Feature

Rates of overweight and obesity have more than doubled in the United States during the last three decades, according to a new analysis. By 2050, it’s anticipated that 213 million adults (age, > 25 years) and 43 million children and adolescents will have overweight or obesity. The results led authors of a study to describe obesity as having reached a “crisis point” requiring urgent action and interventions.

Are glucagon-like peptide 1 receptor agonists (GLP-1 RAs), originally developed and prescribed for diabetes and now approved for weight loss, the answer? 

Their popularity is certainly surging. Between the last 6 months of 2022 vs the last 6 months of 2024, the number of patients prescribed GLP-1 RAs increased by 132.6%. This is also reflected in a shift in public awareness, with a recent survey of US adults finding that 32% of respondents had heard “a lot” about these drugs, up from 19% in 2023.

GLP-1 RAs (including tirzepatide, which targets not only the GLP-1 receptor but also the glucose-dependent insulinotropic polypeptide receptor) have shown efficacy in weight loss. A 2022 review and meta-analysis of 22 trials (17,183 patients) found that 50.2% and 17.5% of those treated with GLP-1 RAs had a ≥ 5% and ≥ 10% weight loss, respectively, compared with placebo. A 2023 review of 41 trials (15,135 patients) found that compared with controls, GLP-1 RAs significantly reduced body weight, body mass index, waist circumference, and waist-to-hip ratio.

“GLP-1 RAs are great medications,” Andres Acosta, MD, PhD, director of the Precision Medicine for Obesity Laboratory, Mayo Clinic, Rochester, Minnesota, told Medscape Medical News. “We’ve been using them for almost two decades. But now there’s excitement about their utility in treating obesity.”

 

Treating the Four Categories of Obesity 

Daniel Drucker, MD, senior investigator at the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, is a pioneer in diabetes treatment and particularly in the development of GLP-1 RAs. Drucker told Medscape Medical News that despite the efficacy and enormous potential of GLP-1 RAs, “we know some people don’t lose much weight when taking these medicines and others don’t feel well and can’t take them.”

The number of individuals who don’t respond to or aren’t able to tolerate GLP-1 RAs “might be small — less than 10% of people who try to take them — but we don’t fully understand the differences in response across different individuals,” Drucker said.

Acosta agreed, adding that it’s “essential for us to identify who will be the best responders, as we do with medications for other conditions, such as cancer and cardiovascular disease.”

Acosta’s group has spent more than a decade engaged in efforts to identify unique characteristics among patients with obesity and has succeeded in identifying four obesity phenotypes.

“What matters in the space of GLP-1 is that using this classification, we can identify the best responders and those who don’t respond.” 

The first phenotype, described as “Hungry Gut” (HG), includes patients with abnormal postprandial satiety. “Although they may be satiated at the end of a meal, they have accelerated gastric emptying and therefore feel hungry between meals and want to keep eating,” he said.

There are also patients who experience abnormal satiety during meals. According to Acosta, these are the patients who will return to the table for second and third helpings. “They don’t feel full and continue to eat more and more in a single sitting” — a phenomenon referred to as “Hungry Brain.”

The third phenotype — “Emotional Hunger” — consists of people who are “hedonic” about food or engage in emotional eating behavior, whereas in the fourth group, people have “an abnormal metabolism in which they don’t burn enough calories. They have an inefficient metabolic rate.” This latter phenomenon is called “Slow Burn.”

Acosta and colleagues randomized 312 patients attending a weight management center to phenotype-guided or non–phenotype-guided treatment with anti-obesity medications (phentermine, phentermine/topiramate, bupropion/naltrexone, lorcaserin, and liraglutide). The phenotype-guided approach was associated with a 1.75-fold greater weight loss after 1 year than the non–phenotype-guided approach (mean weight loss, 15.9% vs 9.0%, respectively).

 

GLP-1 RAs: Not One-Size-Fits-All

Acosta’s group has developed a genetic test that uses patients’ saliva to identify their obesity phenotype, with the aim of predicting the best responders to GLP-1 RAs. The test, MyPhenome genetic obesity test, is licensed by Acosta’s lab and available through Phenomix Sciences.

Acosta and colleagues presented their findings at the American Gastroenterological Association’s 2024 annual meeting regarding a machine-learning gene risk score (ML-GRS) they developed to predict HG, based on saliva and blood samples. Their genetic studies generated a ML-GRS that classified participants with obesity along a continuum from “HG Positive” (HG+) to “HG Negative” (HG−). Compared with the HG− participants, those who were HG+ had superior total body weight loss with semaglutide at 9 and 12 months. When used to predict response, the ML-GRS had an area under the curve of 0.76 (P = .04) and a positive predictive value of 0.95.

According to Acosta, HG+ patients are “the best responders to the GLP-1 RAs, although we don’t yet understand the mechanism of why they have the phenomenon of abnormal postprandial satiety. It may be an abnormal genetic pathway or abnormal secretion of GLP-1. More studies are needed.”

He noted that GLP-1 RAs “might also be helpful with the second [Hungry Brain] category, but these patients do better with phentermine-topiramate,” as demonstrated in a 2023 study conducted by Acosta and colleagues.

His group has also studied which lifestyle interventions are most effective for each phenotype. “When a unique lifestyle intervention targeting each phenotype was applied, patients lost more weight and had greater metabolic improvement,” he reported.

“Treating obesity no longer needs to be trial-and-error, but should be done using precision medicine because one size doesn’t fit all,” Acosta said.

 

Concerning Side Effects

The popular media has featured stories about individuals who took GLP-1 RAs for weight loss and experienced serious side effects, including a recent account of a British nurse who died after taking tirzepatide. As reported by the BBC, the nurse’s death certificate listed multiple organ failure, septic shock, and pancreatitis as the immediate causes of death, with the “use of prescribed tirzepatide” recorded as a contributing factor. The report went on to note that there were 23 suspected deaths in the United Kingdom tied to semaglutide since 2019.

Beyond brand-name products, there are also risks associated with GLP-1 RAs manufactured by compounding pharmacies. In early November, CNN reported that compounded semaglutide has been linked to at least 10 deaths. Because of a prior shortage of tirzepatide, the US Food and Drug Administration (FDA) had allowed compounding pharmacies to manufacture the drug. In October, the FDA clarified that it won’t take legal action against compounders, even now that the shortage has been resolved.

A pharmacovigilance study using the FDA Adverse Event Reporting System identified “potential safety signals of increased mortality and serious adverse event reporting” associated with certain GLP-1 RAs — especially in younger patients and women (P < .0001 for both groups).

The most common side effects reported with GLP-1 RAs are gastrointestinal events, such as nausea, diarrhea, constipation, and vomiting. Most occur during dose initiation and escalation and wane over the following weeks. However, studies have also reported severe side effects, including a higher risk for pancreatitis, bowel obstruction, and gastroparesis, as well as a significantly higher risk for gallbladder and biliary diseases. In fact, according to one study, patients with diabetes taking GLP-1 RAs reported gastrointestinal-related issues as a “prominent factor” in their decision to discontinue taking these medications.

