Among postmenopausal women who received an epidural steroid injection (ESI) in the lumbar spine to treat back and leg pain arising from a compressed nerve in the spine, levels of bone formation biomarkers were decreased. The decrease in levels persisted more than 12 weeks, results from a new study show.

In addition, serum cortisol levels decreased by 50% at week 1 after the ESI, indicating systemic absorption of the steroid.

“The extent and duration of these effects suggest that patients who receive multiple [ESIs in the lumbar spine] may be at particular risk for harmful skeletal consequences,” Shannon Clare reported in an oral presentation at the annual meeting of the American Society for Bone and Mineral Research.

Further studies are needed of the relationship between these short-term changes in bone turnover and bone loss and the risk for fracture among the burgeoning population treated with ESIs, added Ms. Clare, of the Hospital for Special Surgery, New York.

The researchers examined changes in serum levels of bone formation and resorption markers and other analytes in 24 women who received a lumbar ESI for radicular back pain and in 8 other women from the hospital population who served as control persons.

Among the women who received ESI, 1 week after the injection, serum levels of two bone formation biomarkers – total procollagen type 1 N-terminal peptide (P1NP) and osteocalcin – were about 27% lower than at baseline. The suppression persisted beyond 12 weeks.

Serum levels of the bone resorption biomarker C-terminal telopeptide of type I collagen (CTX) did not differ significantly after ESI.

“Our results are notable because we found that the duration of suppression of bone formation extended beyond 12 weeks, a far longer duration than seen previously with intra-articular injections” of glucocorticoids, said Ms. Clare and senior author Emily M. Stein, MD, director of research for the Metabolic Bone Service and an endocrinologist at the Hospital for Special Surgery and is associate professor of medicine at Weill Cornell Medicine, both in New York.

The findings suggest that patients should not receive multiple doses within a 12-week period, they told this news organization in a joint email response.

Women are not typically screened for osteopenia or osteoporosis before ESI. However, “our results suggest that physicians should consider screening women for osteoporosis who receive ESI, particularly those who are treated with multiple doses,” said Ms. Clare and Dr. Stein. “Steroid exposure should be minimized as much as possible by having patients space injections as far as they can tolerate.”
 

Systemic absorption, negative impact on bone turnover markers

“The hypothesis that [ESIs] interfere with the vertebral osseous microenvironment and increase the risk of vertebral fractures has been supported with evidence in the literature,” Mohamad Bydon, MD, professor of neurosurgery, orthopedic surgery, and health services research at the Mayo Clinic, Rochester, Minn., said in an interview.

Prior studies have demonstrated a decrease in bone mineral density (BMD) and an increase in vertebral fractures following ESI, added Dr. Bydon, senior author of a 2018 review of the effect of ESI on BMD and vertebral fracture risk that was published in Pain Medicine. He was not involved with the current study.

“The article by Clare et al. provides evidence on the systemic absorption of glucocorticoids by demonstrating a drop in serum cortisol following ESI,” he noted. “The measurement of bone metabolism biomarkers offers molecular confirmation of clinical and radiological observations of previous studies” showing that ESI affects the vertebrae.
 

More than 9 million ESIs each year

Each year, more than 9 million ESIs are administered to patients in the United States to relieve radicular back and leg pain that may be caused by a herniated disc or spinal stenosis (a gradual narrowing of the open spaces in the spinal column, which is common in older adults), the researchers explained.

Some patients experience sufficient pain relief with ESIs. Others may not be eligible for surgery and may receive multiple ESIs annually for many years because they provide pain relief.

It is well established that oral and intravenous glucocorticoids profoundly suppress bone formation and transiently increase bone resorption, causing substantial bone loss and increased fracture risk within 3 months of administration, Ms. Clare explained in the session.

Long-term use of high-dose inhaled glucocorticoids has been associated with bone loss and fractures. However, the effect of ESIs on bone has been less well studied.

The researchers hypothesized that ESIs are systemically absorbed and cause suppression of bone formation without a compensatory decrease in bone resorption.

They enrolled 24 patients who had undergone lumbar ESIs and 8 control patients. The mean age of the patients in the two groups was 63 years and 68 years, respectively. Most patients were White (88% and 100%, respectively). The mean body mass index was 27 kg/m² and 28 kg/m², respectively. On average, the patients had entered menopause 12 and 16 years earlier, respectively.

In the group that received steroid injections, almost two-thirds (15 patients, 63%) received triamcinolone. The rest received dexamethasone (six patients, 25%) or betamethasone (three patients, 12%) at doses that were equivalent to 80 mg triamcinolone.

The patients’ baseline serum levels of 25-hydroxy vitamin D, parathyroid hormone, cortisol, P1NP, osteocalcin, and CTX were within the reference ranges and were similar in the two groups.

The researchers also determined serum levels of cortisol (to assess suppression of endogenous glucocorticoids), osteocalcin, P1NP, and CTX in the patients and control persons at 1, 4, 12, 26, and 52 weeks after patients had received the ESI.

The researchers acknowledged that the small sample is a study limitation. In addition, the first serum samples were taken 1 week after the injection, and so any earlier changes in analyte levels were not captured. The patients also received different types of steroids, although the doses were similar when converted to triamcinolone equivalents.

The study was supported by a Spine Service grant from the Hospital for Special Surgery. The authors disclosed no relevant financial relationships.

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

Among postmenopausal women who received an epidural steroid injection (ESI) in the lumbar spine to treat back and leg pain arising from a compressed nerve in the spine, levels of bone formation biomarkers were decreased. The decrease in levels persisted more than 12 weeks, results from a new study show.

In addition, serum cortisol levels decreased by 50% at week 1 after the ESI, indicating systemic absorption of the steroid.

“The extent and duration of these effects suggest that patients who receive multiple [ESIs in the lumbar spine] may be at particular risk for harmful skeletal consequences,” Shannon Clare reported in an oral presentation at the annual meeting of the American Society for Bone and Mineral Research.

Further studies are needed of the relationship between these short-term changes in bone turnover and bone loss and the risk for fracture among the burgeoning population treated with ESIs, added Ms. Clare, of the Hospital for Special Surgery, New York.

The researchers examined changes in serum levels of bone formation and resorption markers and other analytes in 24 women who received a lumbar ESI for radicular back pain and in 8 other women from the hospital population who served as control persons.

Among the women who received ESI, 1 week after the injection, serum levels of two bone formation biomarkers – total procollagen type 1 N-terminal peptide (P1NP) and osteocalcin – were about 27% lower than at baseline. The suppression persisted beyond 12 weeks.

Serum levels of the bone resorption biomarker C-terminal telopeptide of type I collagen (CTX) did not differ significantly after ESI.

“Our results are notable because we found that the duration of suppression of bone formation extended beyond 12 weeks, a far longer duration than seen previously with intra-articular injections” of glucocorticoids, said Ms. Clare and senior author Emily M. Stein, MD, director of research for the Metabolic Bone Service and an endocrinologist at the Hospital for Special Surgery and is associate professor of medicine at Weill Cornell Medicine, both in New York.

The findings suggest that patients should not receive multiple doses within a 12-week period, they told this news organization in a joint email response.

Women are not typically screened for osteopenia or osteoporosis before ESI. However, “our results suggest that physicians should consider screening women for osteoporosis who receive ESI, particularly those who are treated with multiple doses,” said Ms. Clare and Dr. Stein. “Steroid exposure should be minimized as much as possible by having patients space injections as far as they can tolerate.”
 

Systemic absorption, negative impact on bone turnover markers

“The hypothesis that [ESIs] interfere with the vertebral osseous microenvironment and increase the risk of vertebral fractures has been supported with evidence in the literature,” Mohamad Bydon, MD, professor of neurosurgery, orthopedic surgery, and health services research at the Mayo Clinic, Rochester, Minn., said in an interview.

Prior studies have demonstrated a decrease in bone mineral density (BMD) and an increase in vertebral fractures following ESI, added Dr. Bydon, senior author of a 2018 review of the effect of ESI on BMD and vertebral fracture risk that was published in Pain Medicine. He was not involved with the current study.

“The article by Clare et al. provides evidence on the systemic absorption of glucocorticoids by demonstrating a drop in serum cortisol following ESI,” he noted. “The measurement of bone metabolism biomarkers offers molecular confirmation of clinical and radiological observations of previous studies” showing that ESI affects the vertebrae.
 

More than 9 million ESIs each year

Each year, more than 9 million ESIs are administered to patients in the United States to relieve radicular back and leg pain that may be caused by a herniated disc or spinal stenosis (a gradual narrowing of the open spaces in the spinal column, which is common in older adults), the researchers explained.

Some patients experience sufficient pain relief with ESIs. Others may not be eligible for surgery and may receive multiple ESIs annually for many years because they provide pain relief.

It is well established that oral and intravenous glucocorticoids profoundly suppress bone formation and transiently increase bone resorption, causing substantial bone loss and increased fracture risk within 3 months of administration, Ms. Clare explained in the session.

Long-term use of high-dose inhaled glucocorticoids has been associated with bone loss and fractures. However, the effect of ESIs on bone has been less well studied.

The researchers hypothesized that ESIs are systemically absorbed and cause suppression of bone formation without a compensatory decrease in bone resorption.

They enrolled 24 patients who had undergone lumbar ESIs and 8 control patients. The mean age of the patients in the two groups was 63 years and 68 years, respectively. Most patients were White (88% and 100%, respectively). The mean body mass index was 27 kg/m² and 28 kg/m², respectively. On average, the patients had entered menopause 12 and 16 years earlier, respectively.

In the group that received steroid injections, almost two-thirds (15 patients, 63%) received triamcinolone. The rest received dexamethasone (six patients, 25%) or betamethasone (three patients, 12%) at doses that were equivalent to 80 mg triamcinolone.

The patients’ baseline serum levels of 25-hydroxy vitamin D, parathyroid hormone, cortisol, P1NP, osteocalcin, and CTX were within the reference ranges and were similar in the two groups.

The researchers also determined serum levels of cortisol (to assess suppression of endogenous glucocorticoids), osteocalcin, P1NP, and CTX in the patients and control persons at 1, 4, 12, 26, and 52 weeks after patients had received the ESI.

The researchers acknowledged that the small sample is a study limitation. In addition, the first serum samples were taken 1 week after the injection, and so any earlier changes in analyte levels were not captured. The patients also received different types of steroids, although the doses were similar when converted to triamcinolone equivalents.

The study was supported by a Spine Service grant from the Hospital for Special Surgery. The authors disclosed no relevant financial relationships.

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

Among postmenopausal women who received an epidural steroid injection (ESI) in the lumbar spine to treat back and leg pain arising from a compressed nerve in the spine, levels of bone formation biomarkers were decreased. The decrease in levels persisted more than 12 weeks, results from a new study show.

In addition, serum cortisol levels decreased by 50% at week 1 after the ESI, indicating systemic absorption of the steroid.

“The extent and duration of these effects suggest that patients who receive multiple [ESIs in the lumbar spine] may be at particular risk for harmful skeletal consequences,” Shannon Clare reported in an oral presentation at the annual meeting of the American Society for Bone and Mineral Research.

Further studies are needed of the relationship between these short-term changes in bone turnover and bone loss and the risk for fracture among the burgeoning population treated with ESIs, added Ms. Clare, of the Hospital for Special Surgery, New York.

The researchers examined changes in serum levels of bone formation and resorption markers and other analytes in 24 women who received a lumbar ESI for radicular back pain and in 8 other women from the hospital population who served as control persons.

Among the women who received ESI, 1 week after the injection, serum levels of two bone formation biomarkers – total procollagen type 1 N-terminal peptide (P1NP) and osteocalcin – were about 27% lower than at baseline. The suppression persisted beyond 12 weeks.

Serum levels of the bone resorption biomarker C-terminal telopeptide of type I collagen (CTX) did not differ significantly after ESI.

“Our results are notable because we found that the duration of suppression of bone formation extended beyond 12 weeks, a far longer duration than seen previously with intra-articular injections” of glucocorticoids, said Ms. Clare and senior author Emily M. Stein, MD, director of research for the Metabolic Bone Service and an endocrinologist at the Hospital for Special Surgery and is associate professor of medicine at Weill Cornell Medicine, both in New York.

The findings suggest that patients should not receive multiple doses within a 12-week period, they told this news organization in a joint email response.

Women are not typically screened for osteopenia or osteoporosis before ESI. However, “our results suggest that physicians should consider screening women for osteoporosis who receive ESI, particularly those who are treated with multiple doses,” said Ms. Clare and Dr. Stein. “Steroid exposure should be minimized as much as possible by having patients space injections as far as they can tolerate.”
 

Systemic absorption, negative impact on bone turnover markers

“The hypothesis that [ESIs] interfere with the vertebral osseous microenvironment and increase the risk of vertebral fractures has been supported with evidence in the literature,” Mohamad Bydon, MD, professor of neurosurgery, orthopedic surgery, and health services research at the Mayo Clinic, Rochester, Minn., said in an interview.

Prior studies have demonstrated a decrease in bone mineral density (BMD) and an increase in vertebral fractures following ESI, added Dr. Bydon, senior author of a 2018 review of the effect of ESI on BMD and vertebral fracture risk that was published in Pain Medicine. He was not involved with the current study.

“The article by Clare et al. provides evidence on the systemic absorption of glucocorticoids by demonstrating a drop in serum cortisol following ESI,” he noted. “The measurement of bone metabolism biomarkers offers molecular confirmation of clinical and radiological observations of previous studies” showing that ESI affects the vertebrae.
 

More than 9 million ESIs each year

Each year, more than 9 million ESIs are administered to patients in the United States to relieve radicular back and leg pain that may be caused by a herniated disc or spinal stenosis (a gradual narrowing of the open spaces in the spinal column, which is common in older adults), the researchers explained.

Some patients experience sufficient pain relief with ESIs. Others may not be eligible for surgery and may receive multiple ESIs annually for many years because they provide pain relief.

It is well established that oral and intravenous glucocorticoids profoundly suppress bone formation and transiently increase bone resorption, causing substantial bone loss and increased fracture risk within 3 months of administration, Ms. Clare explained in the session.

Long-term use of high-dose inhaled glucocorticoids has been associated with bone loss and fractures. However, the effect of ESIs on bone has been less well studied.

The researchers hypothesized that ESIs are systemically absorbed and cause suppression of bone formation without a compensatory decrease in bone resorption.

They enrolled 24 patients who had undergone lumbar ESIs and 8 control patients. The mean age of the patients in the two groups was 63 years and 68 years, respectively. Most patients were White (88% and 100%, respectively). The mean body mass index was 27 kg/m² and 28 kg/m², respectively. On average, the patients had entered menopause 12 and 16 years earlier, respectively.

In the group that received steroid injections, almost two-thirds (15 patients, 63%) received triamcinolone. The rest received dexamethasone (six patients, 25%) or betamethasone (three patients, 12%) at doses that were equivalent to 80 mg triamcinolone.

The patients’ baseline serum levels of 25-hydroxy vitamin D, parathyroid hormone, cortisol, P1NP, osteocalcin, and CTX were within the reference ranges and were similar in the two groups.

The researchers also determined serum levels of cortisol (to assess suppression of endogenous glucocorticoids), osteocalcin, P1NP, and CTX in the patients and control persons at 1, 4, 12, 26, and 52 weeks after patients had received the ESI.

The researchers acknowledged that the small sample is a study limitation. In addition, the first serum samples were taken 1 week after the injection, and so any earlier changes in analyte levels were not captured. The patients also received different types of steroids, although the doses were similar when converted to triamcinolone equivalents.

The study was supported by a Spine Service grant from the Hospital for Special Surgery. The authors disclosed no relevant financial relationships.

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

Background: Daily labs are often unnecessary on clinically stable inpatients. Additionally, daily labs are frequently drawn very early in the morning, resulting in sleep disruptions. No prior studies have attempted an EHR-based intervention to simultaneously improve both frequency and timing of labs.

Dr. Lockwood is a hospitalist and chief of quality, performance, and patient safety at the Lexington (Ky.) VA Health Care System.

Background: Daily labs are often unnecessary on clinically stable inpatients. Additionally, daily labs are frequently drawn very early in the morning, resulting in sleep disruptions. No prior studies have attempted an EHR-based intervention to simultaneously improve both frequency and timing of labs.

Dr. Lockwood is a hospitalist and chief of quality, performance, and patient safety at the Lexington (Ky.) VA Health Care System.

Background: Daily labs are often unnecessary on clinically stable inpatients. Additionally, daily labs are frequently drawn very early in the morning, resulting in sleep disruptions. No prior studies have attempted an EHR-based intervention to simultaneously improve both frequency and timing of labs.

Dr. Lockwood is a hospitalist and chief of quality, performance, and patient safety at the Lexington (Ky.) VA Health Care System.

A new U.S. government study shows it isn’t risky and may even be a good idea to mix, rather than match, COVID-19 vaccines when getting a booster dose.

