of dietary/lifestyle patterns.

“We theorize that emerging adulthood is a critical period for obesity development given that it is a time when individuals are often undergoing major life transitions such as leaving home, attending higher education, entering the workforce, and developing new relationships,” she emphasized.

As far as causes are concerned, “societal and cultural trends in these areas over the past several decades may have played a role in the observed changes,” she speculated.

The study population was limited to non-Hispanic Black and non-Hispanic White individuals due to changes in how NHANES assessed race and ethnicity over time. Therefore, a study limitation is that the patterns observed may not be generalizable to other races and ethnicities, the authors note.

However, considering the influence lifestyle changes can have, early adulthood “may be an ideal time to intervene in the clinical setting to prevent, manage, or reverse obesity to prevent adverse health outcomes in the future,” Dr. Ellison-Barnes said.

Dr. Ellison-Barnes has reported no relevant financial relationships.

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

A patient with many comorbidities undergoing surgery presents a number of challenges to the healthcare team. This case highlights why solid preparation for the pre-and post-op care of such patients is so important. As demonstrated here, where a procedure is performed is just as critical as who performs it, particularly when outcomes go awry.

A 56-year-old morbidly obese man with a history of hypertension, diabetes, sleep apnea, and elevated cholesterol presented to an ambulatory surgery center for knee arthroscopy. Following a brief pre-op assessment, his airway was rated a III using both the American Society of Anesthesiologists (ASA) and Mallampati classification systems. It was decided to use a laryngeal mask airway (LMA) with 100 µg of fentanyl and 2 mgmidazolam, followed by inhalation anesthesia.

After the procedure, the LMA was removed and the patient was moved to the post-anesthesia care unit (PACU). The patient was unresponsive for about 20 minutes and exhibited signs of respiratory distress. Efforts were made to open the airway with jaw thrusts and nasal trumpet. The anesthesiologist determined that the patient was suffering from congestive heart failure, aspiration, or pulmonary edema.

The anesthesiologist administered 40 µg of naloxone. The patient began to awaken but had oxygen saturation readings in the high 70s. The patient was encouraged to take slow, deep breaths. Rhonchi were heard, and the patient complained of shortness of breath. The ECG reading was unchanged from the pre-op test.

Thirty minutes after the first dose, a second dose of 40 µg naloxone was administered with no improvement. Oxygen saturation remained between 79% and 88%. Albuterol was given with little effect. The patient’s respiration rate was 44.

The patient was reintubated. Copious pink, frothy fluid was suctioned from the endotracheal tube. The patient received propofol, urosemide, and paralytic agents with the code team present to assist. The patient’s heart rate continued to decline to about 45 beats/min. The patient was transferred to a hospital emergency department.

Upon arrival in the emergency department, the patient was in asystolic arrest. Attempts to place a transvenous pacer were unsuccessful. The nasogastric tube returned 400 cc of brown coffee-grounds gastric fluid. After 30 minutes of CPR, the patient was pronounced dead.

The autopsy report noted no apparent airway obstruction, so the pathologist determined that the cause of death was flash pulmonary edema. Negative pressure pulmonary edema is a form of flash pulmonary edema caused by forceful inspiratory efforts made against a blocked airway. Toxic levels of ropivacaine were found in the patient’s blood. The pathologist noted hypertrophic cardiomyopathy and a grossly enlarged heart.

The patient’s family filed a claim after his death. The plaintiffs argued that the LMA was removed too soon for a patient with sleep apnea and a class III Mallampati score. They raised questions about the high levels of ropivacaine and wondered whether it contributed to bradycardia. They claimed that the reintubation took too long, resulting in high end-tidal CO₂. They also noted inconsistent documentation between PACU nurses and the anesthesiologist.

Some defense experts were supportive of the care, stating that the cause of death was probably from a fatal arrhythmia due to hypotension and an enlarged heart. The defense experts questioned whether undiagnosed pulmonary hypertension would explain the failure to respond to furosemide. It was noted that both of the patient’s parents had died suddenly following surgeries. The assumed cause of their deaths was coronary artery disease. This case settled.
 

How the claim may have been prevented: Dr. Feldman’s tips

Prevent adverse events by managing clinical decisions based on the individual patient’s needs. The history of sleep apnea and a rating of a Mallampati class III airway in this ASA III patient indicated a high risk for a difficult intubation. Consideration should have been given to performing the procedure in a hospital rather than in an ambulatory surgery center. The overall goal is to maintain a secure airway until the patient is able to maintain it on their own.

Preclude malpractice claims by having good communication with patients. Unfortunately, anesthesiologists don’t typically have an opportunity to develop a relationship with patients, but for patients at high risk, like this one, mandatory visits or calls to an anesthesiology-run pre-op clinic or ambulatory surgery center would give the anesthesiologist the opportunity to have a lengthy and informative discussion about risks, benefits, and alternatives. In addition, it would give the anesthesiologist time to discuss risks with both the surgeon and the patient.

Prevail in lawsuits by fully documenting the preoperative anesthesia assessment. There were questions about inconsistencies in documentation between the PACU nurses and anesthesiologists. Frequent huddles between the PACU staff (including nurses and physicians) may lead not only to more coordinated care but also to more consistent documentation, which will show that the care team acted together in caring for the patient.

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

A patient with many comorbidities undergoing surgery presents a number of challenges to the healthcare team. This case highlights why solid preparation for the pre-and post-op care of such patients is so important. As demonstrated here, where a procedure is performed is just as critical as who performs it, particularly when outcomes go awry.

A 56-year-old morbidly obese man with a history of hypertension, diabetes, sleep apnea, and elevated cholesterol presented to an ambulatory surgery center for knee arthroscopy. Following a brief pre-op assessment, his airway was rated a III using both the American Society of Anesthesiologists (ASA) and Mallampati classification systems. It was decided to use a laryngeal mask airway (LMA) with 100 µg of fentanyl and 2 mgmidazolam, followed by inhalation anesthesia.

After the procedure, the LMA was removed and the patient was moved to the post-anesthesia care unit (PACU). The patient was unresponsive for about 20 minutes and exhibited signs of respiratory distress. Efforts were made to open the airway with jaw thrusts and nasal trumpet. The anesthesiologist determined that the patient was suffering from congestive heart failure, aspiration, or pulmonary edema.