Several types of cancer are potentially associated with GLP-1 RAs, but findings regarding this potential link have been inconsistent. In a recent review article, Drucker noted there were only inconsistent data linking GLP-1 RAs with thyroid cancer and medullary thyroid cancer and that their potential association with pancreatic has “not been supported by results from randomized controlled trials or real-world data.” 

Concerns have been raised about loss of lean mass and muscle strength and function, especially in older individuals with obesity and advanced liver, cardiovascular, or kidney disease. However, as Drucker pointed out in his review article, muscle function may not correlate with the loss of lean mass. In fact, there are “consistent reductions” in lean mass after bariatric surgery, but “little evidence to date for impairment of muscle function.” He added that newer GLP-1 agents under development for obesity treatment are focusing on “developing complementary therapies that preferentially reduce adipose tissue, while sparing lean mass.”

As covered by Medscape Medical News, there have been reports of potential suicidal ideation associated with GLP-1 RAs. This triggered a 2023 review from the European Medicines Agency. However, recent results from a cohort study and a post hoc analysis of randomized controlled trials concluded that there is no evidence that these drugs increase suicidal ideation or behavior.

In early November, the FDA updated the labels for the GLP-1 RAs to include a warning regarding pulmonary aspiration during general anesthesia or deep sedation. Guidance from a group of societies, led by the American Society of Anesthesiologists, contains recommendations regarding nuances of addressing this concern in surgical patients taking these agents.

 

Not a Standalone Treatment

Marc-Andre Cornier, MD, professor of medicine, James A. Keating Endowed Chair in Diabetes, and director of the Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, told Medscape Medical News that GLP-1 RAs should not be viewed as cosmetic interventions but rather as medical treatments, “not only for weight loss but to reverse obesity-associated complications.” 

Moreover, they should be used “as an adjunct to lifestyle changes,” emphasized Cornier. “We want our patients to have a high-quality diet with high protein content, fluid, vitamins, and minerals, and we want them to exercise.” Especially with the concern of potential loss of muscle mass with these agents, “resistance exercise might help mitigate that concern.”

Recently published recommendations can assist clinicians in guiding patients taking GLP-1 RAs to optimize nutrition. The recommendations note that patients should be referred to a registered dietitian to “complement and support” treatment with anti-obesity medications.

 

What Do Patients Want?

Despite the ever-rising popularity of GLP-1 RAs, a new national survey of over 2200 US adults conducted by the Physicians Committee for Responsible Medicine suggests that most Americans don’t want to use them. Among those who wanted to lose weight, almost three-quarters “disagreed” or “strongly disagreed” with the idea of taking a weight-loss injectable, and 68% of those who wanted to lose weight “agreed” or “strongly agreed” that they would be willing to try a plant-based diet, if it could lead to significant weight loss.

Moreover, many individuals treated with GLP-1 RAs discontinue their use, despite the probability of regaining the weight, according to a report that found only 46.3% of GLP-1 users were still taking the medications at 6 months and only 32.3% at 1 year. The authors commented that their real-world findings show a “substantially lower” 1-year persistence rate, compared with the rate reported in clinical trials. They suggest that the financial burden (> $12,000/year) may contribute to discontinuation.

Discontinuation of GLP-1 RAs can lead to worsening cardiometabolic parameters, with a potential increased risk for adverse outcomes; moreover, weight cycling (“yo-yo dieting”) carries its own risks. In light of these concerns, it’s particularly important to select appropriate patients and to determine whether potential short-term therapy has any enduring benefit.

Acosta agreed. “It’s exciting when looking at the data on how to find the best responders and who should make the effort to take these medications — not only in terms of side effects but also in terms of cost and which patients will receive maximum benefits and should be covered by insurance.” 

Drucker has served as a consultant or speaker for Altimmune, Amgen, AstraZeneca, Arrowhead, Boehringer Ingelheim, Kallyope, Merck Research Laboratories, Novo Nordisk, Pfizer, and Zealand Pharma. He holds nonexercised options in Kallyope. Mount Sinai Hospital receives research support for investigator-initiated studies in the Drucker laboratory from Amgen, Novo Nordisk, Pfizer, and Zealand Pharma. Gila Therapeutics and Phenomix Sciences have licensed Acosta’s research technologies from University of Florida and Mayo Clinic. Acosta received consultant fees in the last 5 years from Rhythm Pharmaceuticals, Gila Therapeutics, Amgen, General Mills, Regeneron Pharmaceuticals, Boehringer Ingelheim, Novo Nordisk, Currax, Nestlé, Phenomix Sciences, Bausch Health, and Rare Disease. He received funding support from the National Institutes of Health, Vivus Pharmaceuticals, Novo Nordisk, Apollo Endosurgery, Satiogen Pharmaceuticals, Spatz Medical, Rhythm Pharmaceuticals, Regeneron Pharmaceuticals, Boehringer Ingelheim, and Novo Nordisk. In the past, Cornier has served as a consultant for Novo Nordisk.

 

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

Rates of overweight and obesity have more than doubled in the United States during the last three decades, according to a new analysis. By 2050, it’s anticipated that 213 million adults (age, > 25 years) and 43 million children and adolescents will have overweight or obesity. The results led authors of a study to describe obesity as having reached a “crisis point” requiring urgent action and interventions.

Are glucagon-like peptide 1 receptor agonists (GLP-1 RAs), originally developed and prescribed for diabetes and now approved for weight loss, the answer? 

Their popularity is certainly surging. Between the last 6 months of 2022 vs the last 6 months of 2024, the number of patients prescribed GLP-1 RAs increased by 132.6%. This is also reflected in a shift in public awareness, with a recent survey of US adults finding that 32% of respondents had heard “a lot” about these drugs, up from 19% in 2023.

GLP-1 RAs (including tirzepatide, which targets not only the GLP-1 receptor but also the glucose-dependent insulinotropic polypeptide receptor) have shown efficacy in weight loss. A 2022 review and meta-analysis of 22 trials (17,183 patients) found that 50.2% and 17.5% of those treated with GLP-1 RAs had a ≥ 5% and ≥ 10% weight loss, respectively, compared with placebo. A 2023 review of 41 trials (15,135 patients) found that compared with controls, GLP-1 RAs significantly reduced body weight, body mass index, waist circumference, and waist-to-hip ratio.

“GLP-1 RAs are great medications,” Andres Acosta, MD, PhD, director of the Precision Medicine for Obesity Laboratory, Mayo Clinic, Rochester, Minnesota, told Medscape Medical News. “We’ve been using them for almost two decades. But now there’s excitement about their utility in treating obesity.”