The study also shows mixing different kinds of vaccines appears to spur the body to make higher levels of virus-blocking antibodies than they would have gotten by boosting with a dose of the vaccine the person already had.

If regulators endorse the study findings, it should make getting a COVID-19 booster as easy as getting a yearly influenza vaccine.

“Currently when you go to do your flu shot nobody asks you what kind you had last year. Nobody cares what you had last year. And we were hoping that that was the same — that we would be able to boost regardless of what you had [previously],” said the study’s senior author, John Beigel, MD, who is associate director for clinical research in the division of microbiology and infectious diseases at the National Institutes of Health.

“But we needed to have the data,” he said.

Studies have suggested that higher antibody levels translate into better protection against disease, though the exact level that confers protection is not yet known.

“The antibody responses are so much higher [with mix and match], it’s really impressive,” said William Schaffner, MD, an infectious disease specialist at Vanderbilt University in Nashville, who was not involved in the study.

Dr. Shaffner said if the U.S. Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) sign off on the approach, he would especially recommend that people who got the Johnson & Johnson vaccine follow up with a dose of an mRNA vaccine from Pfizer or Moderna.

“It is a broader stimulation of the immune system, and I think that broader stimulation is advantageous,” he said.

Minimal side effects

The preprint study was published late Oct. 13 in medRxiv ahead of peer review, just before a slate of meetings involving vaccine experts that advise the FDA and CDC. 

These experts are tasked with trying to figure out whether additional shots of Moderna and Johnson & Johnson vaccines are safe and effective for boosting immunity against COVID-19.

The FDA’s panel is the Vaccines and Related Biological Products Advisory Committee (VRBPAC), and the CDC’s panel is the Advisory Committee on Immunization Practices (ACIP). 

During the pandemic, they have been meeting almost in lock step to tackle important vaccine-related questions.

“We got this data out because we knew VRBPAC was coming and we knew ACIP was going to grapple with these issues,” Dr. Beigel said.

He noted that these are just the first results. The study will continue for a year, and the researchers aim to deeply characterize the breadth and depth of the immune response to all nine of the different vaccine combinations included in the study.

The study included 458 participants at 10 study sites around the country who had been fully vaccinated with one of the three COVID-19 vaccines authorized for use in the United States: Moderna, Johnson & Johnson, or Pfizer-BioNTech. 

About 150 study participants were recruited from each group. Everyone in the study had finished their primary series at least 12 weeks before starting the study. None had a prior SARS-CoV-2 infection.

About 50 participants from each vaccine group were randomly assigned to get a third (booster) dose of either the same vaccine as the one they had already received, or a different vaccine, creating nine possible combinations of shots.

About half of study participants reported mild side effects — including pain at the injection site, fatigue, headache, and muscle aches.

Two study participants had serious medical problems during the study, but they were judged to be unrelated to vaccination. One study participant experienced kidney failure after their muscles broke down following a fall. The other experienced cholecystitis, or an inflamed gallbladder. 

Up to 1 month after the booster shots, no other serious adverse events were seen.

The study didn’t look at whether people got COVID-19, so it’s not possible to say that they were better protected against disease after their boosters.

Increase in antibodies

But all the groups saw substantial increases in their antibody levels, which is thought to indicate that they were better protected.

Overall, groups that got the same vaccine as their primary series saw 4 to 20-fold increases in their antibody levels. Groups that got different shots than the ones in their primary series got 6 to 76 fold increases in their antibody levels.

People who had originally gotten a Johnson & Johnson vaccine saw far bigger increases in antibodies, and were more likely to see a protective rise in antibodies if they got a second dose of an mRNA vaccine.

Dr. Schaffner noted that European countries had already been mixing the vaccine doses this way, giving people who had received the AstraZeneca vaccine, which is similar to the Johnson & Johnson shot, another dose of an mRNA vaccine.

German Chancellor Angela Merkel received a Moderna vaccine for her second dose after an initial shot of the Oxford-AstraZeneca vaccines, for example.

No safety signals related to mixing vaccines has been seen in countries that routinely use the approach for their initial series.

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

A new U.S. government study shows it isn’t risky and may even be a good idea to mix, rather than match, COVID-19 vaccines when getting a booster dose.

The study also shows mixing different kinds of vaccines appears to spur the body to make higher levels of virus-blocking antibodies than they would have gotten by boosting with a dose of the vaccine the person already had.

If regulators endorse the study findings, it should make getting a COVID-19 booster as easy as getting a yearly influenza vaccine.

“Currently when you go to do your flu shot nobody asks you what kind you had last year. Nobody cares what you had last year. And we were hoping that that was the same — that we would be able to boost regardless of what you had [previously],” said the study’s senior author, John Beigel, MD, who is associate director for clinical research in the division of microbiology and infectious diseases at the National Institutes of Health.

“But we needed to have the data,” he said.

Studies have suggested that higher antibody levels translate into better protection against disease, though the exact level that confers protection is not yet known.

“The antibody responses are so much higher [with mix and match], it’s really impressive,” said William Schaffner, MD, an infectious disease specialist at Vanderbilt University in Nashville, who was not involved in the study.

Dr. Shaffner said if the U.S. Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) sign off on the approach, he would especially recommend that people who got the Johnson & Johnson vaccine follow up with a dose of an mRNA vaccine from Pfizer or Moderna.

“It is a broader stimulation of the immune system, and I think that broader stimulation is advantageous,” he said.

Minimal side effects

The preprint study was published late Oct. 13 in medRxiv ahead of peer review, just before a slate of meetings involving vaccine experts that advise the FDA and CDC. 

These experts are tasked with trying to figure out whether additional shots of Moderna and Johnson & Johnson vaccines are safe and effective for boosting immunity against COVID-19.

The FDA’s panel is the Vaccines and Related Biological Products Advisory Committee (VRBPAC), and the CDC’s panel is the Advisory Committee on Immunization Practices (ACIP). 

During the pandemic, they have been meeting almost in lock step to tackle important vaccine-related questions.

“We got this data out because we knew VRBPAC was coming and we knew ACIP was going to grapple with these issues,” Dr. Beigel said.

He noted that these are just the first results. The study will continue for a year, and the researchers aim to deeply characterize the breadth and depth of the immune response to all nine of the different vaccine combinations included in the study.

The study included 458 participants at 10 study sites around the country who had been fully vaccinated with one of the three COVID-19 vaccines authorized for use in the United States: Moderna, Johnson & Johnson, or Pfizer-BioNTech. 

About 150 study participants were recruited from each group. Everyone in the study had finished their primary series at least 12 weeks before starting the study. None had a prior SARS-CoV-2 infection.

About 50 participants from each vaccine group were randomly assigned to get a third (booster) dose of either the same vaccine as the one they had already received, or a different vaccine, creating nine possible combinations of shots.

About half of study participants reported mild side effects — including pain at the injection site, fatigue, headache, and muscle aches.

Two study participants had serious medical problems during the study, but they were judged to be unrelated to vaccination. One study participant experienced kidney failure after their muscles broke down following a fall. The other experienced cholecystitis, or an inflamed gallbladder. 

Up to 1 month after the booster shots, no other serious adverse events were seen.

The study didn’t look at whether people got COVID-19, so it’s not possible to say that they were better protected against disease after their boosters.

Increase in antibodies

But all the groups saw substantial increases in their antibody levels, which is thought to indicate that they were better protected.

Overall, groups that got the same vaccine as their primary series saw 4 to 20-fold increases in their antibody levels. Groups that got different shots than the ones in their primary series got 6 to 76 fold increases in their antibody levels.

People who had originally gotten a Johnson & Johnson vaccine saw far bigger increases in antibodies, and were more likely to see a protective rise in antibodies if they got a second dose of an mRNA vaccine.

Dr. Schaffner noted that European countries had already been mixing the vaccine doses this way, giving people who had received the AstraZeneca vaccine, which is similar to the Johnson & Johnson shot, another dose of an mRNA vaccine.

German Chancellor Angela Merkel received a Moderna vaccine for her second dose after an initial shot of the Oxford-AstraZeneca vaccines, for example.

No safety signals related to mixing vaccines has been seen in countries that routinely use the approach for their initial series.

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

A new U.S. government study shows it isn’t risky and may even be a good idea to mix, rather than match, COVID-19 vaccines when getting a booster dose.

The study also shows mixing different kinds of vaccines appears to spur the body to make higher levels of virus-blocking antibodies than they would have gotten by boosting with a dose of the vaccine the person already had.

If regulators endorse the study findings, it should make getting a COVID-19 booster as easy as getting a yearly influenza vaccine.

“Currently when you go to do your flu shot nobody asks you what kind you had last year. Nobody cares what you had last year. And we were hoping that that was the same — that we would be able to boost regardless of what you had [previously],” said the study’s senior author, John Beigel, MD, who is associate director for clinical research in the division of microbiology and infectious diseases at the National Institutes of Health.

“But we needed to have the data,” he said.

Studies have suggested that higher antibody levels translate into better protection against disease, though the exact level that confers protection is not yet known.

“The antibody responses are so much higher [with mix and match], it’s really impressive,” said William Schaffner, MD, an infectious disease specialist at Vanderbilt University in Nashville, who was not involved in the study.

Dr. Shaffner said if the U.S. Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) sign off on the approach, he would especially recommend that people who got the Johnson & Johnson vaccine follow up with a dose of an mRNA vaccine from Pfizer or Moderna.

“It is a broader stimulation of the immune system, and I think that broader stimulation is advantageous,” he said.

Minimal side effects

The preprint study was published late Oct. 13 in medRxiv ahead of peer review, just before a slate of meetings involving vaccine experts that advise the FDA and CDC. 

These experts are tasked with trying to figure out whether additional shots of Moderna and Johnson & Johnson vaccines are safe and effective for boosting immunity against COVID-19.

The FDA’s panel is the Vaccines and Related Biological Products Advisory Committee (VRBPAC), and the CDC’s panel is the Advisory Committee on Immunization Practices (ACIP). 

During the pandemic, they have been meeting almost in lock step to tackle important vaccine-related questions.

“We got this data out because we knew VRBPAC was coming and we knew ACIP was going to grapple with these issues,” Dr. Beigel said.

He noted that these are just the first results. The study will continue for a year, and the researchers aim to deeply characterize the breadth and depth of the immune response to all nine of the different vaccine combinations included in the study.

The study included 458 participants at 10 study sites around the country who had been fully vaccinated with one of the three COVID-19 vaccines authorized for use in the United States: Moderna, Johnson & Johnson, or Pfizer-BioNTech. 

About 150 study participants were recruited from each group. Everyone in the study had finished their primary series at least 12 weeks before starting the study. None had a prior SARS-CoV-2 infection.

About 50 participants from each vaccine group were randomly assigned to get a third (booster) dose of either the same vaccine as the one they had already received, or a different vaccine, creating nine possible combinations of shots.

About half of study participants reported mild side effects — including pain at the injection site, fatigue, headache, and muscle aches.

Two study participants had serious medical problems during the study, but they were judged to be unrelated to vaccination. One study participant experienced kidney failure after their muscles broke down following a fall. The other experienced cholecystitis, or an inflamed gallbladder. 

Up to 1 month after the booster shots, no other serious adverse events were seen.

The study didn’t look at whether people got COVID-19, so it’s not possible to say that they were better protected against disease after their boosters.

Increase in antibodies

But all the groups saw substantial increases in their antibody levels, which is thought to indicate that they were better protected.

Overall, groups that got the same vaccine as their primary series saw 4 to 20-fold increases in their antibody levels. Groups that got different shots than the ones in their primary series got 6 to 76 fold increases in their antibody levels.

People who had originally gotten a Johnson & Johnson vaccine saw far bigger increases in antibodies, and were more likely to see a protective rise in antibodies if they got a second dose of an mRNA vaccine.

Dr. Schaffner noted that European countries had already been mixing the vaccine doses this way, giving people who had received the AstraZeneca vaccine, which is similar to the Johnson & Johnson shot, another dose of an mRNA vaccine.

German Chancellor Angela Merkel received a Moderna vaccine for her second dose after an initial shot of the Oxford-AstraZeneca vaccines, for example.

No safety signals related to mixing vaccines has been seen in countries that routinely use the approach for their initial series.

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

A clinical practice update expert review from the American Gastroenterological Association gives advice on management of endoscopic perforations in the gastrointestinal tract, including esophageal, gastric, duodenal and periampullary, and colon perforation.

There are various techniques for dealing with perforations, including through-the-scope clips (TTSCs), over-the-scope clips (OTSCs), self-expanding metal stents (SEMS), and endoscopic suturing. Newer methods include biological glue and esophageal vacuum therapy. These techniques have been the subject of various retrospective analyses, but few prospective studies have examined their safety and efficacy.

In the expert review, published in Clinical Gastroenterology and Hepatology, authors led by Jeffrey H. Lee, MD, MPH, AGAF, of the department of gastroenterology at the University of Texas MD Anderson Cancer Center, Houston, emphasized that gastroenterologists should have a perforation protocol in place and practice procedures that will be used to address perforations. Endoscopists should also recognize their own limits and know when a patient should be sent to experienced, high-volume centers for further care.

In the event of a perforation, the entire team should be notified immediately, and carbon dioxide insufflation should be used at a low flow setting. The endoscopist should clean up luminal material to reduce the chance of peritoneal contamination, and then treat with an antibiotic regimen that counters gram-negative and anaerobic bacteria.
 

Esophageal perforation

Esophageal perforations most commonly occur during dilation of strictures, endoscopic mucosal resection (EMR), and endoscopic submucosal dissection (ESD). Perforations of the mucosal flap may happen during so-called third-space endoscopy techniques like peroral endoscopic myotomy (POEM). Small perforations can be readily addressed with TTSCs. Larger perforations call for some combination of TTSCs, endoscopic suturing, fibrin glue injection, or esophageal stenting, though the latter is discouraged because of the potential for erosion.

A more concerning complication of POEM is delayed barrier failure, which can cause leaks, mediastinitis, or peritonitis. These complications have been estimated to occur in 0.2%-1.1% of cases.

In the event of an esophageal perforation, the area should be kept clean by suctioning, or by altering patient position if required. Perforations 1-2 cm in size can be closed using OTSCs. Excessive bleeding or larger tears can be addressed using a fully covered SEMS.

Leaks that occur in the ensuing days after the procedure should be closed using TTSCs, OTSCs, or endosuturing, followed by putting in a fully covered stent. Esophageal fistula should be addressed with a fully covered stent with a tight fit.

Endoscopic vacuum therapy is a newer technique to address large or persistent esophageal perforations. A review found it had a 96% success rate for esophageal perforations.
 

Gastric perforations

Gastric perforations often result from peptic ulcer disease or ingestion of something caustic, and it is a high risk during EMR and ESD procedures (0.4%-0.7% intraprocedural risk). The proximal gastric wall isn’t thick as in the gastric antrum, so proximal endoscopic resections require extra care. Lengthy procedures should be done under anesthesia. Ongoing gaseous insufflation during a perforation may worsen the problem because of heightened intraperitoneal pressure. OTSCs may be a better choice than TTSCs for 1-3 cm perforations, while endoloop/TTSC can be used for larger ones.

Duodenal and periampullary perforations

Duodenal and periampullary perforations occur during duodenal stricture dilation, EMR, endoscopic submucosal dissection, endoscopic ultrasound, and endoscopic retrograde cholangiopancreatography (ECRP). The thin duodenal wall makes it more susceptible to perforation than the esophagus, stomach, or colon.

Closing a duodenum perforation can be difficult. Type 1 perforations typically show sudden bleeding and lumen deflation, and often require surgical intervention. Some recent reports have suggested success with TTSCs, OTSCs, band ligation, and endoloops. Type 2 perforations are less obvious, and the endoscopist must examine the gas pattern on fluoroscopic beneath the liver or in the area of the right kidney. Retroperitoneal air following ERCP, if asymptomatic, doesn’t necessarily require intervention.

The challenges presented by the duodenum mean that, for large duodenal polyps, EMR should only be done by experienced endoscopists who are skilled at mucosal closure, and only experts should attempt ESD. Proteolytic enzymes from the pancreas can also pool in the duodenum, which can degrade muscle tissue and lead to delayed perforations. TTSC, OTSC, endosuturing, polymer gels or sheets, and TTSC combined with endoloop cinching have been used to close resection-associated perforations.
 

Colon perforation

Colon perforation may be caused by diverticulitis, inflammatory bowel disease, or occasionally colonic obstruction. Iatrogenic causes are more common and include endoscopic resection, hot forceps biopsy, dilation of stricture resulting from radiation or Crohn’s disease, colonic stenting, and advancement of colonoscope across angulations or into diverticula without straightening the endoscope

Large perforations are usually immediately noticeable and should be treated surgically, as should hemodynamic instability or delayed perforations with peritoneal signs.