The anesthesiologist administered 40 µg of naloxone. The patient began to awaken but had oxygen saturation readings in the high 70s. The patient was encouraged to take slow, deep breaths. Rhonchi were heard, and the patient complained of shortness of breath. The ECG reading was unchanged from the pre-op test.

Thirty minutes after the first dose, a second dose of 40 µg naloxone was administered with no improvement. Oxygen saturation remained between 79% and 88%. Albuterol was given with little effect. The patient’s respiration rate was 44.

The patient was reintubated. Copious pink, frothy fluid was suctioned from the endotracheal tube. The patient received propofol, urosemide, and paralytic agents with the code team present to assist. The patient’s heart rate continued to decline to about 45 beats/min. The patient was transferred to a hospital emergency department.

Upon arrival in the emergency department, the patient was in asystolic arrest. Attempts to place a transvenous pacer were unsuccessful. The nasogastric tube returned 400 cc of brown coffee-grounds gastric fluid. After 30 minutes of CPR, the patient was pronounced dead.

The autopsy report noted no apparent airway obstruction, so the pathologist determined that the cause of death was flash pulmonary edema. Negative pressure pulmonary edema is a form of flash pulmonary edema caused by forceful inspiratory efforts made against a blocked airway. Toxic levels of ropivacaine were found in the patient’s blood. The pathologist noted hypertrophic cardiomyopathy and a grossly enlarged heart.

The patient’s family filed a claim after his death. The plaintiffs argued that the LMA was removed too soon for a patient with sleep apnea and a class III Mallampati score. They raised questions about the high levels of ropivacaine and wondered whether it contributed to bradycardia. They claimed that the reintubation took too long, resulting in high end-tidal CO₂. They also noted inconsistent documentation between PACU nurses and the anesthesiologist.

Some defense experts were supportive of the care, stating that the cause of death was probably from a fatal arrhythmia due to hypotension and an enlarged heart. The defense experts questioned whether undiagnosed pulmonary hypertension would explain the failure to respond to furosemide. It was noted that both of the patient’s parents had died suddenly following surgeries. The assumed cause of their deaths was coronary artery disease. This case settled.
 

How the claim may have been prevented: Dr. Feldman’s tips

Prevent adverse events by managing clinical decisions based on the individual patient’s needs. The history of sleep apnea and a rating of a Mallampati class III airway in this ASA III patient indicated a high risk for a difficult intubation. Consideration should have been given to performing the procedure in a hospital rather than in an ambulatory surgery center. The overall goal is to maintain a secure airway until the patient is able to maintain it on their own.

Preclude malpractice claims by having good communication with patients. Unfortunately, anesthesiologists don’t typically have an opportunity to develop a relationship with patients, but for patients at high risk, like this one, mandatory visits or calls to an anesthesiology-run pre-op clinic or ambulatory surgery center would give the anesthesiologist the opportunity to have a lengthy and informative discussion about risks, benefits, and alternatives. In addition, it would give the anesthesiologist time to discuss risks with both the surgeon and the patient.

Prevail in lawsuits by fully documenting the preoperative anesthesia assessment. There were questions about inconsistencies in documentation between the PACU nurses and anesthesiologists. Frequent huddles between the PACU staff (including nurses and physicians) may lead not only to more coordinated care but also to more consistent documentation, which will show that the care team acted together in caring for the patient.

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

A patient with many comorbidities undergoing surgery presents a number of challenges to the healthcare team. This case highlights why solid preparation for the pre-and post-op care of such patients is so important. As demonstrated here, where a procedure is performed is just as critical as who performs it, particularly when outcomes go awry.

A 56-year-old morbidly obese man with a history of hypertension, diabetes, sleep apnea, and elevated cholesterol presented to an ambulatory surgery center for knee arthroscopy. Following a brief pre-op assessment, his airway was rated a III using both the American Society of Anesthesiologists (ASA) and Mallampati classification systems. It was decided to use a laryngeal mask airway (LMA) with 100 µg of fentanyl and 2 mgmidazolam, followed by inhalation anesthesia.

After the procedure, the LMA was removed and the patient was moved to the post-anesthesia care unit (PACU). The patient was unresponsive for about 20 minutes and exhibited signs of respiratory distress. Efforts were made to open the airway with jaw thrusts and nasal trumpet. The anesthesiologist determined that the patient was suffering from congestive heart failure, aspiration, or pulmonary edema.

The anesthesiologist administered 40 µg of naloxone. The patient began to awaken but had oxygen saturation readings in the high 70s. The patient was encouraged to take slow, deep breaths. Rhonchi were heard, and the patient complained of shortness of breath. The ECG reading was unchanged from the pre-op test.

Thirty minutes after the first dose, a second dose of 40 µg naloxone was administered with no improvement. Oxygen saturation remained between 79% and 88%. Albuterol was given with little effect. The patient’s respiration rate was 44.

The patient was reintubated. Copious pink, frothy fluid was suctioned from the endotracheal tube. The patient received propofol, urosemide, and paralytic agents with the code team present to assist. The patient’s heart rate continued to decline to about 45 beats/min. The patient was transferred to a hospital emergency department.

Upon arrival in the emergency department, the patient was in asystolic arrest. Attempts to place a transvenous pacer were unsuccessful. The nasogastric tube returned 400 cc of brown coffee-grounds gastric fluid. After 30 minutes of CPR, the patient was pronounced dead.

The autopsy report noted no apparent airway obstruction, so the pathologist determined that the cause of death was flash pulmonary edema. Negative pressure pulmonary edema is a form of flash pulmonary edema caused by forceful inspiratory efforts made against a blocked airway. Toxic levels of ropivacaine were found in the patient’s blood. The pathologist noted hypertrophic cardiomyopathy and a grossly enlarged heart.

The patient’s family filed a claim after his death. The plaintiffs argued that the LMA was removed too soon for a patient with sleep apnea and a class III Mallampati score. They raised questions about the high levels of ropivacaine and wondered whether it contributed to bradycardia. They claimed that the reintubation took too long, resulting in high end-tidal CO₂. They also noted inconsistent documentation between PACU nurses and the anesthesiologist.