 

Treating the Four Categories of Obesity 

Daniel Drucker, MD, senior investigator at the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, is a pioneer in diabetes treatment and particularly in the development of GLP-1 RAs. Drucker told Medscape Medical News that despite the efficacy and enormous potential of GLP-1 RAs, “we know some people don’t lose much weight when taking these medicines and others don’t feel well and can’t take them.”

The number of individuals who don’t respond to or aren’t able to tolerate GLP-1 RAs “might be small — less than 10% of people who try to take them — but we don’t fully understand the differences in response across different individuals,” Drucker said.

Acosta agreed, adding that it’s “essential for us to identify who will be the best responders, as we do with medications for other conditions, such as cancer and cardiovascular disease.”

Acosta’s group has spent more than a decade engaged in efforts to identify unique characteristics among patients with obesity and has succeeded in identifying four obesity phenotypes.

“What matters in the space of GLP-1 is that using this classification, we can identify the best responders and those who don’t respond.” 

The first phenotype, described as “Hungry Gut” (HG), includes patients with abnormal postprandial satiety. “Although they may be satiated at the end of a meal, they have accelerated gastric emptying and therefore feel hungry between meals and want to keep eating,” he said.

There are also patients who experience abnormal satiety during meals. According to Acosta, these are the patients who will return to the table for second and third helpings. “They don’t feel full and continue to eat more and more in a single sitting” — a phenomenon referred to as “Hungry Brain.”

The third phenotype — “Emotional Hunger” — consists of people who are “hedonic” about food or engage in emotional eating behavior, whereas in the fourth group, people have “an abnormal metabolism in which they don’t burn enough calories. They have an inefficient metabolic rate.” This latter phenomenon is called “Slow Burn.”

Acosta and colleagues randomized 312 patients attending a weight management center to phenotype-guided or non–phenotype-guided treatment with anti-obesity medications (phentermine, phentermine/topiramate, bupropion/naltrexone, lorcaserin, and liraglutide). The phenotype-guided approach was associated with a 1.75-fold greater weight loss after 1 year than the non–phenotype-guided approach (mean weight loss, 15.9% vs 9.0%, respectively).

 

GLP-1 RAs: Not One-Size-Fits-All

Acosta’s group has developed a genetic test that uses patients’ saliva to identify their obesity phenotype, with the aim of predicting the best responders to GLP-1 RAs. The test, MyPhenome genetic obesity test, is licensed by Acosta’s lab and available through Phenomix Sciences.

Acosta and colleagues presented their findings at the American Gastroenterological Association’s 2024 annual meeting regarding a machine-learning gene risk score (ML-GRS) they developed to predict HG, based on saliva and blood samples. Their genetic studies generated a ML-GRS that classified participants with obesity along a continuum from “HG Positive” (HG+) to “HG Negative” (HG−). Compared with the HG− participants, those who were HG+ had superior total body weight loss with semaglutide at 9 and 12 months. When used to predict response, the ML-GRS had an area under the curve of 0.76 (P = .04) and a positive predictive value of 0.95.

According to Acosta, HG+ patients are “the best responders to the GLP-1 RAs, although we don’t yet understand the mechanism of why they have the phenomenon of abnormal postprandial satiety. It may be an abnormal genetic pathway or abnormal secretion of GLP-1. More studies are needed.”

He noted that GLP-1 RAs “might also be helpful with the second [Hungry Brain] category, but these patients do better with phentermine-topiramate,” as demonstrated in a 2023 study conducted by Acosta and colleagues.

His group has also studied which lifestyle interventions are most effective for each phenotype. “When a unique lifestyle intervention targeting each phenotype was applied, patients lost more weight and had greater metabolic improvement,” he reported.

“Treating obesity no longer needs to be trial-and-error, but should be done using precision medicine because one size doesn’t fit all,” Acosta said.

 

Concerning Side Effects

The popular media has featured stories about individuals who took GLP-1 RAs for weight loss and experienced serious side effects, including a recent account of a British nurse who died after taking tirzepatide. As reported by the BBC, the nurse’s death certificate listed multiple organ failure, septic shock, and pancreatitis as the immediate causes of death, with the “use of prescribed tirzepatide” recorded as a contributing factor. The report went on to note that there were 23 suspected deaths in the United Kingdom tied to semaglutide since 2019.

Beyond brand-name products, there are also risks associated with GLP-1 RAs manufactured by compounding pharmacies. In early November, CNN reported that compounded semaglutide has been linked to at least 10 deaths. Because of a prior shortage of tirzepatide, the US Food and Drug Administration (FDA) had allowed compounding pharmacies to manufacture the drug. In October, the FDA clarified that it won’t take legal action against compounders, even now that the shortage has been resolved.

A pharmacovigilance study using the FDA Adverse Event Reporting System identified “potential safety signals of increased mortality and serious adverse event reporting” associated with certain GLP-1 RAs — especially in younger patients and women (P < .0001 for both groups).

The most common side effects reported with GLP-1 RAs are gastrointestinal events, such as nausea, diarrhea, constipation, and vomiting. Most occur during dose initiation and escalation and wane over the following weeks. However, studies have also reported severe side effects, including a higher risk for pancreatitis, bowel obstruction, and gastroparesis, as well as a significantly higher risk for gallbladder and biliary diseases. In fact, according to one study, patients with diabetes taking GLP-1 RAs reported gastrointestinal-related issues as a “prominent factor” in their decision to discontinue taking these medications.

Several types of cancer are potentially associated with GLP-1 RAs, but findings regarding this potential link have been inconsistent. In a recent review article, Drucker noted there were only inconsistent data linking GLP-1 RAs with thyroid cancer and medullary thyroid cancer and that their potential association with pancreatic has “not been supported by results from randomized controlled trials or real-world data.” 

Concerns have been raised about loss of lean mass and muscle strength and function, especially in older individuals with obesity and advanced liver, cardiovascular, or kidney disease. However, as Drucker pointed out in his review article, muscle function may not correlate with the loss of lean mass. In fact, there are “consistent reductions” in lean mass after bariatric surgery, but “little evidence to date for impairment of muscle function.” He added that newer GLP-1 agents under development for obesity treatment are focusing on “developing complementary therapies that preferentially reduce adipose tissue, while sparing lean mass.”

As covered by Medscape Medical News, there have been reports of potential suicidal ideation associated with GLP-1 RAs. This triggered a 2023 review from the European Medicines Agency. However, recent results from a cohort study and a post hoc analysis of randomized controlled trials concluded that there is no evidence that these drugs increase suicidal ideation or behavior.

In early November, the FDA updated the labels for the GLP-1 RAs to include a warning regarding pulmonary aspiration during general anesthesia or deep sedation. Guidance from a group of societies, led by the American Society of Anesthesiologists, contains recommendations regarding nuances of addressing this concern in surgical patients taking these agents.