Endoscopic closure should be attempted when the perforation site is clean, and lower rectal perforations can generally be repaired with TTSC, OTSC, or endoscopic suturing. In the cecum, or in a torturous or unclean colon, it may be difficult or dangerous to remove the colonoscope and insert an OTSC, and endoscopic suturing may not be possible, making TTSC the only procedure available for right colon perforations. The X-Tack Endoscopic HeliX Tacking System is a recently introduced, through-the-scope technology that places suture-tethered tacks into tissue surrounding the perforation and cinches it together. The system in principle can close large or irregular colonic and small bowel perforations using gastroscopes and colonoscopes, but no human studies have yet been published.
 

Conclusion

This update was a collaborative effort by four endoscopists who felt that it was timely to review the issue of perforations since they can be serious and challenging to manage. The evolution of endoscopic techniques over the last few years, however, has made the closure of spontaneous and iatrogenic perforations much less fear provoking, and they wished to summarize the approaches to a variety of such situations in order to guide practitioners who may encounter them.

“Although perforation is a serious event, with novel endoscopic techniques and tools, the endoscopist should no longer be paralyzed when it occurs,” the authors concluded.

Some authors reported relationships, such as consulting for or royalties from, device companies such as Medtronic and Boston Scientific. The remaining authors disclosed no conflicts.

This article was updated Oct. 25, 2021.

A clinical practice update expert review from the American Gastroenterological Association gives advice on management of endoscopic perforations in the gastrointestinal tract, including esophageal, gastric, duodenal and periampullary, and colon perforation.

There are various techniques for dealing with perforations, including through-the-scope clips (TTSCs), over-the-scope clips (OTSCs), self-expanding metal stents (SEMS), and endoscopic suturing. Newer methods include biological glue and esophageal vacuum therapy. These techniques have been the subject of various retrospective analyses, but few prospective studies have examined their safety and efficacy.

In the expert review, published in Clinical Gastroenterology and Hepatology, authors led by Jeffrey H. Lee, MD, MPH, AGAF, of the department of gastroenterology at the University of Texas MD Anderson Cancer Center, Houston, emphasized that gastroenterologists should have a perforation protocol in place and practice procedures that will be used to address perforations. Endoscopists should also recognize their own limits and know when a patient should be sent to experienced, high-volume centers for further care.

In the event of a perforation, the entire team should be notified immediately, and carbon dioxide insufflation should be used at a low flow setting. The endoscopist should clean up luminal material to reduce the chance of peritoneal contamination, and then treat with an antibiotic regimen that counters gram-negative and anaerobic bacteria.
 

Esophageal perforation

Esophageal perforations most commonly occur during dilation of strictures, endoscopic mucosal resection (EMR), and endoscopic submucosal dissection (ESD). Perforations of the mucosal flap may happen during so-called third-space endoscopy techniques like peroral endoscopic myotomy (POEM). Small perforations can be readily addressed with TTSCs. Larger perforations call for some combination of TTSCs, endoscopic suturing, fibrin glue injection, or esophageal stenting, though the latter is discouraged because of the potential for erosion.

A more concerning complication of POEM is delayed barrier failure, which can cause leaks, mediastinitis, or peritonitis. These complications have been estimated to occur in 0.2%-1.1% of cases.

In the event of an esophageal perforation, the area should be kept clean by suctioning, or by altering patient position if required. Perforations 1-2 cm in size can be closed using OTSCs. Excessive bleeding or larger tears can be addressed using a fully covered SEMS.

Leaks that occur in the ensuing days after the procedure should be closed using TTSCs, OTSCs, or endosuturing, followed by putting in a fully covered stent. Esophageal fistula should be addressed with a fully covered stent with a tight fit.

Endoscopic vacuum therapy is a newer technique to address large or persistent esophageal perforations. A review found it had a 96% success rate for esophageal perforations.
 

Gastric perforations

Gastric perforations often result from peptic ulcer disease or ingestion of something caustic, and it is a high risk during EMR and ESD procedures (0.4%-0.7% intraprocedural risk). The proximal gastric wall isn’t thick as in the gastric antrum, so proximal endoscopic resections require extra care. Lengthy procedures should be done under anesthesia. Ongoing gaseous insufflation during a perforation may worsen the problem because of heightened intraperitoneal pressure. OTSCs may be a better choice than TTSCs for 1-3 cm perforations, while endoloop/TTSC can be used for larger ones.

Duodenal and periampullary perforations

Duodenal and periampullary perforations occur during duodenal stricture dilation, EMR, endoscopic submucosal dissection, endoscopic ultrasound, and endoscopic retrograde cholangiopancreatography (ECRP). The thin duodenal wall makes it more susceptible to perforation than the esophagus, stomach, or colon.

Closing a duodenum perforation can be difficult. Type 1 perforations typically show sudden bleeding and lumen deflation, and often require surgical intervention. Some recent reports have suggested success with TTSCs, OTSCs, band ligation, and endoloops. Type 2 perforations are less obvious, and the endoscopist must examine the gas pattern on fluoroscopic beneath the liver or in the area of the right kidney. Retroperitoneal air following ERCP, if asymptomatic, doesn’t necessarily require intervention.

The challenges presented by the duodenum mean that, for large duodenal polyps, EMR should only be done by experienced endoscopists who are skilled at mucosal closure, and only experts should attempt ESD. Proteolytic enzymes from the pancreas can also pool in the duodenum, which can degrade muscle tissue and lead to delayed perforations. TTSC, OTSC, endosuturing, polymer gels or sheets, and TTSC combined with endoloop cinching have been used to close resection-associated perforations.
 

Colon perforation

Colon perforation may be caused by diverticulitis, inflammatory bowel disease, or occasionally colonic obstruction. Iatrogenic causes are more common and include endoscopic resection, hot forceps biopsy, dilation of stricture resulting from radiation or Crohn’s disease, colonic stenting, and advancement of colonoscope across angulations or into diverticula without straightening the endoscope

Large perforations are usually immediately noticeable and should be treated surgically, as should hemodynamic instability or delayed perforations with peritoneal signs.

Endoscopic closure should be attempted when the perforation site is clean, and lower rectal perforations can generally be repaired with TTSC, OTSC, or endoscopic suturing. In the cecum, or in a torturous or unclean colon, it may be difficult or dangerous to remove the colonoscope and insert an OTSC, and endoscopic suturing may not be possible, making TTSC the only procedure available for right colon perforations. The X-Tack Endoscopic HeliX Tacking System is a recently introduced, through-the-scope technology that places suture-tethered tacks into tissue surrounding the perforation and cinches it together. The system in principle can close large or irregular colonic and small bowel perforations using gastroscopes and colonoscopes, but no human studies have yet been published.
 

Conclusion

This update was a collaborative effort by four endoscopists who felt that it was timely to review the issue of perforations since they can be serious and challenging to manage. The evolution of endoscopic techniques over the last few years, however, has made the closure of spontaneous and iatrogenic perforations much less fear provoking, and they wished to summarize the approaches to a variety of such situations in order to guide practitioners who may encounter them.

“Although perforation is a serious event, with novel endoscopic techniques and tools, the endoscopist should no longer be paralyzed when it occurs,” the authors concluded.

Some authors reported relationships, such as consulting for or royalties from, device companies such as Medtronic and Boston Scientific. The remaining authors disclosed no conflicts.

This article was updated Oct. 25, 2021.

A clinical practice update expert review from the American Gastroenterological Association gives advice on management of endoscopic perforations in the gastrointestinal tract, including esophageal, gastric, duodenal and periampullary, and colon perforation.

There are various techniques for dealing with perforations, including through-the-scope clips (TTSCs), over-the-scope clips (OTSCs), self-expanding metal stents (SEMS), and endoscopic suturing. Newer methods include biological glue and esophageal vacuum therapy. These techniques have been the subject of various retrospective analyses, but few prospective studies have examined their safety and efficacy.

In the expert review, published in Clinical Gastroenterology and Hepatology, authors led by Jeffrey H. Lee, MD, MPH, AGAF, of the department of gastroenterology at the University of Texas MD Anderson Cancer Center, Houston, emphasized that gastroenterologists should have a perforation protocol in place and practice procedures that will be used to address perforations. Endoscopists should also recognize their own limits and know when a patient should be sent to experienced, high-volume centers for further care.

In the event of a perforation, the entire team should be notified immediately, and carbon dioxide insufflation should be used at a low flow setting. The endoscopist should clean up luminal material to reduce the chance of peritoneal contamination, and then treat with an antibiotic regimen that counters gram-negative and anaerobic bacteria.
 

Esophageal perforation

Esophageal perforations most commonly occur during dilation of strictures, endoscopic mucosal resection (EMR), and endoscopic submucosal dissection (ESD). Perforations of the mucosal flap may happen during so-called third-space endoscopy techniques like peroral endoscopic myotomy (POEM). Small perforations can be readily addressed with TTSCs. Larger perforations call for some combination of TTSCs, endoscopic suturing, fibrin glue injection, or esophageal stenting, though the latter is discouraged because of the potential for erosion.

A more concerning complication of POEM is delayed barrier failure, which can cause leaks, mediastinitis, or peritonitis. These complications have been estimated to occur in 0.2%-1.1% of cases.

In the event of an esophageal perforation, the area should be kept clean by suctioning, or by altering patient position if required. Perforations 1-2 cm in size can be closed using OTSCs. Excessive bleeding or larger tears can be addressed using a fully covered SEMS.

Leaks that occur in the ensuing days after the procedure should be closed using TTSCs, OTSCs, or endosuturing, followed by putting in a fully covered stent. Esophageal fistula should be addressed with a fully covered stent with a tight fit.

Endoscopic vacuum therapy is a newer technique to address large or persistent esophageal perforations. A review found it had a 96% success rate for esophageal perforations.
 

Gastric perforations

Gastric perforations often result from peptic ulcer disease or ingestion of something caustic, and it is a high risk during EMR and ESD procedures (0.4%-0.7% intraprocedural risk). The proximal gastric wall isn’t thick as in the gastric antrum, so proximal endoscopic resections require extra care. Lengthy procedures should be done under anesthesia. Ongoing gaseous insufflation during a perforation may worsen the problem because of heightened intraperitoneal pressure. OTSCs may be a better choice than TTSCs for 1-3 cm perforations, while endoloop/TTSC can be used for larger ones.

Duodenal and periampullary perforations

Duodenal and periampullary perforations occur during duodenal stricture dilation, EMR, endoscopic submucosal dissection, endoscopic ultrasound, and endoscopic retrograde cholangiopancreatography (ECRP). The thin duodenal wall makes it more susceptible to perforation than the esophagus, stomach, or colon.

Closing a duodenum perforation can be difficult. Type 1 perforations typically show sudden bleeding and lumen deflation, and often require surgical intervention. Some recent reports have suggested success with TTSCs, OTSCs, band ligation, and endoloops. Type 2 perforations are less obvious, and the endoscopist must examine the gas pattern on fluoroscopic beneath the liver or in the area of the right kidney. Retroperitoneal air following ERCP, if asymptomatic, doesn’t necessarily require intervention.

The challenges presented by the duodenum mean that, for large duodenal polyps, EMR should only be done by experienced endoscopists who are skilled at mucosal closure, and only experts should attempt ESD. Proteolytic enzymes from the pancreas can also pool in the duodenum, which can degrade muscle tissue and lead to delayed perforations. TTSC, OTSC, endosuturing, polymer gels or sheets, and TTSC combined with endoloop cinching have been used to close resection-associated perforations.
 

Colon perforation

Colon perforation may be caused by diverticulitis, inflammatory bowel disease, or occasionally colonic obstruction. Iatrogenic causes are more common and include endoscopic resection, hot forceps biopsy, dilation of stricture resulting from radiation or Crohn’s disease, colonic stenting, and advancement of colonoscope across angulations or into diverticula without straightening the endoscope

Large perforations are usually immediately noticeable and should be treated surgically, as should hemodynamic instability or delayed perforations with peritoneal signs.

Endoscopic closure should be attempted when the perforation site is clean, and lower rectal perforations can generally be repaired with TTSC, OTSC, or endoscopic suturing. In the cecum, or in a torturous or unclean colon, it may be difficult or dangerous to remove the colonoscope and insert an OTSC, and endoscopic suturing may not be possible, making TTSC the only procedure available for right colon perforations. The X-Tack Endoscopic HeliX Tacking System is a recently introduced, through-the-scope technology that places suture-tethered tacks into tissue surrounding the perforation and cinches it together. The system in principle can close large or irregular colonic and small bowel perforations using gastroscopes and colonoscopes, but no human studies have yet been published.
 

Conclusion

This update was a collaborative effort by four endoscopists who felt that it was timely to review the issue of perforations since they can be serious and challenging to manage. The evolution of endoscopic techniques over the last few years, however, has made the closure of spontaneous and iatrogenic perforations much less fear provoking, and they wished to summarize the approaches to a variety of such situations in order to guide practitioners who may encounter them.

“Although perforation is a serious event, with novel endoscopic techniques and tools, the endoscopist should no longer be paralyzed when it occurs,” the authors concluded.

Some authors reported relationships, such as consulting for or royalties from, device companies such as Medtronic and Boston Scientific. The remaining authors disclosed no conflicts.

This article was updated Oct. 25, 2021.

Homework adherence between behavior therapy sessions is a significant predictor of therapeutic improvement in patients with Tourette’s disorder (TD), a study of 119 youth and adults suggests.

The assigning of “homework” to be completed between sessions – often used in cognitive-behavioral therapy – has been shown to reinforce learning but has not been well studied in TD.

“Understanding the relationship between homework adherence and therapeutic improvement from behavior therapy for TD may offer new insights for enhancing tic severity reductions achieved during this evidence-based treatment,” wrote Joey Ka-Yee Essoe, PhD, of the department of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore, and colleagues.

To conduct the study, published in Behaviour Research and Therapy, the researchers recruited 70 youth and 49 adults with TD, ranging in age from 9 to 67 years, who underwent treatment at a single center. The average age was 21 years, and 80 participants were male. Treatment response was based on the Clinical Global Impressions of Improvement scale (CGI-I). Participants were assessed at baseline for tic severity and received eight sessions over 10 weeks. During those sessions, they were taught to perform a competing response to inhibit the expression of a tic when the tic or urge was detected.

Participants received homework at each weekly therapy session; most consisted of three to four practice sessions of about 30 minutes per week. Therapists reviewed the homework at the following session and adapted as needed to improve tic reduction skills.

After eight sessions of behavior therapy, overall greater homework adherence significantly predicted reduced tic severity and therapeutic improvement. However, early homework adherence predicted therapeutic improvement in youth, while late homework adherence predicted it in adults.

Overall, homework adherence significantly predicted tic reductions, compared with baseline (P = .037), based on the clinician-rated Yale Global Tic Severity Scale.

However, homework adherence dipped midway through treatment in youth and showed a linear decline in adults, the researchers noted.

Among youth, baseline predictors of early homework adherence included lower levels of hyperactivity/impulsivity and caregiver strain. Among adults, baseline predictors of early homework adherence included lower anger scores, less social disability, and greater work disability.

The study findings were limited by several factors, including the absence of complete data on baseline predictors of homework adherence, reliance on a single measure of tic severity and improvement, and reliance on therapists’ reports of homework adherence, the researchers noted.

Future research should include objective measures of homework adherence, such as time-stamped videos, and different strategies may be needed for youth vs. adults, they added.

“Strategies that optimize homework adherence may enhance the efficacy of behavioral therapy, lead to greater tic severity reductions, and higher treatment response rates,” Dr. Essoe and colleagues wrote.

The study was supported by the Tourette Association of America, the National Institute of Mental Health, the American Academy of Neurology, and the American Psychological Foundation.

Homework adherence between behavior therapy sessions is a significant predictor of therapeutic improvement in patients with Tourette’s disorder (TD), a study of 119 youth and adults suggests.

The assigning of “homework” to be completed between sessions – often used in cognitive-behavioral therapy – has been shown to reinforce learning but has not been well studied in TD.

“Understanding the relationship between homework adherence and therapeutic improvement from behavior therapy for TD may offer new insights for enhancing tic severity reductions achieved during this evidence-based treatment,” wrote Joey Ka-Yee Essoe, PhD, of the department of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore, and colleagues.

To conduct the study, published in Behaviour Research and Therapy, the researchers recruited 70 youth and 49 adults with TD, ranging in age from 9 to 67 years, who underwent treatment at a single center. The average age was 21 years, and 80 participants were male. Treatment response was based on the Clinical Global Impressions of Improvement scale (CGI-I). Participants were assessed at baseline for tic severity and received eight sessions over 10 weeks. During those sessions, they were taught to perform a competing response to inhibit the expression of a tic when the tic or urge was detected.

Participants received homework at each weekly therapy session; most consisted of three to four practice sessions of about 30 minutes per week. Therapists reviewed the homework at the following session and adapted as needed to improve tic reduction skills.

After eight sessions of behavior therapy, overall greater homework adherence significantly predicted reduced tic severity and therapeutic improvement. However, early homework adherence predicted therapeutic improvement in youth, while late homework adherence predicted it in adults.