Some defense experts were supportive of the care, stating that the cause of death was probably from a fatal arrhythmia due to hypotension and an enlarged heart. The defense experts questioned whether undiagnosed pulmonary hypertension would explain the failure to respond to furosemide. It was noted that both of the patient’s parents had died suddenly following surgeries. The assumed cause of their deaths was coronary artery disease. This case settled.
 

How the claim may have been prevented: Dr. Feldman’s tips

Prevent adverse events by managing clinical decisions based on the individual patient’s needs. The history of sleep apnea and a rating of a Mallampati class III airway in this ASA III patient indicated a high risk for a difficult intubation. Consideration should have been given to performing the procedure in a hospital rather than in an ambulatory surgery center. The overall goal is to maintain a secure airway until the patient is able to maintain it on their own.

Preclude malpractice claims by having good communication with patients. Unfortunately, anesthesiologists don’t typically have an opportunity to develop a relationship with patients, but for patients at high risk, like this one, mandatory visits or calls to an anesthesiology-run pre-op clinic or ambulatory surgery center would give the anesthesiologist the opportunity to have a lengthy and informative discussion about risks, benefits, and alternatives. In addition, it would give the anesthesiologist time to discuss risks with both the surgeon and the patient.

Prevail in lawsuits by fully documenting the preoperative anesthesia assessment. There were questions about inconsistencies in documentation between the PACU nurses and anesthesiologists. Frequent huddles between the PACU staff (including nurses and physicians) may lead not only to more coordinated care but also to more consistent documentation, which will show that the care team acted together in caring for the patient.

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

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry. All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact [email protected].
 

Since the recent legalization and decriminalization of cannabis (marijuana) use throughout the United States, adolescents’ access to, and use of, cannabis has increased.¹ Cannabis products have been marketed in ways that attract adolescents, such as edible gummies, cookies, and hard candies, as well as by vaping.¹ The adolescent years are a delicate period of development during which individuals are prone to psychiatric illness, including depression, anxiety, and psychosis.^2,3 Here we discuss the relationship between adolescent cannabis use and the development of psychosis.

How cannabis can affect the adolescent brain

The 2 main psychotropic substances found within the cannabis plant are tetrahydrocannabinol (THC) and cannabidiol (CBD).^1,4 Endocannabinoids are fatty acid derivatives produced in the brain that bind to cannabinoid (CB) receptors found in the brain and the peripheral nervous system.^1,4

During adolescence, neurodevelopment and neurochemical balances are evolving, and it’s during this period that the bulk of prefrontal pruning occurs, especially in the glutamatergic and gamma aminobutyric acidergic (GABAergic) neural pathways.⁵ THC affects the CB1 receptors by downregulating the neuron receptors, which then alters the maturation of the prefrontal cortical GABAergic neurons. Also, THC affects the upregulation of the microglia located on the CB2 receptors, thereby altering synaptic pruning even further.^2,5

All of these changes can cause brain insults that can contribute to the precipitation of psychotic decompensation in adolescents who ingest products that contain THC. In addition, consuming THC might hasten the progression of disorder in adolescents who are genetically predisposed to psychotic disorders. However, existing studies must be interpreted with caution because there are other contributing risk factors for psychosis, such as social isolation, that can alter dopamine signaling as well as oligodendrocyte maturation, which can affect myelination in the prefrontal area of the evolving brain. Factors such as increased academic demand can alter the release of cortisol, which in turn affects the dopamine response as well as the structure of the hippocampus as it responds to cortisol. With all of these contributing factors, it is difficult to attribute psychosis in adolescents solely to the use of THC.⁵

How to discuss cannabis usewith adolescents

Clinicians should engage in open-ended therapeutic conversations about cannabis use with their adolescent patients, including the various types of cannabis and methods of use (ingestion vs inhalation, etc). Educate patients about the acute and long-term effects of THC use, including an increased risk of depression, schizophrenia, and substance abuse in adulthood.

For a patient who has experienced a psychotic episode, early intervention has proven to result in greater treatment response and functional improvement because it reduces brain exposure to neurotoxic effects in adolescents.³ Access to community resources such as school counselors can help to create coping strategies and enhance family support, which can optimize treatment outcomes and medication adherence, all of which will minimize the likelihood of another psychotic episode. Kelleher et al⁶ found an increased risk of suicidal behavior after a psychotic experience from any cause in adolescents and young adults, and thereby recommended that clinicians conduct continuous assessment of suicidal ideation in such patients.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry. All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact [email protected].
 

Since the recent legalization and decriminalization of cannabis (marijuana) use throughout the United States, adolescents’ access to, and use of, cannabis has increased.¹ Cannabis products have been marketed in ways that attract adolescents, such as edible gummies, cookies, and hard candies, as well as by vaping.¹ The adolescent years are a delicate period of development during which individuals are prone to psychiatric illness, including depression, anxiety, and psychosis.^2,3 Here we discuss the relationship between adolescent cannabis use and the development of psychosis.

How cannabis can affect the adolescent brain

The 2 main psychotropic substances found within the cannabis plant are tetrahydrocannabinol (THC) and cannabidiol (CBD).^1,4 Endocannabinoids are fatty acid derivatives produced in the brain that bind to cannabinoid (CB) receptors found in the brain and the peripheral nervous system.^1,4

During adolescence, neurodevelopment and neurochemical balances are evolving, and it’s during this period that the bulk of prefrontal pruning occurs, especially in the glutamatergic and gamma aminobutyric acidergic (GABAergic) neural pathways.⁵ THC affects the CB1 receptors by downregulating the neuron receptors, which then alters the maturation of the prefrontal cortical GABAergic neurons. Also, THC affects the upregulation of the microglia located on the CB2 receptors, thereby altering synaptic pruning even further.^2,5

All of these changes can cause brain insults that can contribute to the precipitation of psychotic decompensation in adolescents who ingest products that contain THC. In addition, consuming THC might hasten the progression of disorder in adolescents who are genetically predisposed to psychotic disorders. However, existing studies must be interpreted with caution because there are other contributing risk factors for psychosis, such as social isolation, that can alter dopamine signaling as well as oligodendrocyte maturation, which can affect myelination in the prefrontal area of the evolving brain. Factors such as increased academic demand can alter the release of cortisol, which in turn affects the dopamine response as well as the structure of the hippocampus as it responds to cortisol. With all of these contributing factors, it is difficult to attribute psychosis in adolescents solely to the use of THC.⁵

How to discuss cannabis usewith adolescents

Clinicians should engage in open-ended therapeutic conversations about cannabis use with their adolescent patients, including the various types of cannabis and methods of use (ingestion vs inhalation, etc). Educate patients about the acute and long-term effects of THC use, including an increased risk of depression, schizophrenia, and substance abuse in adulthood.