 

Not a Standalone Treatment

Marc-Andre Cornier, MD, professor of medicine, James A. Keating Endowed Chair in Diabetes, and director of the Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, told Medscape Medical News that GLP-1 RAs should not be viewed as cosmetic interventions but rather as medical treatments, “not only for weight loss but to reverse obesity-associated complications.” 

Moreover, they should be used “as an adjunct to lifestyle changes,” emphasized Cornier. “We want our patients to have a high-quality diet with high protein content, fluid, vitamins, and minerals, and we want them to exercise.” Especially with the concern of potential loss of muscle mass with these agents, “resistance exercise might help mitigate that concern.”

Recently published recommendations can assist clinicians in guiding patients taking GLP-1 RAs to optimize nutrition. The recommendations note that patients should be referred to a registered dietitian to “complement and support” treatment with anti-obesity medications.

 

What Do Patients Want?

Despite the ever-rising popularity of GLP-1 RAs, a new national survey of over 2200 US adults conducted by the Physicians Committee for Responsible Medicine suggests that most Americans don’t want to use them. Among those who wanted to lose weight, almost three-quarters “disagreed” or “strongly disagreed” with the idea of taking a weight-loss injectable, and 68% of those who wanted to lose weight “agreed” or “strongly agreed” that they would be willing to try a plant-based diet, if it could lead to significant weight loss.

Moreover, many individuals treated with GLP-1 RAs discontinue their use, despite the probability of regaining the weight, according to a report that found only 46.3% of GLP-1 users were still taking the medications at 6 months and only 32.3% at 1 year. The authors commented that their real-world findings show a “substantially lower” 1-year persistence rate, compared with the rate reported in clinical trials. They suggest that the financial burden (> $12,000/year) may contribute to discontinuation.

Discontinuation of GLP-1 RAs can lead to worsening cardiometabolic parameters, with a potential increased risk for adverse outcomes; moreover, weight cycling (“yo-yo dieting”) carries its own risks. In light of these concerns, it’s particularly important to select appropriate patients and to determine whether potential short-term therapy has any enduring benefit.

Acosta agreed. “It’s exciting when looking at the data on how to find the best responders and who should make the effort to take these medications — not only in terms of side effects but also in terms of cost and which patients will receive maximum benefits and should be covered by insurance.” 

Drucker has served as a consultant or speaker for Altimmune, Amgen, AstraZeneca, Arrowhead, Boehringer Ingelheim, Kallyope, Merck Research Laboratories, Novo Nordisk, Pfizer, and Zealand Pharma. He holds nonexercised options in Kallyope. Mount Sinai Hospital receives research support for investigator-initiated studies in the Drucker laboratory from Amgen, Novo Nordisk, Pfizer, and Zealand Pharma. Gila Therapeutics and Phenomix Sciences have licensed Acosta’s research technologies from University of Florida and Mayo Clinic. Acosta received consultant fees in the last 5 years from Rhythm Pharmaceuticals, Gila Therapeutics, Amgen, General Mills, Regeneron Pharmaceuticals, Boehringer Ingelheim, Novo Nordisk, Currax, Nestlé, Phenomix Sciences, Bausch Health, and Rare Disease. He received funding support from the National Institutes of Health, Vivus Pharmaceuticals, Novo Nordisk, Apollo Endosurgery, Satiogen Pharmaceuticals, Spatz Medical, Rhythm Pharmaceuticals, Regeneron Pharmaceuticals, Boehringer Ingelheim, and Novo Nordisk. In the past, Cornier has served as a consultant for Novo Nordisk.

 

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

Rates of overweight and obesity have more than doubled in the United States during the last three decades, according to a new analysis. By 2050, it’s anticipated that 213 million adults (age, > 25 years) and 43 million children and adolescents will have overweight or obesity. The results led authors of a study to describe obesity as having reached a “crisis point” requiring urgent action and interventions.

Are glucagon-like peptide 1 receptor agonists (GLP-1 RAs), originally developed and prescribed for diabetes and now approved for weight loss, the answer? 

Their popularity is certainly surging. Between the last 6 months of 2022 vs the last 6 months of 2024, the number of patients prescribed GLP-1 RAs increased by 132.6%. This is also reflected in a shift in public awareness, with a recent survey of US adults finding that 32% of respondents had heard “a lot” about these drugs, up from 19% in 2023.

GLP-1 RAs (including tirzepatide, which targets not only the GLP-1 receptor but also the glucose-dependent insulinotropic polypeptide receptor) have shown efficacy in weight loss. A 2022 review and meta-analysis of 22 trials (17,183 patients) found that 50.2% and 17.5% of those treated with GLP-1 RAs had a ≥ 5% and ≥ 10% weight loss, respectively, compared with placebo. A 2023 review of 41 trials (15,135 patients) found that compared with controls, GLP-1 RAs significantly reduced body weight, body mass index, waist circumference, and waist-to-hip ratio.

“GLP-1 RAs are great medications,” Andres Acosta, MD, PhD, director of the Precision Medicine for Obesity Laboratory, Mayo Clinic, Rochester, Minnesota, told Medscape Medical News. “We’ve been using them for almost two decades. But now there’s excitement about their utility in treating obesity.”

 

Treating the Four Categories of Obesity 

Daniel Drucker, MD, senior investigator at the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, is a pioneer in diabetes treatment and particularly in the development of GLP-1 RAs. Drucker told Medscape Medical News that despite the efficacy and enormous potential of GLP-1 RAs, “we know some people don’t lose much weight when taking these medicines and others don’t feel well and can’t take them.”

The number of individuals who don’t respond to or aren’t able to tolerate GLP-1 RAs “might be small — less than 10% of people who try to take them — but we don’t fully understand the differences in response across different individuals,” Drucker said.

Acosta agreed, adding that it’s “essential for us to identify who will be the best responders, as we do with medications for other conditions, such as cancer and cardiovascular disease.”

Acosta’s group has spent more than a decade engaged in efforts to identify unique characteristics among patients with obesity and has succeeded in identifying four obesity phenotypes.

“What matters in the space of GLP-1 is that using this classification, we can identify the best responders and those who don’t respond.” 

The first phenotype, described as “Hungry Gut” (HG), includes patients with abnormal postprandial satiety. “Although they may be satiated at the end of a meal, they have accelerated gastric emptying and therefore feel hungry between meals and want to keep eating,” he said.

There are also patients who experience abnormal satiety during meals. According to Acosta, these are the patients who will return to the table for second and third helpings. “They don’t feel full and continue to eat more and more in a single sitting” — a phenomenon referred to as “Hungry Brain.”

The third phenotype — “Emotional Hunger” — consists of people who are “hedonic” about food or engage in emotional eating behavior, whereas in the fourth group, people have “an abnormal metabolism in which they don’t burn enough calories. They have an inefficient metabolic rate.” This latter phenomenon is called “Slow Burn.”