Overall, homework adherence significantly predicted tic reductions, compared with baseline (P = .037), based on the clinician-rated Yale Global Tic Severity Scale.

However, homework adherence dipped midway through treatment in youth and showed a linear decline in adults, the researchers noted.

Among youth, baseline predictors of early homework adherence included lower levels of hyperactivity/impulsivity and caregiver strain. Among adults, baseline predictors of early homework adherence included lower anger scores, less social disability, and greater work disability.

The study findings were limited by several factors, including the absence of complete data on baseline predictors of homework adherence, reliance on a single measure of tic severity and improvement, and reliance on therapists’ reports of homework adherence, the researchers noted.

Future research should include objective measures of homework adherence, such as time-stamped videos, and different strategies may be needed for youth vs. adults, they added.

“Strategies that optimize homework adherence may enhance the efficacy of behavioral therapy, lead to greater tic severity reductions, and higher treatment response rates,” Dr. Essoe and colleagues wrote.

The study was supported by the Tourette Association of America, the National Institute of Mental Health, the American Academy of Neurology, and the American Psychological Foundation.

Homework adherence between behavior therapy sessions is a significant predictor of therapeutic improvement in patients with Tourette’s disorder (TD), a study of 119 youth and adults suggests.

The assigning of “homework” to be completed between sessions – often used in cognitive-behavioral therapy – has been shown to reinforce learning but has not been well studied in TD.

“Understanding the relationship between homework adherence and therapeutic improvement from behavior therapy for TD may offer new insights for enhancing tic severity reductions achieved during this evidence-based treatment,” wrote Joey Ka-Yee Essoe, PhD, of the department of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore, and colleagues.

To conduct the study, published in Behaviour Research and Therapy, the researchers recruited 70 youth and 49 adults with TD, ranging in age from 9 to 67 years, who underwent treatment at a single center. The average age was 21 years, and 80 participants were male. Treatment response was based on the Clinical Global Impressions of Improvement scale (CGI-I). Participants were assessed at baseline for tic severity and received eight sessions over 10 weeks. During those sessions, they were taught to perform a competing response to inhibit the expression of a tic when the tic or urge was detected.

Participants received homework at each weekly therapy session; most consisted of three to four practice sessions of about 30 minutes per week. Therapists reviewed the homework at the following session and adapted as needed to improve tic reduction skills.

After eight sessions of behavior therapy, overall greater homework adherence significantly predicted reduced tic severity and therapeutic improvement. However, early homework adherence predicted therapeutic improvement in youth, while late homework adherence predicted it in adults.

Overall, homework adherence significantly predicted tic reductions, compared with baseline (P = .037), based on the clinician-rated Yale Global Tic Severity Scale.

However, homework adherence dipped midway through treatment in youth and showed a linear decline in adults, the researchers noted.

Among youth, baseline predictors of early homework adherence included lower levels of hyperactivity/impulsivity and caregiver strain. Among adults, baseline predictors of early homework adherence included lower anger scores, less social disability, and greater work disability.

The study findings were limited by several factors, including the absence of complete data on baseline predictors of homework adherence, reliance on a single measure of tic severity and improvement, and reliance on therapists’ reports of homework adherence, the researchers noted.

Future research should include objective measures of homework adherence, such as time-stamped videos, and different strategies may be needed for youth vs. adults, they added.

“Strategies that optimize homework adherence may enhance the efficacy of behavioral therapy, lead to greater tic severity reductions, and higher treatment response rates,” Dr. Essoe and colleagues wrote.

The study was supported by the Tourette Association of America, the National Institute of Mental Health, the American Academy of Neurology, and the American Psychological Foundation.

Melatonin improved sleep time and sleep efficiency in patients with multiple sclerosis (MS) who also had sleep disturbance, according to a new pilot study.

The study included only 30 patients, but the findings suggest that melatonin could potentially help patients with MS who have sleep issues, according to Wan-Yu Hsu, PhD, who presented the study at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

There is no optimal management of sleep issues for these patients, and objective studies of sleep in patients with MS are scarce, said Dr. Hsu, who is an associate specialist in the department of neurology at the University of California, San Francisco. She worked with Riley Bove, MD, who is an associate professor of neurology at UCSF Weill Institute for Neurosciences.

“Melatonin use was associated with improvement in sleep quality and sleep disturbance in MS patients, although there was no significant change in other outcomes, like daytime sleepiness, mood, and walking ability” Dr. Hsu said in an interview.

Melatonin is inexpensive and readily available over the counter, but it’s too soon to begin recommending it to MS patients experiencing sleep problems, according to Dr. Hsu. “It’s a good start that we’re seeing some effects here with this relatively small group of people. Larger studies are needed to unravel the complex relationship between MS and sleep disturbances, as well as develop successful interventions. But for now, since melatonin is an over-the-counter, low-cost supplement, many patients are trying it already.”

Melatonin regulates the sleep-wake cycle, and previous research has shown a decrease in melatonin serum levels as a result of corticosteroid administration. Other work has suggested that the decline of melatonin secretion in MS may reflect progressive failure of the pineal gland in the pathogenesis of MS. “The cause of sleep problems can be lesions and neural damage to brain structures involved in sleep, or symptoms that indirectly disrupt sleep,” she said.

Indeed, sleep issues in MS are common and wide-ranging, according to Mark Gudesblatt, MD, who was asked to comment on the study. His group previously reported that 65% of people with MS who reported fatigue had undiagnosed obstructive sleep apnea. He also pointed out that disruption of the neural network also disrupts sleep. “That is not only sleep-disordered breathing, that’s sleep onset, REM latency, and sleep efficiency,” said Dr. Gudesblatt, who is medical director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Patchogue, N.Y.

Dr. Gudesblatt cautioned that melatonin, as a dietary supplement, is unregulated. The potency listed on the package may not be accurate and also may not be the correct dose for the patient. “It’s fraught with problems, but ultimately it’s relatively safe,” said Dr. Gudesblatt.

The study was a double-blind, placebo-controlled, crossover study. Participants had a Pittsburgh Sleep Quality Index (PSQI) score of 5 or more, or an Insomnia Severity Index (ISI) score higher than 14 at baseline. Other baseline assessments included patient-reported outcomes for sleep disturbances, sleep quality, daytime sleepiness, fatigue, walking ability, and mood. Half of the participants received melatonin for the first 2 weeks and then switched to placebo. The other half started with placebo and moved over to melatonin at the beginning of week 3.

Participants in the trial started out at 0.5 mg melatonin and were stepped up to 3.0 mg after 3 days if they didn't feel it was working, both when taking melatonin and when taking placebo. Of the 30 patients, 24 stepped up to 3.0 mg when they were receiving melatonin.*

During the second and fourth weeks, participants wore an actigraph watch to measure their physical and sleep activities, and then repeated the patient-reported outcome measures at the end of weeks 2 and 4. Melatonin improved average sleep time (6.96 vs. 6.67 hours; P = .03) as measured by the actigraph watch. Sleep efficiency was also nominally improved (84.7% vs. 83.2%), though the result was not statistically significant (P = .07). Other trends toward statistical significance included improvements in ISI (–3.5 vs. –2.4; P = .07), change in PSQI component 1 (–0.03 vs. 0.0; P = .07), and change in the NeuroQoL-Fatigue score (–4.7 vs. –2.4; P = .06).

Dr. Hsu hopes to conduct larger studies to examine how the disease-modifying therapies might affect the results of the study.

The study was funded by the National Multiple Sclerosis Society. Dr. Hsu and Dr. Gudesblatt have no relevant financial disclosures.

*This article was updated on Oct. 15.

Melatonin improved sleep time and sleep efficiency in patients with multiple sclerosis (MS) who also had sleep disturbance, according to a new pilot study.

The study included only 30 patients, but the findings suggest that melatonin could potentially help patients with MS who have sleep issues, according to Wan-Yu Hsu, PhD, who presented the study at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

There is no optimal management of sleep issues for these patients, and objective studies of sleep in patients with MS are scarce, said Dr. Hsu, who is an associate specialist in the department of neurology at the University of California, San Francisco. She worked with Riley Bove, MD, who is an associate professor of neurology at UCSF Weill Institute for Neurosciences.

“Melatonin use was associated with improvement in sleep quality and sleep disturbance in MS patients, although there was no significant change in other outcomes, like daytime sleepiness, mood, and walking ability” Dr. Hsu said in an interview.

Melatonin is inexpensive and readily available over the counter, but it’s too soon to begin recommending it to MS patients experiencing sleep problems, according to Dr. Hsu. “It’s a good start that we’re seeing some effects here with this relatively small group of people. Larger studies are needed to unravel the complex relationship between MS and sleep disturbances, as well as develop successful interventions. But for now, since melatonin is an over-the-counter, low-cost supplement, many patients are trying it already.”

Melatonin regulates the sleep-wake cycle, and previous research has shown a decrease in melatonin serum levels as a result of corticosteroid administration. Other work has suggested that the decline of melatonin secretion in MS may reflect progressive failure of the pineal gland in the pathogenesis of MS. “The cause of sleep problems can be lesions and neural damage to brain structures involved in sleep, or symptoms that indirectly disrupt sleep,” she said.

Indeed, sleep issues in MS are common and wide-ranging, according to Mark Gudesblatt, MD, who was asked to comment on the study. His group previously reported that 65% of people with MS who reported fatigue had undiagnosed obstructive sleep apnea. He also pointed out that disruption of the neural network also disrupts sleep. “That is not only sleep-disordered breathing, that’s sleep onset, REM latency, and sleep efficiency,” said Dr. Gudesblatt, who is medical director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Patchogue, N.Y.

Dr. Gudesblatt cautioned that melatonin, as a dietary supplement, is unregulated. The potency listed on the package may not be accurate and also may not be the correct dose for the patient. “It’s fraught with problems, but ultimately it’s relatively safe,” said Dr. Gudesblatt.

The study was a double-blind, placebo-controlled, crossover study. Participants had a Pittsburgh Sleep Quality Index (PSQI) score of 5 or more, or an Insomnia Severity Index (ISI) score higher than 14 at baseline. Other baseline assessments included patient-reported outcomes for sleep disturbances, sleep quality, daytime sleepiness, fatigue, walking ability, and mood. Half of the participants received melatonin for the first 2 weeks and then switched to placebo. The other half started with placebo and moved over to melatonin at the beginning of week 3.

Participants in the trial started out at 0.5 mg melatonin and were stepped up to 3.0 mg after 3 days if they didn't feel it was working, both when taking melatonin and when taking placebo. Of the 30 patients, 24 stepped up to 3.0 mg when they were receiving melatonin.*

During the second and fourth weeks, participants wore an actigraph watch to measure their physical and sleep activities, and then repeated the patient-reported outcome measures at the end of weeks 2 and 4. Melatonin improved average sleep time (6.96 vs. 6.67 hours; P = .03) as measured by the actigraph watch. Sleep efficiency was also nominally improved (84.7% vs. 83.2%), though the result was not statistically significant (P = .07). Other trends toward statistical significance included improvements in ISI (–3.5 vs. –2.4; P = .07), change in PSQI component 1 (–0.03 vs. 0.0; P = .07), and change in the NeuroQoL-Fatigue score (–4.7 vs. –2.4; P = .06).

Dr. Hsu hopes to conduct larger studies to examine how the disease-modifying therapies might affect the results of the study.

The study was funded by the National Multiple Sclerosis Society. Dr. Hsu and Dr. Gudesblatt have no relevant financial disclosures.

*This article was updated on Oct. 15.

Melatonin improved sleep time and sleep efficiency in patients with multiple sclerosis (MS) who also had sleep disturbance, according to a new pilot study.

The study included only 30 patients, but the findings suggest that melatonin could potentially help patients with MS who have sleep issues, according to Wan-Yu Hsu, PhD, who presented the study at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

There is no optimal management of sleep issues for these patients, and objective studies of sleep in patients with MS are scarce, said Dr. Hsu, who is an associate specialist in the department of neurology at the University of California, San Francisco. She worked with Riley Bove, MD, who is an associate professor of neurology at UCSF Weill Institute for Neurosciences.

“Melatonin use was associated with improvement in sleep quality and sleep disturbance in MS patients, although there was no significant change in other outcomes, like daytime sleepiness, mood, and walking ability” Dr. Hsu said in an interview.

Melatonin is inexpensive and readily available over the counter, but it’s too soon to begin recommending it to MS patients experiencing sleep problems, according to Dr. Hsu. “It’s a good start that we’re seeing some effects here with this relatively small group of people. Larger studies are needed to unravel the complex relationship between MS and sleep disturbances, as well as develop successful interventions. But for now, since melatonin is an over-the-counter, low-cost supplement, many patients are trying it already.”

Melatonin regulates the sleep-wake cycle, and previous research has shown a decrease in melatonin serum levels as a result of corticosteroid administration. Other work has suggested that the decline of melatonin secretion in MS may reflect progressive failure of the pineal gland in the pathogenesis of MS. “The cause of sleep problems can be lesions and neural damage to brain structures involved in sleep, or symptoms that indirectly disrupt sleep,” she said.

Indeed, sleep issues in MS are common and wide-ranging, according to Mark Gudesblatt, MD, who was asked to comment on the study. His group previously reported that 65% of people with MS who reported fatigue had undiagnosed obstructive sleep apnea. He also pointed out that disruption of the neural network also disrupts sleep. “That is not only sleep-disordered breathing, that’s sleep onset, REM latency, and sleep efficiency,” said Dr. Gudesblatt, who is medical director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Patchogue, N.Y.

Dr. Gudesblatt cautioned that melatonin, as a dietary supplement, is unregulated. The potency listed on the package may not be accurate and also may not be the correct dose for the patient. “It’s fraught with problems, but ultimately it’s relatively safe,” said Dr. Gudesblatt.

The study was a double-blind, placebo-controlled, crossover study. Participants had a Pittsburgh Sleep Quality Index (PSQI) score of 5 or more, or an Insomnia Severity Index (ISI) score higher than 14 at baseline. Other baseline assessments included patient-reported outcomes for sleep disturbances, sleep quality, daytime sleepiness, fatigue, walking ability, and mood. Half of the participants received melatonin for the first 2 weeks and then switched to placebo. The other half started with placebo and moved over to melatonin at the beginning of week 3.

Participants in the trial started out at 0.5 mg melatonin and were stepped up to 3.0 mg after 3 days if they didn't feel it was working, both when taking melatonin and when taking placebo. Of the 30 patients, 24 stepped up to 3.0 mg when they were receiving melatonin.*

During the second and fourth weeks, participants wore an actigraph watch to measure their physical and sleep activities, and then repeated the patient-reported outcome measures at the end of weeks 2 and 4. Melatonin improved average sleep time (6.96 vs. 6.67 hours; P = .03) as measured by the actigraph watch. Sleep efficiency was also nominally improved (84.7% vs. 83.2%), though the result was not statistically significant (P = .07). Other trends toward statistical significance included improvements in ISI (–3.5 vs. –2.4; P = .07), change in PSQI component 1 (–0.03 vs. 0.0; P = .07), and change in the NeuroQoL-Fatigue score (–4.7 vs. –2.4; P = .06).

Dr. Hsu hopes to conduct larger studies to examine how the disease-modifying therapies might affect the results of the study.

The study was funded by the National Multiple Sclerosis Society. Dr. Hsu and Dr. Gudesblatt have no relevant financial disclosures.

*This article was updated on Oct. 15.

American children gained a lot of weight in the last year, setting a dangerous trajectory towards metabolic disease that requires urgent policy change, according to a new report from the Robert Wood Johnson Foundation.

“Our nation’s safety net is fragile, outdated, and out of reach for millions of eligible kids and caregivers,” said Jamie Bussel, senior program officer at the RWJF, and senior author of the report. She added that the pandemic further fractured an already broken system that disproportionately overlooks “children of color and those who live farthest from economic opportunity”.
 

It’s time to think ‘bigger and better’

Ms. Bussel said, during a press conference, that congress responded to the pandemic with “an array of policy solutions,” but it’s now time to think ‘bigger and better.’

“There have been huge flexibilities deployed across the safety net program and these have been really important reliefs, but the fact is many of them are temporary emergency relief measures,” she explained.

For the past 3 years, the RWJF’s annual State of Childhood Obesity report has drawn national and state obesity data from large surveys including the National Survey of Children’s Health, the Youth Risk Behavior Surveillance System, the WIC Participant and Program Characteristics Survey, and the National Health and Nutrition Examination Survey.

Similar to in past years, this year’s data show that rates of obesity and overweight have remained relatively steady and have been highest among minority and low-income populations. For example, data from the 2019-2020 National Survey of Children’s Health, along with an analysis conducted by the Health Resources and Services Administration’s Maternal and Child Health Bureau, show that one in six – or 16.2% – of youth aged 10-17 years have obesity.