For a patient who has experienced a psychotic episode, early intervention has proven to result in greater treatment response and functional improvement because it reduces brain exposure to neurotoxic effects in adolescents.³ Access to community resources such as school counselors can help to create coping strategies and enhance family support, which can optimize treatment outcomes and medication adherence, all of which will minimize the likelihood of another psychotic episode. Kelleher et al⁶ found an increased risk of suicidal behavior after a psychotic experience from any cause in adolescents and young adults, and thereby recommended that clinicians conduct continuous assessment of suicidal ideation in such patients.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry. All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact [email protected].
 

Since the recent legalization and decriminalization of cannabis (marijuana) use throughout the United States, adolescents’ access to, and use of, cannabis has increased.¹ Cannabis products have been marketed in ways that attract adolescents, such as edible gummies, cookies, and hard candies, as well as by vaping.¹ The adolescent years are a delicate period of development during which individuals are prone to psychiatric illness, including depression, anxiety, and psychosis.^2,3 Here we discuss the relationship between adolescent cannabis use and the development of psychosis.

How cannabis can affect the adolescent brain

The 2 main psychotropic substances found within the cannabis plant are tetrahydrocannabinol (THC) and cannabidiol (CBD).^1,4 Endocannabinoids are fatty acid derivatives produced in the brain that bind to cannabinoid (CB) receptors found in the brain and the peripheral nervous system.^1,4

During adolescence, neurodevelopment and neurochemical balances are evolving, and it’s during this period that the bulk of prefrontal pruning occurs, especially in the glutamatergic and gamma aminobutyric acidergic (GABAergic) neural pathways.⁵ THC affects the CB1 receptors by downregulating the neuron receptors, which then alters the maturation of the prefrontal cortical GABAergic neurons. Also, THC affects the upregulation of the microglia located on the CB2 receptors, thereby altering synaptic pruning even further.^2,5

All of these changes can cause brain insults that can contribute to the precipitation of psychotic decompensation in adolescents who ingest products that contain THC. In addition, consuming THC might hasten the progression of disorder in adolescents who are genetically predisposed to psychotic disorders. However, existing studies must be interpreted with caution because there are other contributing risk factors for psychosis, such as social isolation, that can alter dopamine signaling as well as oligodendrocyte maturation, which can affect myelination in the prefrontal area of the evolving brain. Factors such as increased academic demand can alter the release of cortisol, which in turn affects the dopamine response as well as the structure of the hippocampus as it responds to cortisol. With all of these contributing factors, it is difficult to attribute psychosis in adolescents solely to the use of THC.⁵

How to discuss cannabis usewith adolescents

Clinicians should engage in open-ended therapeutic conversations about cannabis use with their adolescent patients, including the various types of cannabis and methods of use (ingestion vs inhalation, etc). Educate patients about the acute and long-term effects of THC use, including an increased risk of depression, schizophrenia, and substance abuse in adulthood.

For a patient who has experienced a psychotic episode, early intervention has proven to result in greater treatment response and functional improvement because it reduces brain exposure to neurotoxic effects in adolescents.³ Access to community resources such as school counselors can help to create coping strategies and enhance family support, which can optimize treatment outcomes and medication adherence, all of which will minimize the likelihood of another psychotic episode. Kelleher et al⁶ found an increased risk of suicidal behavior after a psychotic experience from any cause in adolescents and young adults, and thereby recommended that clinicians conduct continuous assessment of suicidal ideation in such patients.

The use of opiates in the treatment of headache has a controversial history, and it remains a matter of debate today. Some believe that the medications, though risky, can be a useful tool in the neurologist’s treatment arsenal, while others argue that opioids are just too risky when there are other, safer alternatives available.

Those were the cruxes of arguments put forward by Paul Rizzoli, MD, and Christopher H. Gottschalk, MD, who conducted individual talks at the 2021 Scottsdale Headache Symposium. Dr. Rizzoli, associate professor of neurology at Harvard Medical School, Boston, argued in favor of the use of opioids and butalbital-containing medications. Dr. Gottschalk, assistant professor of neurology at Yale University, New Haven, Conn., argued against their use.

In certain situations opioids are worth the risk

Whether or not to use opioids in the treatment of headache is “a reasonable question, because these medications can clearly be seen as having risk. So perhaps another way to frame this question is as a risk-benefit issue. Are these medications worth the risk? How useful is the benefit of opioids, if the consequence is dependence or addiction?” Dr. Rizzoli began.

Although reviews show effectiveness of opioids in treating migraine, a three-part review in 2012 found greater efficacy of dihydroergotamine (DHE), ketorolac, and chlorpromazine. That’s not surprising, said Dr. Rizzoli, since those competing drugs are migraine-specific.

Dr. Rizzoli quoted a 2014 review indicating that there were incomplete data on the relative efficacy of opioids versus other analgesics, and for some patients opioids would likely be the optimal treatment, such as those who have contraindications to ergot-type medications or neuroleptic medications, pregnant women, or patients who don’t respond to other medications.

Dr. Rizzoli noted that The International Association for the Study of Pain has concluded that no other oral medications provide immediate and effective pain relief, and that short-term use rarely leads to addiction.

“So, to me, the answer is not to avoid opioids or outlaw them but instead to use them judiciously and infrequently, and in a short term or rescue fashion,” said Dr. Rizzoli.

He pointed out that physicians accept risks of other medications, and act to mitigate those risks. He said that risk mitigation with opioids can take the form of avoiding prescriptions in some situations, like when patients have a personal or family history of substance abuse, or in cases of some behavioral or emotional disorders.

Dr. Rizzoli went on to discuss the use of butalbital, which acts as a CNS depressant and has a variety of effects, including sedation, anxiolytic, hypnotic, and antiepileptic effects, but it is only a weak analgesic, but it nevertheless works in headache, said Dr. Rizzoli, citing patient reports and personal experience.