Acosta and colleagues randomized 312 patients attending a weight management center to phenotype-guided or non–phenotype-guided treatment with anti-obesity medications (phentermine, phentermine/topiramate, bupropion/naltrexone, lorcaserin, and liraglutide). The phenotype-guided approach was associated with a 1.75-fold greater weight loss after 1 year than the non–phenotype-guided approach (mean weight loss, 15.9% vs 9.0%, respectively).

 

GLP-1 RAs: Not One-Size-Fits-All

Acosta’s group has developed a genetic test that uses patients’ saliva to identify their obesity phenotype, with the aim of predicting the best responders to GLP-1 RAs. The test, MyPhenome genetic obesity test, is licensed by Acosta’s lab and available through Phenomix Sciences.

Acosta and colleagues presented their findings at the American Gastroenterological Association’s 2024 annual meeting regarding a machine-learning gene risk score (ML-GRS) they developed to predict HG, based on saliva and blood samples. Their genetic studies generated a ML-GRS that classified participants with obesity along a continuum from “HG Positive” (HG+) to “HG Negative” (HG−). Compared with the HG− participants, those who were HG+ had superior total body weight loss with semaglutide at 9 and 12 months. When used to predict response, the ML-GRS had an area under the curve of 0.76 (P = .04) and a positive predictive value of 0.95.

According to Acosta, HG+ patients are “the best responders to the GLP-1 RAs, although we don’t yet understand the mechanism of why they have the phenomenon of abnormal postprandial satiety. It may be an abnormal genetic pathway or abnormal secretion of GLP-1. More studies are needed.”

He noted that GLP-1 RAs “might also be helpful with the second [Hungry Brain] category, but these patients do better with phentermine-topiramate,” as demonstrated in a 2023 study conducted by Acosta and colleagues.

His group has also studied which lifestyle interventions are most effective for each phenotype. “When a unique lifestyle intervention targeting each phenotype was applied, patients lost more weight and had greater metabolic improvement,” he reported.

“Treating obesity no longer needs to be trial-and-error, but should be done using precision medicine because one size doesn’t fit all,” Acosta said.

 

Concerning Side Effects

The popular media has featured stories about individuals who took GLP-1 RAs for weight loss and experienced serious side effects, including a recent account of a British nurse who died after taking tirzepatide. As reported by the BBC, the nurse’s death certificate listed multiple organ failure, septic shock, and pancreatitis as the immediate causes of death, with the “use of prescribed tirzepatide” recorded as a contributing factor. The report went on to note that there were 23 suspected deaths in the United Kingdom tied to semaglutide since 2019.

Beyond brand-name products, there are also risks associated with GLP-1 RAs manufactured by compounding pharmacies. In early November, CNN reported that compounded semaglutide has been linked to at least 10 deaths. Because of a prior shortage of tirzepatide, the US Food and Drug Administration (FDA) had allowed compounding pharmacies to manufacture the drug. In October, the FDA clarified that it won’t take legal action against compounders, even now that the shortage has been resolved.

A pharmacovigilance study using the FDA Adverse Event Reporting System identified “potential safety signals of increased mortality and serious adverse event reporting” associated with certain GLP-1 RAs — especially in younger patients and women (P < .0001 for both groups).

The most common side effects reported with GLP-1 RAs are gastrointestinal events, such as nausea, diarrhea, constipation, and vomiting. Most occur during dose initiation and escalation and wane over the following weeks. However, studies have also reported severe side effects, including a higher risk for pancreatitis, bowel obstruction, and gastroparesis, as well as a significantly higher risk for gallbladder and biliary diseases. In fact, according to one study, patients with diabetes taking GLP-1 RAs reported gastrointestinal-related issues as a “prominent factor” in their decision to discontinue taking these medications.

Several types of cancer are potentially associated with GLP-1 RAs, but findings regarding this potential link have been inconsistent. In a recent review article, Drucker noted there were only inconsistent data linking GLP-1 RAs with thyroid cancer and medullary thyroid cancer and that their potential association with pancreatic has “not been supported by results from randomized controlled trials or real-world data.” 

Concerns have been raised about loss of lean mass and muscle strength and function, especially in older individuals with obesity and advanced liver, cardiovascular, or kidney disease. However, as Drucker pointed out in his review article, muscle function may not correlate with the loss of lean mass. In fact, there are “consistent reductions” in lean mass after bariatric surgery, but “little evidence to date for impairment of muscle function.” He added that newer GLP-1 agents under development for obesity treatment are focusing on “developing complementary therapies that preferentially reduce adipose tissue, while sparing lean mass.”

As covered by Medscape Medical News, there have been reports of potential suicidal ideation associated with GLP-1 RAs. This triggered a 2023 review from the European Medicines Agency. However, recent results from a cohort study and a post hoc analysis of randomized controlled trials concluded that there is no evidence that these drugs increase suicidal ideation or behavior.

In early November, the FDA updated the labels for the GLP-1 RAs to include a warning regarding pulmonary aspiration during general anesthesia or deep sedation. Guidance from a group of societies, led by the American Society of Anesthesiologists, contains recommendations regarding nuances of addressing this concern in surgical patients taking these agents.

 

Not a Standalone Treatment

Marc-Andre Cornier, MD, professor of medicine, James A. Keating Endowed Chair in Diabetes, and director of the Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, told Medscape Medical News that GLP-1 RAs should not be viewed as cosmetic interventions but rather as medical treatments, “not only for weight loss but to reverse obesity-associated complications.” 

Moreover, they should be used “as an adjunct to lifestyle changes,” emphasized Cornier. “We want our patients to have a high-quality diet with high protein content, fluid, vitamins, and minerals, and we want them to exercise.” Especially with the concern of potential loss of muscle mass with these agents, “resistance exercise might help mitigate that concern.”

Recently published recommendations can assist clinicians in guiding patients taking GLP-1 RAs to optimize nutrition. The recommendations note that patients should be referred to a registered dietitian to “complement and support” treatment with anti-obesity medications.

 

What Do Patients Want?

Despite the ever-rising popularity of GLP-1 RAs, a new national survey of over 2200 US adults conducted by the Physicians Committee for Responsible Medicine suggests that most Americans don’t want to use them. Among those who wanted to lose weight, almost three-quarters “disagreed” or “strongly disagreed” with the idea of taking a weight-loss injectable, and 68% of those who wanted to lose weight “agreed” or “strongly agreed” that they would be willing to try a plant-based diet, if it could lead to significant weight loss.

Moreover, many individuals treated with GLP-1 RAs discontinue their use, despite the probability of regaining the weight, according to a report that found only 46.3% of GLP-1 users were still taking the medications at 6 months and only 32.3% at 1 year. The authors commented that their real-world findings show a “substantially lower” 1-year persistence rate, compared with the rate reported in clinical trials. They suggest that the financial burden (> $12,000/year) may contribute to discontinuation.

Discontinuation of GLP-1 RAs can lead to worsening cardiometabolic parameters, with a potential increased risk for adverse outcomes; moreover, weight cycling (“yo-yo dieting”) carries its own risks. In light of these concerns, it’s particularly important to select appropriate patients and to determine whether potential short-term therapy has any enduring benefit.