While non-Hispanic Asian children had the lowest obesity rate (8.1%), followed by non-Hispanic White children (12.1%), rates were significantly higher for Hispanic (21.4%), non-Hispanic Black (23.8%), and non-Hispanic American Indian/Alaska Native (28.7%) children, according to the report.

“Additional years of data are needed to assess whether obesity rates changed after the onset of the pandemic,” explained Ms. Bussel.
 

Digging deeper

Other studies included in this year’s report were specifically designed to measure the impact of the pandemic, and show a distinct rise in overweight and obesity, especially in younger children. For example, a retrospective cohort study using data from Kaiser Permanente Southern California showed the rate of overweight and obesity in children aged 5-11 years rose to 45.7% between March 2020 and January 2021, up from 36.2% before the pandemic.

Another of these studies, which was based on national electronic health records of more than 430,000 children, showed the obesity rate crept from 19.3% to 22.4% between August 2019 and August 2020.

“The lid we had been trying desperately to put on the obesity epidemic has come off again,” said Sandra G Hassink, MD, MSc, who is medical director of the American Academy of Pediatrics Institute for Healthy Childhood Weight.

“In the absence of COVID we had been seeing slow upticks in the numbers – and in some groups we’d been thinking maybe we were headed toward stabilization – but these numbers blow that out of the water ... COVID has escalated the rates,” she said in an interview.

“Unfortunately, these two crises – the COVID pandemic, the childhood obesity epidemic – in so many ways have exacerbated one another,” said Ms. Bussel. “It’s not a huge surprise that we’re seeing an increase in childhood obesity rates given the complete and utter disruption of every single system that circumscribes our lives.”
 

The systems that feed obesity

Addressing childhood obesity requires targeting far beyond healthy eating and physical activity, Ms. Bussel said.

“As important is whether that child has a safe place to call home. Does mom or dad or their care provider have a stable income? Is there reliable transportation? Is their access to health insurance? Is there access to high-quality health care? ... All of those factors influence the child and the family’s opportunities to live well, be healthy, and be at a healthy weight,” she noted.

The report includes a list of five main policy recommendations.

• Making free, universal school meal programs permanent.
• Extending eligibility for WIC, the Special Supplemental Nutrition Program for Women, Infants, and Children, to postpartum mothers and to children through age 6.
• Extending and expanding other programs, such as the Child Tax Credit.
• Closing the Medicaid coverage gap.
• Developing a consistent approach to collecting obesity data organized by race, ethnicity, and income level.

“Collectively, over at least the course of the last generation or two, our policy approach to obesity prevention has not been sufficient. But that doesn’t mean all of our policy approaches have been failures,” Ms. Bussel said during an interview. “Policy change does not always need to be dramatic to have a real impact on families.”

Fighting complacency

For Dr. Hassink, one of the barriers to change is society’s level of acceptance. She said an identifiable explanation for pandemic weight gain doesn’t mean society should simply shrug it off.

“If we regarded childhood obesity as the population level catastrophe that it is for chronic disease maybe people would be activated around these policy changes,” she said.

“We’re accepting a disease process that wreaks havoc on people,” noted Dr. Hassink, who was not involved in the new report. “I think it’s hard for people to realize the magnitude of the disease burden that we’re seeing. If you’re in a weight management clinic or any pediatrician’s office you would see it – you would see kids coming in with liver disease, 9-year-olds on [continuous positive airway pressure] for sleep apnea, kids needing their hips pinned because they had a hip fracture because of obesity.

“So, those of us that see the disease burden see what’s behind those numbers. The sadness of what we’re talking about is we know a lot about what could push the dial and help reduce this epidemic and we’re not doing what we already know,” added Dr. Hassink.

Ms. Bussel and Dr. Hassink reported no conflicts.

American children gained a lot of weight in the last year, setting a dangerous trajectory towards metabolic disease that requires urgent policy change, according to a new report from the Robert Wood Johnson Foundation.

“Our nation’s safety net is fragile, outdated, and out of reach for millions of eligible kids and caregivers,” said Jamie Bussel, senior program officer at the RWJF, and senior author of the report. She added that the pandemic further fractured an already broken system that disproportionately overlooks “children of color and those who live farthest from economic opportunity”.
 

It’s time to think ‘bigger and better’

Ms. Bussel said, during a press conference, that congress responded to the pandemic with “an array of policy solutions,” but it’s now time to think ‘bigger and better.’

“There have been huge flexibilities deployed across the safety net program and these have been really important reliefs, but the fact is many of them are temporary emergency relief measures,” she explained.

For the past 3 years, the RWJF’s annual State of Childhood Obesity report has drawn national and state obesity data from large surveys including the National Survey of Children’s Health, the Youth Risk Behavior Surveillance System, the WIC Participant and Program Characteristics Survey, and the National Health and Nutrition Examination Survey.

Similar to in past years, this year’s data show that rates of obesity and overweight have remained relatively steady and have been highest among minority and low-income populations. For example, data from the 2019-2020 National Survey of Children’s Health, along with an analysis conducted by the Health Resources and Services Administration’s Maternal and Child Health Bureau, show that one in six – or 16.2% – of youth aged 10-17 years have obesity.

While non-Hispanic Asian children had the lowest obesity rate (8.1%), followed by non-Hispanic White children (12.1%), rates were significantly higher for Hispanic (21.4%), non-Hispanic Black (23.8%), and non-Hispanic American Indian/Alaska Native (28.7%) children, according to the report.

“Additional years of data are needed to assess whether obesity rates changed after the onset of the pandemic,” explained Ms. Bussel.
 

Digging deeper

Other studies included in this year’s report were specifically designed to measure the impact of the pandemic, and show a distinct rise in overweight and obesity, especially in younger children. For example, a retrospective cohort study using data from Kaiser Permanente Southern California showed the rate of overweight and obesity in children aged 5-11 years rose to 45.7% between March 2020 and January 2021, up from 36.2% before the pandemic.

Another of these studies, which was based on national electronic health records of more than 430,000 children, showed the obesity rate crept from 19.3% to 22.4% between August 2019 and August 2020.

“The lid we had been trying desperately to put on the obesity epidemic has come off again,” said Sandra G Hassink, MD, MSc, who is medical director of the American Academy of Pediatrics Institute for Healthy Childhood Weight.

“In the absence of COVID we had been seeing slow upticks in the numbers – and in some groups we’d been thinking maybe we were headed toward stabilization – but these numbers blow that out of the water ... COVID has escalated the rates,” she said in an interview.

“Unfortunately, these two crises – the COVID pandemic, the childhood obesity epidemic – in so many ways have exacerbated one another,” said Ms. Bussel. “It’s not a huge surprise that we’re seeing an increase in childhood obesity rates given the complete and utter disruption of every single system that circumscribes our lives.”
 

The systems that feed obesity

Addressing childhood obesity requires targeting far beyond healthy eating and physical activity, Ms. Bussel said.

“As important is whether that child has a safe place to call home. Does mom or dad or their care provider have a stable income? Is there reliable transportation? Is their access to health insurance? Is there access to high-quality health care? ... All of those factors influence the child and the family’s opportunities to live well, be healthy, and be at a healthy weight,” she noted.

The report includes a list of five main policy recommendations.

• Making free, universal school meal programs permanent.
• Extending eligibility for WIC, the Special Supplemental Nutrition Program for Women, Infants, and Children, to postpartum mothers and to children through age 6.
• Extending and expanding other programs, such as the Child Tax Credit.
• Closing the Medicaid coverage gap.
• Developing a consistent approach to collecting obesity data organized by race, ethnicity, and income level.

“Collectively, over at least the course of the last generation or two, our policy approach to obesity prevention has not been sufficient. But that doesn’t mean all of our policy approaches have been failures,” Ms. Bussel said during an interview. “Policy change does not always need to be dramatic to have a real impact on families.”

Fighting complacency

For Dr. Hassink, one of the barriers to change is society’s level of acceptance. She said an identifiable explanation for pandemic weight gain doesn’t mean society should simply shrug it off.

“If we regarded childhood obesity as the population level catastrophe that it is for chronic disease maybe people would be activated around these policy changes,” she said.

“We’re accepting a disease process that wreaks havoc on people,” noted Dr. Hassink, who was not involved in the new report. “I think it’s hard for people to realize the magnitude of the disease burden that we’re seeing. If you’re in a weight management clinic or any pediatrician’s office you would see it – you would see kids coming in with liver disease, 9-year-olds on [continuous positive airway pressure] for sleep apnea, kids needing their hips pinned because they had a hip fracture because of obesity.

“So, those of us that see the disease burden see what’s behind those numbers. The sadness of what we’re talking about is we know a lot about what could push the dial and help reduce this epidemic and we’re not doing what we already know,” added Dr. Hassink.

Ms. Bussel and Dr. Hassink reported no conflicts.

American children gained a lot of weight in the last year, setting a dangerous trajectory towards metabolic disease that requires urgent policy change, according to a new report from the Robert Wood Johnson Foundation.

“Our nation’s safety net is fragile, outdated, and out of reach for millions of eligible kids and caregivers,” said Jamie Bussel, senior program officer at the RWJF, and senior author of the report. She added that the pandemic further fractured an already broken system that disproportionately overlooks “children of color and those who live farthest from economic opportunity”.
 

It’s time to think ‘bigger and better’

Ms. Bussel said, during a press conference, that congress responded to the pandemic with “an array of policy solutions,” but it’s now time to think ‘bigger and better.’

“There have been huge flexibilities deployed across the safety net program and these have been really important reliefs, but the fact is many of them are temporary emergency relief measures,” she explained.

For the past 3 years, the RWJF’s annual State of Childhood Obesity report has drawn national and state obesity data from large surveys including the National Survey of Children’s Health, the Youth Risk Behavior Surveillance System, the WIC Participant and Program Characteristics Survey, and the National Health and Nutrition Examination Survey.

Similar to in past years, this year’s data show that rates of obesity and overweight have remained relatively steady and have been highest among minority and low-income populations. For example, data from the 2019-2020 National Survey of Children’s Health, along with an analysis conducted by the Health Resources and Services Administration’s Maternal and Child Health Bureau, show that one in six – or 16.2% – of youth aged 10-17 years have obesity.

While non-Hispanic Asian children had the lowest obesity rate (8.1%), followed by non-Hispanic White children (12.1%), rates were significantly higher for Hispanic (21.4%), non-Hispanic Black (23.8%), and non-Hispanic American Indian/Alaska Native (28.7%) children, according to the report.

“Additional years of data are needed to assess whether obesity rates changed after the onset of the pandemic,” explained Ms. Bussel.
 

Digging deeper

Other studies included in this year’s report were specifically designed to measure the impact of the pandemic, and show a distinct rise in overweight and obesity, especially in younger children. For example, a retrospective cohort study using data from Kaiser Permanente Southern California showed the rate of overweight and obesity in children aged 5-11 years rose to 45.7% between March 2020 and January 2021, up from 36.2% before the pandemic.

Another of these studies, which was based on national electronic health records of more than 430,000 children, showed the obesity rate crept from 19.3% to 22.4% between August 2019 and August 2020.

“The lid we had been trying desperately to put on the obesity epidemic has come off again,” said Sandra G Hassink, MD, MSc, who is medical director of the American Academy of Pediatrics Institute for Healthy Childhood Weight.

“In the absence of COVID we had been seeing slow upticks in the numbers – and in some groups we’d been thinking maybe we were headed toward stabilization – but these numbers blow that out of the water ... COVID has escalated the rates,” she said in an interview.

“Unfortunately, these two crises – the COVID pandemic, the childhood obesity epidemic – in so many ways have exacerbated one another,” said Ms. Bussel. “It’s not a huge surprise that we’re seeing an increase in childhood obesity rates given the complete and utter disruption of every single system that circumscribes our lives.”
 

The systems that feed obesity

Addressing childhood obesity requires targeting far beyond healthy eating and physical activity, Ms. Bussel said.

“As important is whether that child has a safe place to call home. Does mom or dad or their care provider have a stable income? Is there reliable transportation? Is their access to health insurance? Is there access to high-quality health care? ... All of those factors influence the child and the family’s opportunities to live well, be healthy, and be at a healthy weight,” she noted.

The report includes a list of five main policy recommendations.

• Making free, universal school meal programs permanent.
• Extending eligibility for WIC, the Special Supplemental Nutrition Program for Women, Infants, and Children, to postpartum mothers and to children through age 6.
• Extending and expanding other programs, such as the Child Tax Credit.
• Closing the Medicaid coverage gap.
• Developing a consistent approach to collecting obesity data organized by race, ethnicity, and income level.

“Collectively, over at least the course of the last generation or two, our policy approach to obesity prevention has not been sufficient. But that doesn’t mean all of our policy approaches have been failures,” Ms. Bussel said during an interview. “Policy change does not always need to be dramatic to have a real impact on families.”

Fighting complacency

For Dr. Hassink, one of the barriers to change is society’s level of acceptance. She said an identifiable explanation for pandemic weight gain doesn’t mean society should simply shrug it off.

“If we regarded childhood obesity as the population level catastrophe that it is for chronic disease maybe people would be activated around these policy changes,” she said.

“We’re accepting a disease process that wreaks havoc on people,” noted Dr. Hassink, who was not involved in the new report. “I think it’s hard for people to realize the magnitude of the disease burden that we’re seeing. If you’re in a weight management clinic or any pediatrician’s office you would see it – you would see kids coming in with liver disease, 9-year-olds on [continuous positive airway pressure] for sleep apnea, kids needing their hips pinned because they had a hip fracture because of obesity.

“So, those of us that see the disease burden see what’s behind those numbers. The sadness of what we’re talking about is we know a lot about what could push the dial and help reduce this epidemic and we’re not doing what we already know,” added Dr. Hassink.

Ms. Bussel and Dr. Hassink reported no conflicts.

Children in foster care are far more likely to be prescribed psychotropic medication, compared with children who are not in foster care, an analysis of Medicaid claims data shows.

Different rates of mental health disorders in these groups do not fully explain the “alarming trend,” which persists across psychotropic medication classes, said study author Rachael J. Keefe, MD, MPH.

Misdiagnosis, overprescribing, and frequent transitions to new doctors may contribute to this phenomenon, doctors suggested.

Dr. Keefe, with Baylor College of Medicine, Houston, and colleagues analyzed Medicaid claims data from two managed care organizations to compare the prevalence of psychotropic medication use among children in foster care versus children insured by Medicaid but not in foster care. The study focused on claims from the same region in southeast Texas between July 2014 and June 2016.

The researchers included 388,914 children in Medicaid and 8,426 children in foster care in their analysis. They excluded children with a seizure or epilepsy diagnosis.

About 8% of children not in foster care received psychotropic medications, compared with 35% of those in foster care.

Children in foster care were 27 times more likely to receive antipsychotic medication (21.2% of children in foster care vs. 0.8% of children not in foster care) and twice as likely to receive antianxiety medication (6% vs. 3%).

For children in foster care, the rate of alpha-agonist use was 15 times higher, the rate of antidepressant use was 13 times higher, the rate of mood stabilizer use was 26 times higher, and the rate of stimulant use was 6 times higher.

The researchers have a limited understanding of the full context in which these medications were prescribed, and psychotropic medications have a role in the treatment of children in foster care, Dr. Keefe acknowledged.

“We have to be careful not to have a knee-jerk reaction” and inappropriately withhold medication from children in foster care, she said in an interview.

But overprescribing has been a concern. Dr. Keefe leads a foster care clinical service at Texas Children’s Hospital in Houston.

“The overprescribing of psychotropic medications to children in foster care is something I feel every day in my clinical practice, but it’s different to see it on paper,” Dr. Keefe said in a news release highlighting the research, which she presented on Oct. 11 at the annual meeting of the American Academy of Pediatrics. “It’s especially shocking to see these dramatic differences in children of preschool and elementary age.”

Misdiagnosis can be a common problem among children in foster care, said Danielle Shaw, MD, a child and adolescent psychiatrist in Camarillo, Calif., during a question-and-answer period following the presentation.

“I see incorrect diagnoses very frequently,” Dr. Shaw said. “The history of trauma or [adverse childhood experiences] is not even included in the assessment. Mood lability from trauma is misdiagnosed as bipolar disorder, despite not meeting criteria. This will justify the use of antipsychotic medication and mood stabilizers. Flashbacks can be mistaken for a psychotic disorder, which again justifies the use of antipsychotic medication.”

Children in foster care have experienced numerous traumatic experiences that affect brain development and the hypothalamic-pituitary-adrenal axis, Dr. Keefe said.

“Although from previous research we know that children in foster care are more likely to carry mental health and developmental disorder diagnoses, this does not account for the significant difference in prescribing practices in this population,” Dr. Keefe said in an interview.

Although the study focused on data in Texas, Dr. Keefe expects similar patterns exist in other regions, based on anecdotal reports. “I work with foster care pediatricians across the country, and many have seen similar concerning trends within their own clinical practices,” she said.