“It’s difficult to appreciate this theme of efficacy behind all the hype in the literature and in the press against butalbital, and the fact that it has not been adequately studied. But I would submit that the fact that we are even having this discussion is support enough for the use of butalbital. If butalbital either didn’t work or was simply a drug of abuse, it would likely have faded away by now,” said Dr. Rizzoli. He conceded that butalbital can be overused and may lead episodic headache to become chronic daily headache, but he noted that Seymour Solomon, MD, professor emeritus at Albert Einstein College of Medicine, New York, has estimated that removal of butalbital from the market would reduce chronic headache in the general population by only a small fraction of one percent.

Butalbital also has another interesting effect, which is that patients may quickly return to normal functioning after the headache resolves. “Maybe this is all due to management of anxiety, the presumed mechanism of action of barbiturates. So, instead of lobbying for its removal, I would propose that we should take a closer look at what’s going on here, and what the mechanism of action of this fairly interesting compound might be,” said Dr. Rizzoli.

Dr. Rizzoli also said there is some evidence that migraine-specific drugs also affect the tolerance to opioid drugs. “Somehow, they seem to interact with the opioid pain system. If that’s true, the implication is that you probably cannot escape the opioid receptors in the management of migraine,” said Dr. Rizzoli.

Ultimately, he supports the judicious use of opioids and butalbital containing-medications for headache relief. “My argument is that it is just too simplistic to cease use of these meds. Yes, they should be used in a restricted and careful way, but not abandoned,” said Dr. Rizzoli.
 

Opiates should be avoided

Following Dr. Rizzoli’s presentation, Dr. Gottschalk presented an argument against the use of opioids in the treatment of headache.

He began by quoting the ABIM Choosing Wisely Campaign of 2012, which concluded that fioricet and narcotics should be avoided in headache unless the patient is desperate. “As a headache specialist, I can tell you that I have not faced situations sufficiently desperate to use any of these. The American Headache Society in a series of evidence assessments has concluded similarly, that they are of no use,” said Dr. Gottschalk.

Opiates and barbiturates may also increase risk of migraine chronification. One study found that triptans are associated with low rates of chronification, at just a few percent when used fewer than 4 days a month, and about 20% per year when used 10-14 days per month. Opiate use showed a broadly similar pattern, while barbiturates showed a particularly alarming pattern: “Every level of use was associated with astronomically high rates and measurably higher at the highest level of use. For opiates, the odds ratio was about 2 – statistically significant. For barbiturates it was clearly greater than 2, whereas with triptans, the odds ratio showed a nonsignificant, slight increase in risk. And for NSAIDs, the odds ratio was, if anything, less than 1,” said Dr. Gottschalk.

He also discussed aspects of behavioral pharmacology, in which positive reinforcement associated with decreased headache may encourage repeated use of the drug. “Given these, it should be no surprise to anyone that emergency room treatment with opiates for acute migraine is clearly associated with increased recidivism for patients given those drugs,” said Dr. Gottschalk.

Opiate use is associated with increased pain sensitivity, and in the case of migraine, it may interfere with the activity of other treatments.

As for butalbital-containing compounds, they are positive-reinforcing drugs, and they are not indicated for migraine, only tension headache. There is no evidence of benefit in migraine, but butalbital is anxiolytic, which could lead an individual to increase its use.

A recent meta-analysis of therapies for episodic migraine found that hydromorphone and meperidine are less effective than standard therapies such as prochlorperazine or metoclopramide. Another study suggested that opioid use may interfere with the efficacy of NSAIDs in the emergency room environment, while a post hoc analysis of rizatriptan clinical trials found that recent opiate use was associated with a lower response rate, and the effect was more pronounced in women.

Among patients with chronic migraine, a 2004 study found that opiates were the most commonly used medication, and other studies found that chronic migraine does not arise in nonmigraine patients treated with opiates, “suggesting that migraine is specifically prone to opiate-induced hyperalgesia of migraine itself,” said Dr. Gottschalk.

Even under careful monitoring, misuse occurs in more than 50% of patients, “suggesting that even under the best circumstances, it is difficult to use this class of drugs safely in long term,” said Dr. Gottschalk.

He pointed out that the risk of drug addiction rises with various clinical and socioeconomic factors, including living in impoverished environments, adverse childhood experiences, low socioeconomic status, exposure to pollutants, and stressors. “In other words, all features associated with systemic racism are clearly associated with an increased risk of addiction,” said Dr. Gottschalk. Other factors include availability of the drug, such as whether or not a physician prescribes it, and repeated use.

These concerns, combined with positive-reinforcing properties of opiates and association with migraine progression and refractoriness, and the lack of progression risk found with use of NSAIDs and triptans, and the fact that effective acute therapy is associated with a lower risk of progression, argue against the use of opiates, said Dr. Gottschalk.

There is even a potential risk that the experience of migraine and its relief due to self-administration may become a rewarding experience that propagates the problem. It’s possible that anticipatory anxiety related to fear stressors could lead to migraine, or to physical sensations interpreted as migraine prodrome. “[It] raises the question of whether or not positive reinforcement by drugs makes migraine itself a rewarding experience and therefore more likely to occur as a cue for drug self-administration. The question I pose is: Is there any reason to test this theory in drugs of no proven benefit in the treatment of migraine? I would say very clearly, No,” said Dr. Gottschalk.
 

Clarifying the finer points of the debate

In the Q&A session after the talk, Dr. Rizzoli said that he doesn’t advocate for long-term use of opiates, except in rare cases where the diagnosis gets changed to a chronic pain syndrome. “We’re talking about intermittent use for treatment of an acute event. Do we put limits on them? I think the answer is clearly Yes, and the limits are more strict than those for triptans. My own sense as a clinician is I want all of the available tools. From a clinical perspective, there are a large number of people who do just fine with intermittent use of these medicines, and so I wouldn’t restrict them,” said Dr. Rizzoli.

Dr. Gottschalk agreed that opiates may make sense for some patients, but expressed concerns about any and all physicians prescribing them. “The part about the tools is partly a question of: Who gets to use them? In the hands of a headache specialist in those isolated cases with careful restrictions, sure. But what I’m making is a slippery slope argument: What we know is that in emergency rooms, these are used routinely, and that [those] patients are precisely the ones who are at higher risk of addiction. So in some sense, I’m just saying I think we need to have much clearer boundaries,” he said.