Acosta agreed. “It’s exciting when looking at the data on how to find the best responders and who should make the effort to take these medications — not only in terms of side effects but also in terms of cost and which patients will receive maximum benefits and should be covered by insurance.” 

Drucker has served as a consultant or speaker for Altimmune, Amgen, AstraZeneca, Arrowhead, Boehringer Ingelheim, Kallyope, Merck Research Laboratories, Novo Nordisk, Pfizer, and Zealand Pharma. He holds nonexercised options in Kallyope. Mount Sinai Hospital receives research support for investigator-initiated studies in the Drucker laboratory from Amgen, Novo Nordisk, Pfizer, and Zealand Pharma. Gila Therapeutics and Phenomix Sciences have licensed Acosta’s research technologies from University of Florida and Mayo Clinic. Acosta received consultant fees in the last 5 years from Rhythm Pharmaceuticals, Gila Therapeutics, Amgen, General Mills, Regeneron Pharmaceuticals, Boehringer Ingelheim, Novo Nordisk, Currax, Nestlé, Phenomix Sciences, Bausch Health, and Rare Disease. He received funding support from the National Institutes of Health, Vivus Pharmaceuticals, Novo Nordisk, Apollo Endosurgery, Satiogen Pharmaceuticals, Spatz Medical, Rhythm Pharmaceuticals, Regeneron Pharmaceuticals, Boehringer Ingelheim, and Novo Nordisk. In the past, Cornier has served as a consultant for Novo Nordisk.

 

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

The Food and Drug Administration (FDA) has approved zanidatamab (Ziihera, Jazz Pharmaceuticals) as monotherapy for previously treated, unresectable or metastatic HER2-positive biliary tract cancer (BTC). This approval makes the bispecific antibody the first HER2-targeted treatment to carry the indication. 

Zanidatamab binds two separate regions on the HER2 cell surface protein, crosslinking neighboring HER2 proteins, blocking HER2 signaling, and inducing cytotoxic immune responses.

The FDA simultaneously announced that it has also approved VENTANA PATHWAY anti–HER2/neu (4B5) Rabbit Monoclonal Primary Antibody (Ventana Medical Systems, Inc./Roche Diagnostics) as a companion diagnostic device to aid in identifying patients with BTC who may be eligible for treatment with zanidatamab.

 

Zanidatamab Trial Results

The approval of zanidatamab was based on the phase 2b HERIZON-BTC-01 trial— which was open-label, multicenter, and single-arm — involving 62 patients with unresectable or metastatic HER2-positive (IHC3+) BTC. In this trial, zanidatamab 20 mg/kg was administered every 2 weeks to patients who had received gemcitabine-containing chemotherapy previously but not a HER2-targeted therapy.

The objective response rate was 52%, and the median duration of response was 14.9 months, according to the statement from the FDA.

The life expectancy for advanced BTC treated in the second line with standard chemotherapy is approximately 6-9 months, according to Jazz Pharmaceuticals. 

 

Boxed Warning and Adverse Events

The prescribing information contains a boxed warning for embryo-fetal toxicity. The most common adverse reactions reported in at least 20% of patients who received zanidatamab were diarrhea, infusion-related reactions, abdominal pain, and fatigue.

The recommended zanidatamab dose is 20 mg/kg, administered as an intravenous infusion once every 2 weeks until progression or unacceptable toxicity. 

Jazz Pharmaceuticals’ application was granted priority review, breakthrough therapy designation, and orphan drug designation.

An ongoing phase 3 trial, HERIZON-BTC-302, is testing zanidatamab in combination with standard-of-care therapy in the first-line setting for advanced or metastatic HER2-positive BTC. The bispecific antibody is also being developed for HER2-positive advanced/metastatic gastroesophageal adenocarcinoma.

A version of this article appeared on Medscape.com. 

The Food and Drug Administration (FDA) has approved zanidatamab (Ziihera, Jazz Pharmaceuticals) as monotherapy for previously treated, unresectable or metastatic HER2-positive biliary tract cancer (BTC). This approval makes the bispecific antibody the first HER2-targeted treatment to carry the indication. 

Zanidatamab binds two separate regions on the HER2 cell surface protein, crosslinking neighboring HER2 proteins, blocking HER2 signaling, and inducing cytotoxic immune responses.

The FDA simultaneously announced that it has also approved VENTANA PATHWAY anti–HER2/neu (4B5) Rabbit Monoclonal Primary Antibody (Ventana Medical Systems, Inc./Roche Diagnostics) as a companion diagnostic device to aid in identifying patients with BTC who may be eligible for treatment with zanidatamab.

 

Zanidatamab Trial Results

The approval of zanidatamab was based on the phase 2b HERIZON-BTC-01 trial— which was open-label, multicenter, and single-arm — involving 62 patients with unresectable or metastatic HER2-positive (IHC3+) BTC. In this trial, zanidatamab 20 mg/kg was administered every 2 weeks to patients who had received gemcitabine-containing chemotherapy previously but not a HER2-targeted therapy.

The objective response rate was 52%, and the median duration of response was 14.9 months, according to the statement from the FDA.

The life expectancy for advanced BTC treated in the second line with standard chemotherapy is approximately 6-9 months, according to Jazz Pharmaceuticals. 

 

Boxed Warning and Adverse Events

The prescribing information contains a boxed warning for embryo-fetal toxicity. The most common adverse reactions reported in at least 20% of patients who received zanidatamab were diarrhea, infusion-related reactions, abdominal pain, and fatigue.

The recommended zanidatamab dose is 20 mg/kg, administered as an intravenous infusion once every 2 weeks until progression or unacceptable toxicity. 

Jazz Pharmaceuticals’ application was granted priority review, breakthrough therapy designation, and orphan drug designation.

An ongoing phase 3 trial, HERIZON-BTC-302, is testing zanidatamab in combination with standard-of-care therapy in the first-line setting for advanced or metastatic HER2-positive BTC. The bispecific antibody is also being developed for HER2-positive advanced/metastatic gastroesophageal adenocarcinoma.

A version of this article appeared on Medscape.com. 

The Food and Drug Administration (FDA) has approved zanidatamab (Ziihera, Jazz Pharmaceuticals) as monotherapy for previously treated, unresectable or metastatic HER2-positive biliary tract cancer (BTC). This approval makes the bispecific antibody the first HER2-targeted treatment to carry the indication. 

Zanidatamab binds two separate regions on the HER2 cell surface protein, crosslinking neighboring HER2 proteins, blocking HER2 signaling, and inducing cytotoxic immune responses.

The FDA simultaneously announced that it has also approved VENTANA PATHWAY anti–HER2/neu (4B5) Rabbit Monoclonal Primary Antibody (Ventana Medical Systems, Inc./Roche Diagnostics) as a companion diagnostic device to aid in identifying patients with BTC who may be eligible for treatment with zanidatamab.