The use of appropriate therapies, minimizing transitions between providers, improved record keeping, the development of deprescribing algorithms, and placement of children in foster care in long-term homes as early as possible are measures that potentially could reduce inappropriate psychotropic prescribing for children in foster care, Dr. Keefe suggested.

The research was funded by a Texas Medical Center Health Policy Research Grant. The study authors and Dr. Shaw had no relevant financial disclosures.

[email protected]

Children in foster care are far more likely to be prescribed psychotropic medication, compared with children who are not in foster care, an analysis of Medicaid claims data shows.

Different rates of mental health disorders in these groups do not fully explain the “alarming trend,” which persists across psychotropic medication classes, said study author Rachael J. Keefe, MD, MPH.

Misdiagnosis, overprescribing, and frequent transitions to new doctors may contribute to this phenomenon, doctors suggested.

Dr. Keefe, with Baylor College of Medicine, Houston, and colleagues analyzed Medicaid claims data from two managed care organizations to compare the prevalence of psychotropic medication use among children in foster care versus children insured by Medicaid but not in foster care. The study focused on claims from the same region in southeast Texas between July 2014 and June 2016.

The researchers included 388,914 children in Medicaid and 8,426 children in foster care in their analysis. They excluded children with a seizure or epilepsy diagnosis.

About 8% of children not in foster care received psychotropic medications, compared with 35% of those in foster care.

Children in foster care were 27 times more likely to receive antipsychotic medication (21.2% of children in foster care vs. 0.8% of children not in foster care) and twice as likely to receive antianxiety medication (6% vs. 3%).

For children in foster care, the rate of alpha-agonist use was 15 times higher, the rate of antidepressant use was 13 times higher, the rate of mood stabilizer use was 26 times higher, and the rate of stimulant use was 6 times higher.

The researchers have a limited understanding of the full context in which these medications were prescribed, and psychotropic medications have a role in the treatment of children in foster care, Dr. Keefe acknowledged.

“We have to be careful not to have a knee-jerk reaction” and inappropriately withhold medication from children in foster care, she said in an interview.

But overprescribing has been a concern. Dr. Keefe leads a foster care clinical service at Texas Children’s Hospital in Houston.

“The overprescribing of psychotropic medications to children in foster care is something I feel every day in my clinical practice, but it’s different to see it on paper,” Dr. Keefe said in a news release highlighting the research, which she presented on Oct. 11 at the annual meeting of the American Academy of Pediatrics. “It’s especially shocking to see these dramatic differences in children of preschool and elementary age.”

Misdiagnosis can be a common problem among children in foster care, said Danielle Shaw, MD, a child and adolescent psychiatrist in Camarillo, Calif., during a question-and-answer period following the presentation.

“I see incorrect diagnoses very frequently,” Dr. Shaw said. “The history of trauma or [adverse childhood experiences] is not even included in the assessment. Mood lability from trauma is misdiagnosed as bipolar disorder, despite not meeting criteria. This will justify the use of antipsychotic medication and mood stabilizers. Flashbacks can be mistaken for a psychotic disorder, which again justifies the use of antipsychotic medication.”

Children in foster care have experienced numerous traumatic experiences that affect brain development and the hypothalamic-pituitary-adrenal axis, Dr. Keefe said.

“Although from previous research we know that children in foster care are more likely to carry mental health and developmental disorder diagnoses, this does not account for the significant difference in prescribing practices in this population,” Dr. Keefe said in an interview.

Although the study focused on data in Texas, Dr. Keefe expects similar patterns exist in other regions, based on anecdotal reports. “I work with foster care pediatricians across the country, and many have seen similar concerning trends within their own clinical practices,” she said.

The use of appropriate therapies, minimizing transitions between providers, improved record keeping, the development of deprescribing algorithms, and placement of children in foster care in long-term homes as early as possible are measures that potentially could reduce inappropriate psychotropic prescribing for children in foster care, Dr. Keefe suggested.

The research was funded by a Texas Medical Center Health Policy Research Grant. The study authors and Dr. Shaw had no relevant financial disclosures.

[email protected]

Children in foster care are far more likely to be prescribed psychotropic medication, compared with children who are not in foster care, an analysis of Medicaid claims data shows.

Different rates of mental health disorders in these groups do not fully explain the “alarming trend,” which persists across psychotropic medication classes, said study author Rachael J. Keefe, MD, MPH.

Misdiagnosis, overprescribing, and frequent transitions to new doctors may contribute to this phenomenon, doctors suggested.

Dr. Keefe, with Baylor College of Medicine, Houston, and colleagues analyzed Medicaid claims data from two managed care organizations to compare the prevalence of psychotropic medication use among children in foster care versus children insured by Medicaid but not in foster care. The study focused on claims from the same region in southeast Texas between July 2014 and June 2016.

The researchers included 388,914 children in Medicaid and 8,426 children in foster care in their analysis. They excluded children with a seizure or epilepsy diagnosis.

About 8% of children not in foster care received psychotropic medications, compared with 35% of those in foster care.

Children in foster care were 27 times more likely to receive antipsychotic medication (21.2% of children in foster care vs. 0.8% of children not in foster care) and twice as likely to receive antianxiety medication (6% vs. 3%).

For children in foster care, the rate of alpha-agonist use was 15 times higher, the rate of antidepressant use was 13 times higher, the rate of mood stabilizer use was 26 times higher, and the rate of stimulant use was 6 times higher.

The researchers have a limited understanding of the full context in which these medications were prescribed, and psychotropic medications have a role in the treatment of children in foster care, Dr. Keefe acknowledged.

“We have to be careful not to have a knee-jerk reaction” and inappropriately withhold medication from children in foster care, she said in an interview.

But overprescribing has been a concern. Dr. Keefe leads a foster care clinical service at Texas Children’s Hospital in Houston.

“The overprescribing of psychotropic medications to children in foster care is something I feel every day in my clinical practice, but it’s different to see it on paper,” Dr. Keefe said in a news release highlighting the research, which she presented on Oct. 11 at the annual meeting of the American Academy of Pediatrics. “It’s especially shocking to see these dramatic differences in children of preschool and elementary age.”

Misdiagnosis can be a common problem among children in foster care, said Danielle Shaw, MD, a child and adolescent psychiatrist in Camarillo, Calif., during a question-and-answer period following the presentation.

“I see incorrect diagnoses very frequently,” Dr. Shaw said. “The history of trauma or [adverse childhood experiences] is not even included in the assessment. Mood lability from trauma is misdiagnosed as bipolar disorder, despite not meeting criteria. This will justify the use of antipsychotic medication and mood stabilizers. Flashbacks can be mistaken for a psychotic disorder, which again justifies the use of antipsychotic medication.”

Children in foster care have experienced numerous traumatic experiences that affect brain development and the hypothalamic-pituitary-adrenal axis, Dr. Keefe said.

“Although from previous research we know that children in foster care are more likely to carry mental health and developmental disorder diagnoses, this does not account for the significant difference in prescribing practices in this population,” Dr. Keefe said in an interview.

Although the study focused on data in Texas, Dr. Keefe expects similar patterns exist in other regions, based on anecdotal reports. “I work with foster care pediatricians across the country, and many have seen similar concerning trends within their own clinical practices,” she said.

The use of appropriate therapies, minimizing transitions between providers, improved record keeping, the development of deprescribing algorithms, and placement of children in foster care in long-term homes as early as possible are measures that potentially could reduce inappropriate psychotropic prescribing for children in foster care, Dr. Keefe suggested.

The research was funded by a Texas Medical Center Health Policy Research Grant. The study authors and Dr. Shaw had no relevant financial disclosures.

[email protected]

The melatonin precursor tryptophan, an amino acid essential in the human diet, has been shown to display antioxidant effects.¹ FICZ (also known as 6-formylindolo[3,2-b]carbazole) is a photoproduct of tryptophan that is engendered by exposure to UVB.² This column discusses the beneficial and detrimental influence of FICZ in skin health.

Antioxidant activity

In 2005, Trommer and Neubert devised a skin lipid model system to screen 47 various compounds (drugs, plant extracts, other plant constituents, and polysaccharides) for topical antioxidative activity in response to UV-induced lipid peroxidation. Among the drugs evaluated, they observed that tryptophan exerted antioxidant effects.³

Wound healing potential

A murine study by Bandeira et al. in 2015 revealed that tryptophan-induced mitigation of the inflammatory response and indoleamine 2, 3-dioxygenase expression may have enhanced skin wound healing in mice who were repeatedly stressed.⁴

Antifibrotic activity

In 2018, Murai et al. endeavored to clarify the role of FICZ in regulating the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in normal human dermal fibroblasts. They found that FICZ assists in imparting UV-mediated antifibrotic effects through the AHR/MEK/ERK signal pathway in normal human dermal fibroblasts and, thus, shows promise as a therapeutic option for scleroderma.⁵

Cutaneous leishmaniasis

In 2019, Rodrigues et al. conducted a quantitative analysis of the relative expression of 170 genes involved in various biological processes in the skin biopsies from patients with cutaneous leishmaniasis caused by infection with either Leishmania major or L. tropica. They identified tryptophan-2,3-deoxygenase as a restriction factor for the disorder.⁶

Photosensitizing activity

Park et al. showed that FICZ, a tryptophan photoproduct and endogenous high-affinity aryl hydrocarbon receptor (AhR) agonist, exhibits nanomolar photodynamic activity as a UVA photosensitizer in epidermal keratinocytes and, thus, is possibly operative in human skin.⁷ Syed and Mukhtar add that FICZ is effective at nanomolar concentrations and that future research may elucidate its applicability against UV-induced adverse effects and inflammatory skin conditions.⁸

FICZ, oxidative stress, and cancer promotion

FICZ is known to display detrimental, as well as beneficial, influences in skin. The tryptophan photoproduct, comparable to UVB, ligates AhR, generates reactive oxygen species, and strongly photosensitizes for UVA. As Furue et al. note, FICZ upregulates the expression of terminal differentiation molecules (i.e., filaggrin and loricrin via AhR), and its application has been shown to suppress cutaneous inflammation in a psoriasis and dermatitis mouse model.²

In 2016, Reid et al. reported that the protein photodamage brought about by endogenous photosensitizers such as tryptophan tyrosine residues can contribute to the deleterious impact of UVA on human skin.⁹

In 2018, Tanaka et al. showed that FICZ imparts a cascade of events tantamount in some cases to UVB, as it promoted the synthesis of proinflammatory cytokines such as interleukin (IL)-1 alpha, IL-1 beta, and IL-6 and boosted reactive oxygen species generation in human HaCaT keratinocytes in an AhR-dependent fashion. They concluded that observing FICZ activity contributes to the understanding of how UVB damages organisms.¹⁰

That same year, Murai et al. assessed the effects of FICZ on TGF-beta-mediated ACTA2 and collagen I expression in normal human dermal fibroblasts. They determined that it may act as a key chromophore and one approach to mitigating the effects of photoaging may be to downregulate FICZ signaling.¹¹

A year earlier, Brem et al. showed that the combined effect of FICZ and UVA engendered significant protein damage in HaCaT human keratinocytes, with the oxidation yielded from the combination of FICZ and UVA blocking the removal of potentially mutagenic UVB-induced DNA photolesions by nucleotide excision repair. The researchers concluded that the development of FICZ may raise the risk of incurring skin cancer resulting from sun exposure via the promotion of photochemical impairment of the nucleotide excision repair proteome, which in turn inhibits the removal of UVB-induced DNA lesions.¹²

Conclusion

Tryptophan, an essential amino acid in the human diet, is known to exhibit antioxidant activity. It is also a precursor to the hormone melatonin, which plays an important role in human health. However, the tryptophan photoproduct FICZ, which results from UVB exposure, presents as a complicated substance, conferring healthy and harmful effects. Much more research is necessary to determine how best to harness and direct the useful activities of tryptophan and FICZ without incurring damaging effects. Nanotechnology may be one useful avenue of investigation for this purpose.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].

References

1. Trommer H et al. J Pharm Pharmacol. 2003 Oct;55(10):1379-88.

2. Furue M et al. G Ital Dermatol Venereol. 2019 Feb;154(1):37-41.

3. Trommer H and Neubert RH. J Pharm Pharm Sci. 2005 Sep 15;8(3):494-506.

4. Bandeira LG et al. PLoS One. 2015 Jun 9:10(6):e0128439.

5. Murai M et al. J Dermatol Sci. 2018 Jul;91(1):97-103.

6. Rodrigues V et al. Front Cell Infect Microbiol. 2019 Oct 4;9:338. eCollection 2019.

7. Park SL et al. J Invest Dermatol. 2015 Jun;135(6):1649-58.

8. Syed DN and Mukhtar H. J Invest Dermatol. 2015 Jun;135(6):1478-81.

9. Reid LO et al. Biochemistry. 2016 Aug 30;55(34):4777-86.

10. Tanaka Y et al. Oxid Med Cell Longev. 2018 Nov 25;2018:9298052.

11. Murai M et al. J Dermatol Sci. 2018 Jan;89(1):19-26.

12. Brem R et al. Sci Rep. 2017 Jun 27;7(1):4310.

The melatonin precursor tryptophan, an amino acid essential in the human diet, has been shown to display antioxidant effects.¹ FICZ (also known as 6-formylindolo[3,2-b]carbazole) is a photoproduct of tryptophan that is engendered by exposure to UVB.² This column discusses the beneficial and detrimental influence of FICZ in skin health.

Antioxidant activity

In 2005, Trommer and Neubert devised a skin lipid model system to screen 47 various compounds (drugs, plant extracts, other plant constituents, and polysaccharides) for topical antioxidative activity in response to UV-induced lipid peroxidation. Among the drugs evaluated, they observed that tryptophan exerted antioxidant effects.³

Wound healing potential

A murine study by Bandeira et al. in 2015 revealed that tryptophan-induced mitigation of the inflammatory response and indoleamine 2, 3-dioxygenase expression may have enhanced skin wound healing in mice who were repeatedly stressed.⁴

Antifibrotic activity

In 2018, Murai et al. endeavored to clarify the role of FICZ in regulating the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in normal human dermal fibroblasts. They found that FICZ assists in imparting UV-mediated antifibrotic effects through the AHR/MEK/ERK signal pathway in normal human dermal fibroblasts and, thus, shows promise as a therapeutic option for scleroderma.⁵

Cutaneous leishmaniasis

In 2019, Rodrigues et al. conducted a quantitative analysis of the relative expression of 170 genes involved in various biological processes in the skin biopsies from patients with cutaneous leishmaniasis caused by infection with either Leishmania major or L. tropica. They identified tryptophan-2,3-deoxygenase as a restriction factor for the disorder.⁶

Photosensitizing activity

Park et al. showed that FICZ, a tryptophan photoproduct and endogenous high-affinity aryl hydrocarbon receptor (AhR) agonist, exhibits nanomolar photodynamic activity as a UVA photosensitizer in epidermal keratinocytes and, thus, is possibly operative in human skin.⁷ Syed and Mukhtar add that FICZ is effective at nanomolar concentrations and that future research may elucidate its applicability against UV-induced adverse effects and inflammatory skin conditions.⁸

FICZ, oxidative stress, and cancer promotion

FICZ is known to display detrimental, as well as beneficial, influences in skin. The tryptophan photoproduct, comparable to UVB, ligates AhR, generates reactive oxygen species, and strongly photosensitizes for UVA. As Furue et al. note, FICZ upregulates the expression of terminal differentiation molecules (i.e., filaggrin and loricrin via AhR), and its application has been shown to suppress cutaneous inflammation in a psoriasis and dermatitis mouse model.²

In 2016, Reid et al. reported that the protein photodamage brought about by endogenous photosensitizers such as tryptophan tyrosine residues can contribute to the deleterious impact of UVA on human skin.⁹

In 2018, Tanaka et al. showed that FICZ imparts a cascade of events tantamount in some cases to UVB, as it promoted the synthesis of proinflammatory cytokines such as interleukin (IL)-1 alpha, IL-1 beta, and IL-6 and boosted reactive oxygen species generation in human HaCaT keratinocytes in an AhR-dependent fashion. They concluded that observing FICZ activity contributes to the understanding of how UVB damages organisms.¹⁰

That same year, Murai et al. assessed the effects of FICZ on TGF-beta-mediated ACTA2 and collagen I expression in normal human dermal fibroblasts. They determined that it may act as a key chromophore and one approach to mitigating the effects of photoaging may be to downregulate FICZ signaling.¹¹

A year earlier, Brem et al. showed that the combined effect of FICZ and UVA engendered significant protein damage in HaCaT human keratinocytes, with the oxidation yielded from the combination of FICZ and UVA blocking the removal of potentially mutagenic UVB-induced DNA photolesions by nucleotide excision repair. The researchers concluded that the development of FICZ may raise the risk of incurring skin cancer resulting from sun exposure via the promotion of photochemical impairment of the nucleotide excision repair proteome, which in turn inhibits the removal of UVB-induced DNA lesions.¹²

Conclusion

Tryptophan, an essential amino acid in the human diet, is known to exhibit antioxidant activity. It is also a precursor to the hormone melatonin, which plays an important role in human health. However, the tryptophan photoproduct FICZ, which results from UVB exposure, presents as a complicated substance, conferring healthy and harmful effects. Much more research is necessary to determine how best to harness and direct the useful activities of tryptophan and FICZ without incurring damaging effects. Nanotechnology may be one useful avenue of investigation for this purpose.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].