Dr. Rizzoli has no relevant financial disclosures. Dr. Gottschalk has been on the advisory boards of Alder, AbbVie, Amgen/Novartis, Biohaven, Theranica, Upsher-Smith, Axsome, Vorso, Currax, and Impel. He has been a consultant for Alder, Alexion, and Spherix Global Insights. He has received research support from Relivion.

The use of opiates in the treatment of headache has a controversial history, and it remains a matter of debate today. Some believe that the medications, though risky, can be a useful tool in the neurologist’s treatment arsenal, while others argue that opioids are just too risky when there are other, safer alternatives available.

Those were the cruxes of arguments put forward by Paul Rizzoli, MD, and Christopher H. Gottschalk, MD, who conducted individual talks at the 2021 Scottsdale Headache Symposium. Dr. Rizzoli, associate professor of neurology at Harvard Medical School, Boston, argued in favor of the use of opioids and butalbital-containing medications. Dr. Gottschalk, assistant professor of neurology at Yale University, New Haven, Conn., argued against their use.

In certain situations opioids are worth the risk

Whether or not to use opioids in the treatment of headache is “a reasonable question, because these medications can clearly be seen as having risk. So perhaps another way to frame this question is as a risk-benefit issue. Are these medications worth the risk? How useful is the benefit of opioids, if the consequence is dependence or addiction?” Dr. Rizzoli began.

Although reviews show effectiveness of opioids in treating migraine, a three-part review in 2012 found greater efficacy of dihydroergotamine (DHE), ketorolac, and chlorpromazine. That’s not surprising, said Dr. Rizzoli, since those competing drugs are migraine-specific.

Dr. Rizzoli quoted a 2014 review indicating that there were incomplete data on the relative efficacy of opioids versus other analgesics, and for some patients opioids would likely be the optimal treatment, such as those who have contraindications to ergot-type medications or neuroleptic medications, pregnant women, or patients who don’t respond to other medications.

Dr. Rizzoli noted that The International Association for the Study of Pain has concluded that no other oral medications provide immediate and effective pain relief, and that short-term use rarely leads to addiction.

“So, to me, the answer is not to avoid opioids or outlaw them but instead to use them judiciously and infrequently, and in a short term or rescue fashion,” said Dr. Rizzoli.

He pointed out that physicians accept risks of other medications, and act to mitigate those risks. He said that risk mitigation with opioids can take the form of avoiding prescriptions in some situations, like when patients have a personal or family history of substance abuse, or in cases of some behavioral or emotional disorders.

Dr. Rizzoli went on to discuss the use of butalbital, which acts as a CNS depressant and has a variety of effects, including sedation, anxiolytic, hypnotic, and antiepileptic effects, but it is only a weak analgesic, but it nevertheless works in headache, said Dr. Rizzoli, citing patient reports and personal experience.

“It’s difficult to appreciate this theme of efficacy behind all the hype in the literature and in the press against butalbital, and the fact that it has not been adequately studied. But I would submit that the fact that we are even having this discussion is support enough for the use of butalbital. If butalbital either didn’t work or was simply a drug of abuse, it would likely have faded away by now,” said Dr. Rizzoli. He conceded that butalbital can be overused and may lead episodic headache to become chronic daily headache, but he noted that Seymour Solomon, MD, professor emeritus at Albert Einstein College of Medicine, New York, has estimated that removal of butalbital from the market would reduce chronic headache in the general population by only a small fraction of one percent.

Butalbital also has another interesting effect, which is that patients may quickly return to normal functioning after the headache resolves. “Maybe this is all due to management of anxiety, the presumed mechanism of action of barbiturates. So, instead of lobbying for its removal, I would propose that we should take a closer look at what’s going on here, and what the mechanism of action of this fairly interesting compound might be,” said Dr. Rizzoli.

Dr. Rizzoli also said there is some evidence that migraine-specific drugs also affect the tolerance to opioid drugs. “Somehow, they seem to interact with the opioid pain system. If that’s true, the implication is that you probably cannot escape the opioid receptors in the management of migraine,” said Dr. Rizzoli.

Ultimately, he supports the judicious use of opioids and butalbital containing-medications for headache relief. “My argument is that it is just too simplistic to cease use of these meds. Yes, they should be used in a restricted and careful way, but not abandoned,” said Dr. Rizzoli.
 

Opiates should be avoided

Following Dr. Rizzoli’s presentation, Dr. Gottschalk presented an argument against the use of opioids in the treatment of headache.

He began by quoting the ABIM Choosing Wisely Campaign of 2012, which concluded that fioricet and narcotics should be avoided in headache unless the patient is desperate. “As a headache specialist, I can tell you that I have not faced situations sufficiently desperate to use any of these. The American Headache Society in a series of evidence assessments has concluded similarly, that they are of no use,” said Dr. Gottschalk.

Opiates and barbiturates may also increase risk of migraine chronification. One study found that triptans are associated with low rates of chronification, at just a few percent when used fewer than 4 days a month, and about 20% per year when used 10-14 days per month. Opiate use showed a broadly similar pattern, while barbiturates showed a particularly alarming pattern: “Every level of use was associated with astronomically high rates and measurably higher at the highest level of use. For opiates, the odds ratio was about 2 – statistically significant. For barbiturates it was clearly greater than 2, whereas with triptans, the odds ratio showed a nonsignificant, slight increase in risk. And for NSAIDs, the odds ratio was, if anything, less than 1,” said Dr. Gottschalk.

He also discussed aspects of behavioral pharmacology, in which positive reinforcement associated with decreased headache may encourage repeated use of the drug. “Given these, it should be no surprise to anyone that emergency room treatment with opiates for acute migraine is clearly associated with increased recidivism for patients given those drugs,” said Dr. Gottschalk.

Opiate use is associated with increased pain sensitivity, and in the case of migraine, it may interfere with the activity of other treatments.

As for butalbital-containing compounds, they are positive-reinforcing drugs, and they are not indicated for migraine, only tension headache. There is no evidence of benefit in migraine, but butalbital is anxiolytic, which could lead an individual to increase its use.