 

Zanidatamab Trial Results

The approval of zanidatamab was based on the phase 2b HERIZON-BTC-01 trial— which was open-label, multicenter, and single-arm — involving 62 patients with unresectable or metastatic HER2-positive (IHC3+) BTC. In this trial, zanidatamab 20 mg/kg was administered every 2 weeks to patients who had received gemcitabine-containing chemotherapy previously but not a HER2-targeted therapy.

The objective response rate was 52%, and the median duration of response was 14.9 months, according to the statement from the FDA.

The life expectancy for advanced BTC treated in the second line with standard chemotherapy is approximately 6-9 months, according to Jazz Pharmaceuticals. 

 

Boxed Warning and Adverse Events

The prescribing information contains a boxed warning for embryo-fetal toxicity. The most common adverse reactions reported in at least 20% of patients who received zanidatamab were diarrhea, infusion-related reactions, abdominal pain, and fatigue.

The recommended zanidatamab dose is 20 mg/kg, administered as an intravenous infusion once every 2 weeks until progression or unacceptable toxicity. 

Jazz Pharmaceuticals’ application was granted priority review, breakthrough therapy designation, and orphan drug designation.

An ongoing phase 3 trial, HERIZON-BTC-302, is testing zanidatamab in combination with standard-of-care therapy in the first-line setting for advanced or metastatic HER2-positive BTC. The bispecific antibody is also being developed for HER2-positive advanced/metastatic gastroesophageal adenocarcinoma.

A version of this article appeared on Medscape.com. 

The National Comprehensive Cancer Network (NCCN) has expanded two cancer genetic risk assessment guidelines to meet the growing understanding of hereditary cancer risk and use of genetic tests in cancer prevention, screening, and treatment. 

Additional cancer types were included in the title and content for both guidelines. Prostate cancer was added to Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate, and endometrial and gastric cancer were added to Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric.

For these cancers, the expanded guidelines include information on when genetic testing is recommended and what type of testing may be best. These guidelines also detail the hereditary conditions and genetic mutations associated with elevated cancer risk and include appropriate “next steps” for individuals who have them, which may involve increased screening or prevention surgeries.

“These updates include the spectrum of genes associated with genetic syndromes, the range of risk associated with each pathogenic variant, the improvements in screening and prevention strategies, the role of genetic data to inform cancer treatment, and the expansion of the role of genetic counseling as this field moves forward,” Mary B. Daly, MD, PhD, with Fox Chase Cancer Center, Philadelphia, Pennsylvania, said in a news release. Daly chaired the panel that updated the breast, ovarian, pancreatic, and prostate cancer guidelines.

Oncologists should, for instance, ask patients about their family and personal history of cancer and known germline variants at time of initial diagnosis. With prostate cancer, if patients meet criteria for germline testing, multigene testing should include a host of variants, including BRCA1, BRCA2, ATM, PALB2, CHEK2, HOXB13, MLH1, MSH2, MSH6, and PMS2.

The updated guidelines on genetic risk assessment of colorectal, endometrial, and gastric cancer include new recommendations to consider for hereditary cancer screening in patients with newly diagnosed endometrial cancer, for evaluating and managing CDH1-associated gastric cancer risk, and for managing gastric cancer risk in patients with APC pathogenic variants. 

For CDH1-associated gastric cancer, for instance, the guidelines recommend carriers be referred to institutions with expertise in managing risks for cancer associated with CDH1, “given the still limited understanding and rarity of this syndrome.” 

“These expanded guidelines reflect the recommendations from leading experts on genetic testing based on the latest scientific research across the cancer spectrum, consolidated into two convenient resources,” said NCCN CEO Crystal S. Denlinger, MD, with Fox Chase Cancer Center, in a news release. 

“This information is critical for guiding shared decision-making between health care providers and their patients, enhancing screening practices as appropriate, and potentially choosing options for prevention and targeted treatment choices. Genetic testing guidelines enable us to better care for people with cancer and their family members,” Denlinger added.

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

The National Comprehensive Cancer Network (NCCN) has expanded two cancer genetic risk assessment guidelines to meet the growing understanding of hereditary cancer risk and use of genetic tests in cancer prevention, screening, and treatment. 

Additional cancer types were included in the title and content for both guidelines. Prostate cancer was added to Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate, and endometrial and gastric cancer were added to Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric.

For these cancers, the expanded guidelines include information on when genetic testing is recommended and what type of testing may be best. These guidelines also detail the hereditary conditions and genetic mutations associated with elevated cancer risk and include appropriate “next steps” for individuals who have them, which may involve increased screening or prevention surgeries.

“These updates include the spectrum of genes associated with genetic syndromes, the range of risk associated with each pathogenic variant, the improvements in screening and prevention strategies, the role of genetic data to inform cancer treatment, and the expansion of the role of genetic counseling as this field moves forward,” Mary B. Daly, MD, PhD, with Fox Chase Cancer Center, Philadelphia, Pennsylvania, said in a news release. Daly chaired the panel that updated the breast, ovarian, pancreatic, and prostate cancer guidelines.

Oncologists should, for instance, ask patients about their family and personal history of cancer and known germline variants at time of initial diagnosis. With prostate cancer, if patients meet criteria for germline testing, multigene testing should include a host of variants, including BRCA1, BRCA2, ATM, PALB2, CHEK2, HOXB13, MLH1, MSH2, MSH6, and PMS2.

The updated guidelines on genetic risk assessment of colorectal, endometrial, and gastric cancer include new recommendations to consider for hereditary cancer screening in patients with newly diagnosed endometrial cancer, for evaluating and managing CDH1-associated gastric cancer risk, and for managing gastric cancer risk in patients with APC pathogenic variants. 

For CDH1-associated gastric cancer, for instance, the guidelines recommend carriers be referred to institutions with expertise in managing risks for cancer associated with CDH1, “given the still limited understanding and rarity of this syndrome.” 

“These expanded guidelines reflect the recommendations from leading experts on genetic testing based on the latest scientific research across the cancer spectrum, consolidated into two convenient resources,” said NCCN CEO Crystal S. Denlinger, MD, with Fox Chase Cancer Center, in a news release. 

“This information is critical for guiding shared decision-making between health care providers and their patients, enhancing screening practices as appropriate, and potentially choosing options for prevention and targeted treatment choices. Genetic testing guidelines enable us to better care for people with cancer and their family members,” Denlinger added.

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

The National Comprehensive Cancer Network (NCCN) has expanded two cancer genetic risk assessment guidelines to meet the growing understanding of hereditary cancer risk and use of genetic tests in cancer prevention, screening, and treatment. 

Additional cancer types were included in the title and content for both guidelines. Prostate cancer was added to Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate, and endometrial and gastric cancer were added to Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric.