References

1. Trommer H et al. J Pharm Pharmacol. 2003 Oct;55(10):1379-88.

2. Furue M et al. G Ital Dermatol Venereol. 2019 Feb;154(1):37-41.

3. Trommer H and Neubert RH. J Pharm Pharm Sci. 2005 Sep 15;8(3):494-506.

4. Bandeira LG et al. PLoS One. 2015 Jun 9:10(6):e0128439.

5. Murai M et al. J Dermatol Sci. 2018 Jul;91(1):97-103.

6. Rodrigues V et al. Front Cell Infect Microbiol. 2019 Oct 4;9:338. eCollection 2019.

7. Park SL et al. J Invest Dermatol. 2015 Jun;135(6):1649-58.

8. Syed DN and Mukhtar H. J Invest Dermatol. 2015 Jun;135(6):1478-81.

9. Reid LO et al. Biochemistry. 2016 Aug 30;55(34):4777-86.

10. Tanaka Y et al. Oxid Med Cell Longev. 2018 Nov 25;2018:9298052.

11. Murai M et al. J Dermatol Sci. 2018 Jan;89(1):19-26.

12. Brem R et al. Sci Rep. 2017 Jun 27;7(1):4310.

The melatonin precursor tryptophan, an amino acid essential in the human diet, has been shown to display antioxidant effects.¹ FICZ (also known as 6-formylindolo[3,2-b]carbazole) is a photoproduct of tryptophan that is engendered by exposure to UVB.² This column discusses the beneficial and detrimental influence of FICZ in skin health.

Antioxidant activity

In 2005, Trommer and Neubert devised a skin lipid model system to screen 47 various compounds (drugs, plant extracts, other plant constituents, and polysaccharides) for topical antioxidative activity in response to UV-induced lipid peroxidation. Among the drugs evaluated, they observed that tryptophan exerted antioxidant effects.³

Wound healing potential

A murine study by Bandeira et al. in 2015 revealed that tryptophan-induced mitigation of the inflammatory response and indoleamine 2, 3-dioxygenase expression may have enhanced skin wound healing in mice who were repeatedly stressed.⁴

Antifibrotic activity

In 2018, Murai et al. endeavored to clarify the role of FICZ in regulating the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in normal human dermal fibroblasts. They found that FICZ assists in imparting UV-mediated antifibrotic effects through the AHR/MEK/ERK signal pathway in normal human dermal fibroblasts and, thus, shows promise as a therapeutic option for scleroderma.⁵

Cutaneous leishmaniasis

In 2019, Rodrigues et al. conducted a quantitative analysis of the relative expression of 170 genes involved in various biological processes in the skin biopsies from patients with cutaneous leishmaniasis caused by infection with either Leishmania major or L. tropica. They identified tryptophan-2,3-deoxygenase as a restriction factor for the disorder.⁶

Photosensitizing activity

Park et al. showed that FICZ, a tryptophan photoproduct and endogenous high-affinity aryl hydrocarbon receptor (AhR) agonist, exhibits nanomolar photodynamic activity as a UVA photosensitizer in epidermal keratinocytes and, thus, is possibly operative in human skin.⁷ Syed and Mukhtar add that FICZ is effective at nanomolar concentrations and that future research may elucidate its applicability against UV-induced adverse effects and inflammatory skin conditions.⁸

FICZ, oxidative stress, and cancer promotion

FICZ is known to display detrimental, as well as beneficial, influences in skin. The tryptophan photoproduct, comparable to UVB, ligates AhR, generates reactive oxygen species, and strongly photosensitizes for UVA. As Furue et al. note, FICZ upregulates the expression of terminal differentiation molecules (i.e., filaggrin and loricrin via AhR), and its application has been shown to suppress cutaneous inflammation in a psoriasis and dermatitis mouse model.²

In 2016, Reid et al. reported that the protein photodamage brought about by endogenous photosensitizers such as tryptophan tyrosine residues can contribute to the deleterious impact of UVA on human skin.⁹

In 2018, Tanaka et al. showed that FICZ imparts a cascade of events tantamount in some cases to UVB, as it promoted the synthesis of proinflammatory cytokines such as interleukin (IL)-1 alpha, IL-1 beta, and IL-6 and boosted reactive oxygen species generation in human HaCaT keratinocytes in an AhR-dependent fashion. They concluded that observing FICZ activity contributes to the understanding of how UVB damages organisms.¹⁰

That same year, Murai et al. assessed the effects of FICZ on TGF-beta-mediated ACTA2 and collagen I expression in normal human dermal fibroblasts. They determined that it may act as a key chromophore and one approach to mitigating the effects of photoaging may be to downregulate FICZ signaling.¹¹

A year earlier, Brem et al. showed that the combined effect of FICZ and UVA engendered significant protein damage in HaCaT human keratinocytes, with the oxidation yielded from the combination of FICZ and UVA blocking the removal of potentially mutagenic UVB-induced DNA photolesions by nucleotide excision repair. The researchers concluded that the development of FICZ may raise the risk of incurring skin cancer resulting from sun exposure via the promotion of photochemical impairment of the nucleotide excision repair proteome, which in turn inhibits the removal of UVB-induced DNA lesions.¹²

Conclusion

Tryptophan, an essential amino acid in the human diet, is known to exhibit antioxidant activity. It is also a precursor to the hormone melatonin, which plays an important role in human health. However, the tryptophan photoproduct FICZ, which results from UVB exposure, presents as a complicated substance, conferring healthy and harmful effects. Much more research is necessary to determine how best to harness and direct the useful activities of tryptophan and FICZ without incurring damaging effects. Nanotechnology may be one useful avenue of investigation for this purpose.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].

References

1. Trommer H et al. J Pharm Pharmacol. 2003 Oct;55(10):1379-88.

2. Furue M et al. G Ital Dermatol Venereol. 2019 Feb;154(1):37-41.

3. Trommer H and Neubert RH. J Pharm Pharm Sci. 2005 Sep 15;8(3):494-506.

4. Bandeira LG et al. PLoS One. 2015 Jun 9:10(6):e0128439.

5. Murai M et al. J Dermatol Sci. 2018 Jul;91(1):97-103.

6. Rodrigues V et al. Front Cell Infect Microbiol. 2019 Oct 4;9:338. eCollection 2019.

7. Park SL et al. J Invest Dermatol. 2015 Jun;135(6):1649-58.

8. Syed DN and Mukhtar H. J Invest Dermatol. 2015 Jun;135(6):1478-81.

9. Reid LO et al. Biochemistry. 2016 Aug 30;55(34):4777-86.

10. Tanaka Y et al. Oxid Med Cell Longev. 2018 Nov 25;2018:9298052.

11. Murai M et al. J Dermatol Sci. 2018 Jan;89(1):19-26.

12. Brem R et al. Sci Rep. 2017 Jun 27;7(1):4310.

Andrea Rapkin, MD, is Board Certified by the American College of Obstetricians and Gynecologists (of which she is also a fellow). After obtaining her MD, she completed her residency in OBGYN at UCLA then joined the faculty at UCLA and is a Professor of Obstetrics and Gynecology. She was one of the first Obstetrician-Gynecologists to adapt the multidisciplinary pain management approach to the evaluation and treatment of women with pelvic and vulvar pain.

You are the founder and director of a clinic focused on a multidisciplinary pain management approach to the evaluation and treatment of women with pelvic and vulvar pain. How did you identify such a clinic as a therapeutic need for patients? 

Dr. Rapkin: The short answer is that a significant proportion of women were not experiencing pain relief or had incomplete relief with traditional medical or surgical therapy. At the time, we also identified various red flags for traditional treatment failures. These red flags included the following: pain of greater than 6 months duration, pain out of proportion to pathology found on examination, multiple visceral and somatic complaints, and psychosocial abnormalities. We now understand more about the neurobiology underpinning these red flags.  

With the widespread availability of laparoscopy in the late 70s and early 80s, many studies investigated the relationship between endometriosis lesions and pain. The general consensus is that there is no relationship between the location or severity of the endometriosis lesions or the disease stage (American Society for Reproductive Medicine staging) with type of symptoms, symptom severity, treatment response, recurrence, or even prognosis. In fact, pain recurrence after adequate surgical treatment is unrelated to the presence of endometriosis lesions found at the time of repeat laparoscopy. This lack of association between pain and presence of visible disease was supported by a recent New England Journal of Medicine article by Zondervan and colleagues demonstrating that up to 30% of women with chronic pelvic pain, present after excision of endometriotic lesions, become unresponsive to conventional treatment.

The neurobiological responses in an individual with chronic pain are more complicated than those seen in the setting of acute pain. Chronic pain may be triggered or maintained by an inflammatory process such as endometriosis but, over time, altered neural processing and psychosocial maladaptation can occur. The altered processing consists of both peripheral and central sensitization which change the way sensory information from the pelvic viscera and surrounding somatic structures in the periphery is transmitted and interpreted in the central nervous system (spinal cord and brain). Visceral pelvic pain can emanate from the uterus, ovaries and fallopian tubes, the urinary bladder, and the bowel, while the somatic sources include the surrounding abdominal wall, low back and pelvic floor muscles, and fascia, and bones. Signal amplification or peripheral sensitization in the pelvic region in women with endometriosis starts with localized inflammation, neovascularization, invasion and innervation of endometriotic implants. As the pelvic organs share thoracolumbar and sacral autonomic neural pathways, inflammation or dysfunction in one organ or tissue, such as the uterus, over time can sensitize or lead to dysfunction in other pelvic organs, such as the bladder or bowel (called viscero-visceral cross sensitization). Finally, somatic structures sharing intervention with the pelvic viscera, such as the fascia and muscles of the lower abdomen, pelvic floor lower back also become sources of pain because of a process called viscero-somatic sensitization. Women who have endometriosis are therefore more likely to experience IBS, bladder pain syndrome/interstitial cystitis and vulvodynia, and up to 80% of individuals can develop myofascial pain related to trigger points and muscle dysfunction. Up to 50% of women with bladder pain have endometriosis. Those with endometriosis or bladder pain are 2.5 times more likely to also have IBS. 

Over time, other visceral and somatic structures innervated by higher levels of the spinal cord can be affected, leading to more widespread pain. Central sensitization manifests as an amplification of pain in the spinal cord and brain. The presence of more than two chronic “unexplained” pain conditions, such as chronic pelvic pain, vulvodynia, myofascial pain, headache, etc suggest the presence of central sensitization. Anxiety, depression, and maladaptive coping strategies often ensue. Functional MRI studies have documented altered central processing in the brain in many chronic pain states including endometriosis. Interdisciplinary therapy including physical therapy, mental health, and pain management/anesthesiology is more effective compared with medical and or surgical therapy alone for endometriosis-related pain in the setting of peripheral and central sensitization.

What should clinicians look for, or what stands out to them, to confirm the endometriosis diagnosis when pain is the presenting symptom?

Dr. Rapkin: There are no pathognomonic symptoms or biomarkers for endometriosis; however, the following historical features have been shown to be linked with a greater likelihood of finding endometriosis:

• persistent dysmenorrhea (menstrual pain) despite NSAID and hormonal treatment
• cyclical pain that is premenstrual and menstrual that progresses to chronic pain or is accompanied by abnormal or heavy menstrual bleeding
• deep dyspareunia
• dyschezia (pain with bowel movements), and sometimes bloating.

An individual with menstrual pain since menarche can have up to a 5% increased risk of endometriosis. Endometriosis in a first-degree relative elevates the risk for endometriosis by 7% to 10%.

Given the complexity of chronic pain, it is important not to assume endometriosis is the only source of pain. All the pelvic visceral and somatic structures should be evaluated. A thorough history addresses all the patient’s symptoms, including vaginal, gastrointestinal and genitourinary. Aggravating factors such as menstrual cycle, bowel and bladder functioning, physical activity, sexual intercourse and stress should be queried. In addition, assessment of mood, anxiety or depression, sleep disturbance and effect of pain on daily functioning are relevant as is history of abuse or trauma (physical, sexual or emotional). This history can be lengthy, so a detailed pain questionnaire is helpful. (See the pelvicpain.org website for a user-friendly pain questionnaire).

With the previously mentioned risk factors in mind, and after a thorough history has been obtained, a pain-localizing exam should be conducted including the abdominal wall, pelvic floor, and then the bimanual and rectovaginal exams for the abdominal wall myofascial/neuropathic pain assessment for which Carnett’s test can be very useful—tender points on the abdominal wall are palpitated and the patient is asked to give a numerical rating of the pain (1-10/10) and marked with a pen. The patient is then asked to either perform a bilateral straight leg raise or an abdominal crunch, and the areas are re-palpitated. If the marked areas are more painful to palpation during the abdominal crunch or the bilateral straight leg raise, it suggests an abdominal wall pain (myofascial or neuropathic) or component of the pain. Similarly, pelvic floor muscles should be assessed after the abdominal wall exam is completed. This is best accomplished with a unit-digital exam with palpation of pelvic muscles for tenderness and hypertonia on exam. These myofascial findings are often present in the setting of endometriosis, but they can be primary-unrelated to presence or absence of endometriosis.

What are your focused disciplines for approaching endometriosis-associated pain? How do you recommend these clinicians or specialists come together to effectively manage a patient’s conditions? 

Dr. Rapkin: The gynecologist or primary care provider can address the chronic inflammatory, estrogen-dependent aspect of endometriosis. Begin with nonsteroidal, anti-inflammatory medication and combined estrogen-progestin or high-dose progestin-alone hormonal therapy to lower estrogenic stimulation of lesions and decidualize those progestin-sensitive lesions. For menstrual cycle related pain (luteal periovulatory or menstrual phase) cyclical exacerbation of other chronic pain conditions, early intervention is recommended. Adequately dosed preemptive nonsteroidal inflammatory agents and, if not tolerated or effective, begin combined hormonal contraceptives or intrauterine or higher dose progestins menstrual suppression, with either continuous monophasic hormonal contraceptives or progestins, is very important for pain that is cyclical or exacerbated in a cyclical fashion. Progestins can be administered orally, such as norethindrone acetate; intramuscularly or subdermally (depot medroxyprogesterone acetate or etonogestrel implant); or intrauterine (which does not lower estrogen levels but can be therapeutic for suppression of menses and local treatment of endometriosis). Failure of hormonal therapy and management of other co-occurring pain conditions warrants trial of a second-line medical therapy such as gonadotropin-releasing hormone antagonist or agonist or surgery for definitive diagnosis and surgical ablation or excision of endometriosis lesions.

I would suggest that gynecologists who treat women with endometriosis and chronic pain try to build a team in their geographic area. Relevant specialists for an interdisciplinary approach include:

• Pelvic floor physical therapist to evaluate and address myofascial dysfunction and pain and voiding abnormalities, such as urinary urgency or frequency and constipation
• Gastroenterologist for evaluation and treatment of irritable bowel or functional abdominal pain and bloating syndrome or inflammatory bowel disease. Urologist or urogynecologist to assess and treat bladder pain syndrome/interstitial cystitis
• Primary care evaluation for diffuse myofascial pain, fibromyalgia, arthralgias, and other inflammatory conditions, and for management of headache and migraine. Rheumatology and neurology specialists may be needed
• Mental health providers for treatment of anxiety, depression, or PTSD and to address stress management, coping skills and provide cognitive behavioral therapy
• Interventional pain management specialist such as physical medicine and rehabilitation (PM and R), pain anesthiologist, neurologist or interventional radiologist to provide relevant nerve blocks, trigger point injections, or botulinum toxin injection.
• Gynecologists experienced in the management of chronic pelvic pain also provide nerve blocks, trigger point and botulinum toxin injections.

Andrea Rapkin, MD, is Board Certified by the American College of Obstetricians and Gynecologists (of which she is also a fellow). After obtaining her MD, she completed her residency in OBGYN at UCLA then joined the faculty at UCLA and is a Professor of Obstetrics and Gynecology. She was one of the first Obstetrician-Gynecologists to adapt the multidisciplinary pain management approach to the evaluation and treatment of women with pelvic and vulvar pain.

You are the founder and director of a clinic focused on a multidisciplinary pain management approach to the evaluation and treatment of women with pelvic and vulvar pain. How did you identify such a clinic as a therapeutic need for patients? 

Dr. Rapkin: The short answer is that a significant proportion of women were not experiencing pain relief or had incomplete relief with traditional medical or surgical therapy. At the time, we also identified various red flags for traditional treatment failures. These red flags included the following: pain of greater than 6 months duration, pain out of proportion to pathology found on examination, multiple visceral and somatic complaints, and psychosocial abnormalities. We now understand more about the neurobiology underpinning these red flags.  