A recent meta-analysis of therapies for episodic migraine found that hydromorphone and meperidine are less effective than standard therapies such as prochlorperazine or metoclopramide. Another study suggested that opioid use may interfere with the efficacy of NSAIDs in the emergency room environment, while a post hoc analysis of rizatriptan clinical trials found that recent opiate use was associated with a lower response rate, and the effect was more pronounced in women.

Among patients with chronic migraine, a 2004 study found that opiates were the most commonly used medication, and other studies found that chronic migraine does not arise in nonmigraine patients treated with opiates, “suggesting that migraine is specifically prone to opiate-induced hyperalgesia of migraine itself,” said Dr. Gottschalk.

Even under careful monitoring, misuse occurs in more than 50% of patients, “suggesting that even under the best circumstances, it is difficult to use this class of drugs safely in long term,” said Dr. Gottschalk.

He pointed out that the risk of drug addiction rises with various clinical and socioeconomic factors, including living in impoverished environments, adverse childhood experiences, low socioeconomic status, exposure to pollutants, and stressors. “In other words, all features associated with systemic racism are clearly associated with an increased risk of addiction,” said Dr. Gottschalk. Other factors include availability of the drug, such as whether or not a physician prescribes it, and repeated use.

These concerns, combined with positive-reinforcing properties of opiates and association with migraine progression and refractoriness, and the lack of progression risk found with use of NSAIDs and triptans, and the fact that effective acute therapy is associated with a lower risk of progression, argue against the use of opiates, said Dr. Gottschalk.

There is even a potential risk that the experience of migraine and its relief due to self-administration may become a rewarding experience that propagates the problem. It’s possible that anticipatory anxiety related to fear stressors could lead to migraine, or to physical sensations interpreted as migraine prodrome. “[It] raises the question of whether or not positive reinforcement by drugs makes migraine itself a rewarding experience and therefore more likely to occur as a cue for drug self-administration. The question I pose is: Is there any reason to test this theory in drugs of no proven benefit in the treatment of migraine? I would say very clearly, No,” said Dr. Gottschalk.
 

Clarifying the finer points of the debate

In the Q&A session after the talk, Dr. Rizzoli said that he doesn’t advocate for long-term use of opiates, except in rare cases where the diagnosis gets changed to a chronic pain syndrome. “We’re talking about intermittent use for treatment of an acute event. Do we put limits on them? I think the answer is clearly Yes, and the limits are more strict than those for triptans. My own sense as a clinician is I want all of the available tools. From a clinical perspective, there are a large number of people who do just fine with intermittent use of these medicines, and so I wouldn’t restrict them,” said Dr. Rizzoli.

Dr. Gottschalk agreed that opiates may make sense for some patients, but expressed concerns about any and all physicians prescribing them. “The part about the tools is partly a question of: Who gets to use them? In the hands of a headache specialist in those isolated cases with careful restrictions, sure. But what I’m making is a slippery slope argument: What we know is that in emergency rooms, these are used routinely, and that [those] patients are precisely the ones who are at higher risk of addiction. So in some sense, I’m just saying I think we need to have much clearer boundaries,” he said.

Dr. Rizzoli has no relevant financial disclosures. Dr. Gottschalk has been on the advisory boards of Alder, AbbVie, Amgen/Novartis, Biohaven, Theranica, Upsher-Smith, Axsome, Vorso, Currax, and Impel. He has been a consultant for Alder, Alexion, and Spherix Global Insights. He has received research support from Relivion.

The use of opiates in the treatment of headache has a controversial history, and it remains a matter of debate today. Some believe that the medications, though risky, can be a useful tool in the neurologist’s treatment arsenal, while others argue that opioids are just too risky when there are other, safer alternatives available.

Those were the cruxes of arguments put forward by Paul Rizzoli, MD, and Christopher H. Gottschalk, MD, who conducted individual talks at the 2021 Scottsdale Headache Symposium. Dr. Rizzoli, associate professor of neurology at Harvard Medical School, Boston, argued in favor of the use of opioids and butalbital-containing medications. Dr. Gottschalk, assistant professor of neurology at Yale University, New Haven, Conn., argued against their use.

In certain situations opioids are worth the risk

Whether or not to use opioids in the treatment of headache is “a reasonable question, because these medications can clearly be seen as having risk. So perhaps another way to frame this question is as a risk-benefit issue. Are these medications worth the risk? How useful is the benefit of opioids, if the consequence is dependence or addiction?” Dr. Rizzoli began.

Although reviews show effectiveness of opioids in treating migraine, a three-part review in 2012 found greater efficacy of dihydroergotamine (DHE), ketorolac, and chlorpromazine. That’s not surprising, said Dr. Rizzoli, since those competing drugs are migraine-specific.

Dr. Rizzoli quoted a 2014 review indicating that there were incomplete data on the relative efficacy of opioids versus other analgesics, and for some patients opioids would likely be the optimal treatment, such as those who have contraindications to ergot-type medications or neuroleptic medications, pregnant women, or patients who don’t respond to other medications.

Dr. Rizzoli noted that The International Association for the Study of Pain has concluded that no other oral medications provide immediate and effective pain relief, and that short-term use rarely leads to addiction.

“So, to me, the answer is not to avoid opioids or outlaw them but instead to use them judiciously and infrequently, and in a short term or rescue fashion,” said Dr. Rizzoli.

He pointed out that physicians accept risks of other medications, and act to mitigate those risks. He said that risk mitigation with opioids can take the form of avoiding prescriptions in some situations, like when patients have a personal or family history of substance abuse, or in cases of some behavioral or emotional disorders.

Dr. Rizzoli went on to discuss the use of butalbital, which acts as a CNS depressant and has a variety of effects, including sedation, anxiolytic, hypnotic, and antiepileptic effects, but it is only a weak analgesic, but it nevertheless works in headache, said Dr. Rizzoli, citing patient reports and personal experience.

“It’s difficult to appreciate this theme of efficacy behind all the hype in the literature and in the press against butalbital, and the fact that it has not been adequately studied. But I would submit that the fact that we are even having this discussion is support enough for the use of butalbital. If butalbital either didn’t work or was simply a drug of abuse, it would likely have faded away by now,” said Dr. Rizzoli. He conceded that butalbital can be overused and may lead episodic headache to become chronic daily headache, but he noted that Seymour Solomon, MD, professor emeritus at Albert Einstein College of Medicine, New York, has estimated that removal of butalbital from the market would reduce chronic headache in the general population by only a small fraction of one percent.