With the widespread availability of laparoscopy in the late 70s and early 80s, many studies investigated the relationship between endometriosis lesions and pain. The general consensus is that there is no relationship between the location or severity of the endometriosis lesions or the disease stage (American Society for Reproductive Medicine staging) with type of symptoms, symptom severity, treatment response, recurrence, or even prognosis. In fact, pain recurrence after adequate surgical treatment is unrelated to the presence of endometriosis lesions found at the time of repeat laparoscopy. This lack of association between pain and presence of visible disease was supported by a recent New England Journal of Medicine article by Zondervan and colleagues demonstrating that up to 30% of women with chronic pelvic pain, present after excision of endometriotic lesions, become unresponsive to conventional treatment.

The neurobiological responses in an individual with chronic pain are more complicated than those seen in the setting of acute pain. Chronic pain may be triggered or maintained by an inflammatory process such as endometriosis but, over time, altered neural processing and psychosocial maladaptation can occur. The altered processing consists of both peripheral and central sensitization which change the way sensory information from the pelvic viscera and surrounding somatic structures in the periphery is transmitted and interpreted in the central nervous system (spinal cord and brain). Visceral pelvic pain can emanate from the uterus, ovaries and fallopian tubes, the urinary bladder, and the bowel, while the somatic sources include the surrounding abdominal wall, low back and pelvic floor muscles, and fascia, and bones. Signal amplification or peripheral sensitization in the pelvic region in women with endometriosis starts with localized inflammation, neovascularization, invasion and innervation of endometriotic implants. As the pelvic organs share thoracolumbar and sacral autonomic neural pathways, inflammation or dysfunction in one organ or tissue, such as the uterus, over time can sensitize or lead to dysfunction in other pelvic organs, such as the bladder or bowel (called viscero-visceral cross sensitization). Finally, somatic structures sharing intervention with the pelvic viscera, such as the fascia and muscles of the lower abdomen, pelvic floor lower back also become sources of pain because of a process called viscero-somatic sensitization. Women who have endometriosis are therefore more likely to experience IBS, bladder pain syndrome/interstitial cystitis and vulvodynia, and up to 80% of individuals can develop myofascial pain related to trigger points and muscle dysfunction. Up to 50% of women with bladder pain have endometriosis. Those with endometriosis or bladder pain are 2.5 times more likely to also have IBS. 

Over time, other visceral and somatic structures innervated by higher levels of the spinal cord can be affected, leading to more widespread pain. Central sensitization manifests as an amplification of pain in the spinal cord and brain. The presence of more than two chronic “unexplained” pain conditions, such as chronic pelvic pain, vulvodynia, myofascial pain, headache, etc suggest the presence of central sensitization. Anxiety, depression, and maladaptive coping strategies often ensue. Functional MRI studies have documented altered central processing in the brain in many chronic pain states including endometriosis. Interdisciplinary therapy including physical therapy, mental health, and pain management/anesthesiology is more effective compared with medical and or surgical therapy alone for endometriosis-related pain in the setting of peripheral and central sensitization.

What should clinicians look for, or what stands out to them, to confirm the endometriosis diagnosis when pain is the presenting symptom?

Dr. Rapkin: There are no pathognomonic symptoms or biomarkers for endometriosis; however, the following historical features have been shown to be linked with a greater likelihood of finding endometriosis:

• persistent dysmenorrhea (menstrual pain) despite NSAID and hormonal treatment
• cyclical pain that is premenstrual and menstrual that progresses to chronic pain or is accompanied by abnormal or heavy menstrual bleeding
• deep dyspareunia
• dyschezia (pain with bowel movements), and sometimes bloating.

An individual with menstrual pain since menarche can have up to a 5% increased risk of endometriosis. Endometriosis in a first-degree relative elevates the risk for endometriosis by 7% to 10%.

Given the complexity of chronic pain, it is important not to assume endometriosis is the only source of pain. All the pelvic visceral and somatic structures should be evaluated. A thorough history addresses all the patient’s symptoms, including vaginal, gastrointestinal and genitourinary. Aggravating factors such as menstrual cycle, bowel and bladder functioning, physical activity, sexual intercourse and stress should be queried. In addition, assessment of mood, anxiety or depression, sleep disturbance and effect of pain on daily functioning are relevant as is history of abuse or trauma (physical, sexual or emotional). This history can be lengthy, so a detailed pain questionnaire is helpful. (See the pelvicpain.org website for a user-friendly pain questionnaire).

With the previously mentioned risk factors in mind, and after a thorough history has been obtained, a pain-localizing exam should be conducted including the abdominal wall, pelvic floor, and then the bimanual and rectovaginal exams for the abdominal wall myofascial/neuropathic pain assessment for which Carnett’s test can be very useful—tender points on the abdominal wall are palpitated and the patient is asked to give a numerical rating of the pain (1-10/10) and marked with a pen. The patient is then asked to either perform a bilateral straight leg raise or an abdominal crunch, and the areas are re-palpitated. If the marked areas are more painful to palpation during the abdominal crunch or the bilateral straight leg raise, it suggests an abdominal wall pain (myofascial or neuropathic) or component of the pain. Similarly, pelvic floor muscles should be assessed after the abdominal wall exam is completed. This is best accomplished with a unit-digital exam with palpation of pelvic muscles for tenderness and hypertonia on exam. These myofascial findings are often present in the setting of endometriosis, but they can be primary-unrelated to presence or absence of endometriosis.

What are your focused disciplines for approaching endometriosis-associated pain? How do you recommend these clinicians or specialists come together to effectively manage a patient’s conditions? 

Dr. Rapkin: The gynecologist or primary care provider can address the chronic inflammatory, estrogen-dependent aspect of endometriosis. Begin with nonsteroidal, anti-inflammatory medication and combined estrogen-progestin or high-dose progestin-alone hormonal therapy to lower estrogenic stimulation of lesions and decidualize those progestin-sensitive lesions. For menstrual cycle related pain (luteal periovulatory or menstrual phase) cyclical exacerbation of other chronic pain conditions, early intervention is recommended. Adequately dosed preemptive nonsteroidal inflammatory agents and, if not tolerated or effective, begin combined hormonal contraceptives or intrauterine or higher dose progestins menstrual suppression, with either continuous monophasic hormonal contraceptives or progestins, is very important for pain that is cyclical or exacerbated in a cyclical fashion. Progestins can be administered orally, such as norethindrone acetate; intramuscularly or subdermally (depot medroxyprogesterone acetate or etonogestrel implant); or intrauterine (which does not lower estrogen levels but can be therapeutic for suppression of menses and local treatment of endometriosis). Failure of hormonal therapy and management of other co-occurring pain conditions warrants trial of a second-line medical therapy such as gonadotropin-releasing hormone antagonist or agonist or surgery for definitive diagnosis and surgical ablation or excision of endometriosis lesions.

I would suggest that gynecologists who treat women with endometriosis and chronic pain try to build a team in their geographic area. Relevant specialists for an interdisciplinary approach include:

• Pelvic floor physical therapist to evaluate and address myofascial dysfunction and pain and voiding abnormalities, such as urinary urgency or frequency and constipation
• Gastroenterologist for evaluation and treatment of irritable bowel or functional abdominal pain and bloating syndrome or inflammatory bowel disease. Urologist or urogynecologist to assess and treat bladder pain syndrome/interstitial cystitis
• Primary care evaluation for diffuse myofascial pain, fibromyalgia, arthralgias, and other inflammatory conditions, and for management of headache and migraine. Rheumatology and neurology specialists may be needed
• Mental health providers for treatment of anxiety, depression, or PTSD and to address stress management, coping skills and provide cognitive behavioral therapy
• Interventional pain management specialist such as physical medicine and rehabilitation (PM and R), pain anesthiologist, neurologist or interventional radiologist to provide relevant nerve blocks, trigger point injections, or botulinum toxin injection.
• Gynecologists experienced in the management of chronic pelvic pain also provide nerve blocks, trigger point and botulinum toxin injections.

Andrea Rapkin, MD, is Board Certified by the American College of Obstetricians and Gynecologists (of which she is also a fellow). After obtaining her MD, she completed her residency in OBGYN at UCLA then joined the faculty at UCLA and is a Professor of Obstetrics and Gynecology. She was one of the first Obstetrician-Gynecologists to adapt the multidisciplinary pain management approach to the evaluation and treatment of women with pelvic and vulvar pain.

You are the founder and director of a clinic focused on a multidisciplinary pain management approach to the evaluation and treatment of women with pelvic and vulvar pain. How did you identify such a clinic as a therapeutic need for patients? 

Dr. Rapkin: The short answer is that a significant proportion of women were not experiencing pain relief or had incomplete relief with traditional medical or surgical therapy. At the time, we also identified various red flags for traditional treatment failures. These red flags included the following: pain of greater than 6 months duration, pain out of proportion to pathology found on examination, multiple visceral and somatic complaints, and psychosocial abnormalities. We now understand more about the neurobiology underpinning these red flags.  

With the widespread availability of laparoscopy in the late 70s and early 80s, many studies investigated the relationship between endometriosis lesions and pain. The general consensus is that there is no relationship between the location or severity of the endometriosis lesions or the disease stage (American Society for Reproductive Medicine staging) with type of symptoms, symptom severity, treatment response, recurrence, or even prognosis. In fact, pain recurrence after adequate surgical treatment is unrelated to the presence of endometriosis lesions found at the time of repeat laparoscopy. This lack of association between pain and presence of visible disease was supported by a recent New England Journal of Medicine article by Zondervan and colleagues demonstrating that up to 30% of women with chronic pelvic pain, present after excision of endometriotic lesions, become unresponsive to conventional treatment.

The neurobiological responses in an individual with chronic pain are more complicated than those seen in the setting of acute pain. Chronic pain may be triggered or maintained by an inflammatory process such as endometriosis but, over time, altered neural processing and psychosocial maladaptation can occur. The altered processing consists of both peripheral and central sensitization which change the way sensory information from the pelvic viscera and surrounding somatic structures in the periphery is transmitted and interpreted in the central nervous system (spinal cord and brain). Visceral pelvic pain can emanate from the uterus, ovaries and fallopian tubes, the urinary bladder, and the bowel, while the somatic sources include the surrounding abdominal wall, low back and pelvic floor muscles, and fascia, and bones. Signal amplification or peripheral sensitization in the pelvic region in women with endometriosis starts with localized inflammation, neovascularization, invasion and innervation of endometriotic implants. As the pelvic organs share thoracolumbar and sacral autonomic neural pathways, inflammation or dysfunction in one organ or tissue, such as the uterus, over time can sensitize or lead to dysfunction in other pelvic organs, such as the bladder or bowel (called viscero-visceral cross sensitization). Finally, somatic structures sharing intervention with the pelvic viscera, such as the fascia and muscles of the lower abdomen, pelvic floor lower back also become sources of pain because of a process called viscero-somatic sensitization. Women who have endometriosis are therefore more likely to experience IBS, bladder pain syndrome/interstitial cystitis and vulvodynia, and up to 80% of individuals can develop myofascial pain related to trigger points and muscle dysfunction. Up to 50% of women with bladder pain have endometriosis. Those with endometriosis or bladder pain are 2.5 times more likely to also have IBS. 

Over time, other visceral and somatic structures innervated by higher levels of the spinal cord can be affected, leading to more widespread pain. Central sensitization manifests as an amplification of pain in the spinal cord and brain. The presence of more than two chronic “unexplained” pain conditions, such as chronic pelvic pain, vulvodynia, myofascial pain, headache, etc suggest the presence of central sensitization. Anxiety, depression, and maladaptive coping strategies often ensue. Functional MRI studies have documented altered central processing in the brain in many chronic pain states including endometriosis. Interdisciplinary therapy including physical therapy, mental health, and pain management/anesthesiology is more effective compared with medical and or surgical therapy alone for endometriosis-related pain in the setting of peripheral and central sensitization.

What should clinicians look for, or what stands out to them, to confirm the endometriosis diagnosis when pain is the presenting symptom?

Dr. Rapkin: There are no pathognomonic symptoms or biomarkers for endometriosis; however, the following historical features have been shown to be linked with a greater likelihood of finding endometriosis:

• persistent dysmenorrhea (menstrual pain) despite NSAID and hormonal treatment
• cyclical pain that is premenstrual and menstrual that progresses to chronic pain or is accompanied by abnormal or heavy menstrual bleeding
• deep dyspareunia
• dyschezia (pain with bowel movements), and sometimes bloating.

An individual with menstrual pain since menarche can have up to a 5% increased risk of endometriosis. Endometriosis in a first-degree relative elevates the risk for endometriosis by 7% to 10%.

Given the complexity of chronic pain, it is important not to assume endometriosis is the only source of pain. All the pelvic visceral and somatic structures should be evaluated. A thorough history addresses all the patient’s symptoms, including vaginal, gastrointestinal and genitourinary. Aggravating factors such as menstrual cycle, bowel and bladder functioning, physical activity, sexual intercourse and stress should be queried. In addition, assessment of mood, anxiety or depression, sleep disturbance and effect of pain on daily functioning are relevant as is history of abuse or trauma (physical, sexual or emotional). This history can be lengthy, so a detailed pain questionnaire is helpful. (See the pelvicpain.org website for a user-friendly pain questionnaire).

With the previously mentioned risk factors in mind, and after a thorough history has been obtained, a pain-localizing exam should be conducted including the abdominal wall, pelvic floor, and then the bimanual and rectovaginal exams for the abdominal wall myofascial/neuropathic pain assessment for which Carnett’s test can be very useful—tender points on the abdominal wall are palpitated and the patient is asked to give a numerical rating of the pain (1-10/10) and marked with a pen. The patient is then asked to either perform a bilateral straight leg raise or an abdominal crunch, and the areas are re-palpitated. If the marked areas are more painful to palpation during the abdominal crunch or the bilateral straight leg raise, it suggests an abdominal wall pain (myofascial or neuropathic) or component of the pain. Similarly, pelvic floor muscles should be assessed after the abdominal wall exam is completed. This is best accomplished with a unit-digital exam with palpation of pelvic muscles for tenderness and hypertonia on exam. These myofascial findings are often present in the setting of endometriosis, but they can be primary-unrelated to presence or absence of endometriosis.

What are your focused disciplines for approaching endometriosis-associated pain? How do you recommend these clinicians or specialists come together to effectively manage a patient’s conditions? 

Dr. Rapkin: The gynecologist or primary care provider can address the chronic inflammatory, estrogen-dependent aspect of endometriosis. Begin with nonsteroidal, anti-inflammatory medication and combined estrogen-progestin or high-dose progestin-alone hormonal therapy to lower estrogenic stimulation of lesions and decidualize those progestin-sensitive lesions. For menstrual cycle related pain (luteal periovulatory or menstrual phase) cyclical exacerbation of other chronic pain conditions, early intervention is recommended. Adequately dosed preemptive nonsteroidal inflammatory agents and, if not tolerated or effective, begin combined hormonal contraceptives or intrauterine or higher dose progestins menstrual suppression, with either continuous monophasic hormonal contraceptives or progestins, is very important for pain that is cyclical or exacerbated in a cyclical fashion. Progestins can be administered orally, such as norethindrone acetate; intramuscularly or subdermally (depot medroxyprogesterone acetate or etonogestrel implant); or intrauterine (which does not lower estrogen levels but can be therapeutic for suppression of menses and local treatment of endometriosis). Failure of hormonal therapy and management of other co-occurring pain conditions warrants trial of a second-line medical therapy such as gonadotropin-releasing hormone antagonist or agonist or surgery for definitive diagnosis and surgical ablation or excision of endometriosis lesions.

I would suggest that gynecologists who treat women with endometriosis and chronic pain try to build a team in their geographic area. Relevant specialists for an interdisciplinary approach include:

• Pelvic floor physical therapist to evaluate and address myofascial dysfunction and pain and voiding abnormalities, such as urinary urgency or frequency and constipation
• Gastroenterologist for evaluation and treatment of irritable bowel or functional abdominal pain and bloating syndrome or inflammatory bowel disease. Urologist or urogynecologist to assess and treat bladder pain syndrome/interstitial cystitis
• Primary care evaluation for diffuse myofascial pain, fibromyalgia, arthralgias, and other inflammatory conditions, and for management of headache and migraine. Rheumatology and neurology specialists may be needed
• Mental health providers for treatment of anxiety, depression, or PTSD and to address stress management, coping skills and provide cognitive behavioral therapy
• Interventional pain management specialist such as physical medicine and rehabilitation (PM and R), pain anesthiologist, neurologist or interventional radiologist to provide relevant nerve blocks, trigger point injections, or botulinum toxin injection.
• Gynecologists experienced in the management of chronic pelvic pain also provide nerve blocks, trigger point and botulinum toxin injections.