Butalbital also has another interesting effect, which is that patients may quickly return to normal functioning after the headache resolves. “Maybe this is all due to management of anxiety, the presumed mechanism of action of barbiturates. So, instead of lobbying for its removal, I would propose that we should take a closer look at what’s going on here, and what the mechanism of action of this fairly interesting compound might be,” said Dr. Rizzoli.

Dr. Rizzoli also said there is some evidence that migraine-specific drugs also affect the tolerance to opioid drugs. “Somehow, they seem to interact with the opioid pain system. If that’s true, the implication is that you probably cannot escape the opioid receptors in the management of migraine,” said Dr. Rizzoli.

Ultimately, he supports the judicious use of opioids and butalbital containing-medications for headache relief. “My argument is that it is just too simplistic to cease use of these meds. Yes, they should be used in a restricted and careful way, but not abandoned,” said Dr. Rizzoli.
 

Opiates should be avoided

Following Dr. Rizzoli’s presentation, Dr. Gottschalk presented an argument against the use of opioids in the treatment of headache.

He began by quoting the ABIM Choosing Wisely Campaign of 2012, which concluded that fioricet and narcotics should be avoided in headache unless the patient is desperate. “As a headache specialist, I can tell you that I have not faced situations sufficiently desperate to use any of these. The American Headache Society in a series of evidence assessments has concluded similarly, that they are of no use,” said Dr. Gottschalk.

Opiates and barbiturates may also increase risk of migraine chronification. One study found that triptans are associated with low rates of chronification, at just a few percent when used fewer than 4 days a month, and about 20% per year when used 10-14 days per month. Opiate use showed a broadly similar pattern, while barbiturates showed a particularly alarming pattern: “Every level of use was associated with astronomically high rates and measurably higher at the highest level of use. For opiates, the odds ratio was about 2 – statistically significant. For barbiturates it was clearly greater than 2, whereas with triptans, the odds ratio showed a nonsignificant, slight increase in risk. And for NSAIDs, the odds ratio was, if anything, less than 1,” said Dr. Gottschalk.

He also discussed aspects of behavioral pharmacology, in which positive reinforcement associated with decreased headache may encourage repeated use of the drug. “Given these, it should be no surprise to anyone that emergency room treatment with opiates for acute migraine is clearly associated with increased recidivism for patients given those drugs,” said Dr. Gottschalk.

Opiate use is associated with increased pain sensitivity, and in the case of migraine, it may interfere with the activity of other treatments.

As for butalbital-containing compounds, they are positive-reinforcing drugs, and they are not indicated for migraine, only tension headache. There is no evidence of benefit in migraine, but butalbital is anxiolytic, which could lead an individual to increase its use.

A recent meta-analysis of therapies for episodic migraine found that hydromorphone and meperidine are less effective than standard therapies such as prochlorperazine or metoclopramide. Another study suggested that opioid use may interfere with the efficacy of NSAIDs in the emergency room environment, while a post hoc analysis of rizatriptan clinical trials found that recent opiate use was associated with a lower response rate, and the effect was more pronounced in women.

Among patients with chronic migraine, a 2004 study found that opiates were the most commonly used medication, and other studies found that chronic migraine does not arise in nonmigraine patients treated with opiates, “suggesting that migraine is specifically prone to opiate-induced hyperalgesia of migraine itself,” said Dr. Gottschalk.

Even under careful monitoring, misuse occurs in more than 50% of patients, “suggesting that even under the best circumstances, it is difficult to use this class of drugs safely in long term,” said Dr. Gottschalk.

He pointed out that the risk of drug addiction rises with various clinical and socioeconomic factors, including living in impoverished environments, adverse childhood experiences, low socioeconomic status, exposure to pollutants, and stressors. “In other words, all features associated with systemic racism are clearly associated with an increased risk of addiction,” said Dr. Gottschalk. Other factors include availability of the drug, such as whether or not a physician prescribes it, and repeated use.

These concerns, combined with positive-reinforcing properties of opiates and association with migraine progression and refractoriness, and the lack of progression risk found with use of NSAIDs and triptans, and the fact that effective acute therapy is associated with a lower risk of progression, argue against the use of opiates, said Dr. Gottschalk.

There is even a potential risk that the experience of migraine and its relief due to self-administration may become a rewarding experience that propagates the problem. It’s possible that anticipatory anxiety related to fear stressors could lead to migraine, or to physical sensations interpreted as migraine prodrome. “[It] raises the question of whether or not positive reinforcement by drugs makes migraine itself a rewarding experience and therefore more likely to occur as a cue for drug self-administration. The question I pose is: Is there any reason to test this theory in drugs of no proven benefit in the treatment of migraine? I would say very clearly, No,” said Dr. Gottschalk.
 

Clarifying the finer points of the debate

In the Q&A session after the talk, Dr. Rizzoli said that he doesn’t advocate for long-term use of opiates, except in rare cases where the diagnosis gets changed to a chronic pain syndrome. “We’re talking about intermittent use for treatment of an acute event. Do we put limits on them? I think the answer is clearly Yes, and the limits are more strict than those for triptans. My own sense as a clinician is I want all of the available tools. From a clinical perspective, there are a large number of people who do just fine with intermittent use of these medicines, and so I wouldn’t restrict them,” said Dr. Rizzoli.

Dr. Gottschalk agreed that opiates may make sense for some patients, but expressed concerns about any and all physicians prescribing them. “The part about the tools is partly a question of: Who gets to use them? In the hands of a headache specialist in those isolated cases with careful restrictions, sure. But what I’m making is a slippery slope argument: What we know is that in emergency rooms, these are used routinely, and that [those] patients are precisely the ones who are at higher risk of addiction. So in some sense, I’m just saying I think we need to have much clearer boundaries,” he said.

Dr. Rizzoli has no relevant financial disclosures. Dr. Gottschalk has been on the advisory boards of Alder, AbbVie, Amgen/Novartis, Biohaven, Theranica, Upsher-Smith, Axsome, Vorso, Currax, and Impel. He has been a consultant for Alder, Alexion, and Spherix Global Insights. He has received research support from Relivion.