For these cancers, the expanded guidelines include information on when genetic testing is recommended and what type of testing may be best. These guidelines also detail the hereditary conditions and genetic mutations associated with elevated cancer risk and include appropriate “next steps” for individuals who have them, which may involve increased screening or prevention surgeries.

“These updates include the spectrum of genes associated with genetic syndromes, the range of risk associated with each pathogenic variant, the improvements in screening and prevention strategies, the role of genetic data to inform cancer treatment, and the expansion of the role of genetic counseling as this field moves forward,” Mary B. Daly, MD, PhD, with Fox Chase Cancer Center, Philadelphia, Pennsylvania, said in a news release. Daly chaired the panel that updated the breast, ovarian, pancreatic, and prostate cancer guidelines.

Oncologists should, for instance, ask patients about their family and personal history of cancer and known germline variants at time of initial diagnosis. With prostate cancer, if patients meet criteria for germline testing, multigene testing should include a host of variants, including BRCA1, BRCA2, ATM, PALB2, CHEK2, HOXB13, MLH1, MSH2, MSH6, and PMS2.

The updated guidelines on genetic risk assessment of colorectal, endometrial, and gastric cancer include new recommendations to consider for hereditary cancer screening in patients with newly diagnosed endometrial cancer, for evaluating and managing CDH1-associated gastric cancer risk, and for managing gastric cancer risk in patients with APC pathogenic variants. 

For CDH1-associated gastric cancer, for instance, the guidelines recommend carriers be referred to institutions with expertise in managing risks for cancer associated with CDH1, “given the still limited understanding and rarity of this syndrome.” 

“These expanded guidelines reflect the recommendations from leading experts on genetic testing based on the latest scientific research across the cancer spectrum, consolidated into two convenient resources,” said NCCN CEO Crystal S. Denlinger, MD, with Fox Chase Cancer Center, in a news release. 

“This information is critical for guiding shared decision-making between health care providers and their patients, enhancing screening practices as appropriate, and potentially choosing options for prevention and targeted treatment choices. Genetic testing guidelines enable us to better care for people with cancer and their family members,” Denlinger added.

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

The principle of parsimony, often referred to as “Occam’s razor,” favors a unifying explanation over multiple ones, as long as both explain the data equally well. This heuristic, widely used in medical practice, advocates for simpler explanations rather than complex theories. However, its application in modern medicine has sparked debate.

“Hickam’s dictum,” a counterargument to Occam’s razor, asserts that patients — especially as populations grow older and more fragile — can simultaneously have multiple, unrelated diagnoses. These contrasting perspectives on clinical reasoning, balancing diagnostic simplicity and complexity, are both used in daily medical practice.

But are these two axioms truly in conflict, or is this a false dichotomy?

 

Occam’s Razor and Simple Diagnoses

Interpersonal variability in diagnostic approaches, shaped by the subjective nature of many judgments, complicates the formal evaluation of diagnostic parsimony (Occam’s razor). Indirect evidence suggests that prioritizing simplicity in diagnosis can result in under-detection of secondary conditions, particularly in patients with chronic illnesses.

For example, older patients with a known chronic illness were found to have a 30%-60% lower likelihood of being treated for an unrelated secondary diagnosis than matched peers without the chronic condition. Other studies indicate that a readily available, simple diagnosis can lead clinicians to prematurely close their diagnostic reasoning, overlooking other significant illnesses.

 

Beyond Hickam’s Dictum and Occam’s Razor

A recent study explored the phenomenon of multiple diagnoses by examining the supposed conflict between Hickam’s dictum and Occam’s razor, as well as the ambiguities in how they are interpreted and used by physicians in clinical reasoning.

Part 1: Researchers identified articles on PubMed related to Hickam’s dictum or conflicting with Occam’s razor, categorizing instances into four models of Hickam’s dictum:

1. Incidentaloma: An asymptomatic condition discovered accidentally.

2. Preexisting diagnosis: A known condition in the patient’s medical history.

3. Causally related disease: A complication, association, epiphenomenon, or underlying cause connected to the primary diagnosis.

4. Coincidental and independent disease: A symptomatic condition unrelated to the primary diagnosis.

Part 2: Researchers analyzed 220 case records from Massachusetts General Hospital, Boston, and clinical problem-solving reports published in The New England Journal of Medicine between 2017 and 2023. They found no cases where the final diagnosis was not a unifying one.

Part 3: In an online survey of 265 physicians, 79% identified coincidental symptomatic conditions (category 4) as the least likely type of multiple diagnoses. Preexisting conditions (category 2) emerged as the most common, reflecting the tendency to add new diagnoses to a patient’s existing health profile. Almost one third of instances referencing Hickam’s dictum or violations of Occam’s razor fell into category 2.

Causally related diseases (category 3) were probabilistically dependent, meaning that the presence of one condition increased the likelihood of the other, based on the strength (often unknown) of the causal relationship.

 

Practical Insights

The significant finding of this work was that multiple diagnoses occur in predictable patterns, informed by causal connections between conditions, symptom onset timing, and likelihood. The principle of common causation supports the search for a unifying diagnosis for coincidental symptoms. It is not surprising that causally related phenomena often co-occur, as reflected by the fact that 40% of multiple diagnoses in the study’s first part were causally linked.

Thus, understanding multiple diagnoses goes beyond Hickam’s dictum and Occam’s razor. It requires not only identifying diseases but also examining their causal relationships and the timing of symptom onset. A unifying diagnosis is not equivalent to a single diagnosis; rather, it represents a causal pathway linking underlying pathologic changes to acute presentations.

 

This story was translated from Univadis Italy using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

The principle of parsimony, often referred to as “Occam’s razor,” favors a unifying explanation over multiple ones, as long as both explain the data equally well. This heuristic, widely used in medical practice, advocates for simpler explanations rather than complex theories. However, its application in modern medicine has sparked debate.

“Hickam’s dictum,” a counterargument to Occam’s razor, asserts that patients — especially as populations grow older and more fragile — can simultaneously have multiple, unrelated diagnoses. These contrasting perspectives on clinical reasoning, balancing diagnostic simplicity and complexity, are both used in daily medical practice.

But are these two axioms truly in conflict, or is this a false dichotomy?

 

Occam’s Razor and Simple Diagnoses

Interpersonal variability in diagnostic approaches, shaped by the subjective nature of many judgments, complicates the formal evaluation of diagnostic parsimony (Occam’s razor). Indirect evidence suggests that prioritizing simplicity in diagnosis can result in under-detection of secondary conditions, particularly in patients with chronic illnesses.

For example, older patients with a known chronic illness were found to have a 30%-60% lower likelihood of being treated for an unrelated secondary diagnosis than matched peers without the chronic condition. Other studies indicate that a readily available, simple diagnosis can lead clinicians to prematurely close their diagnostic reasoning, overlooking other significant illnesses.

 

Beyond Hickam’s Dictum and Occam’s Razor

A recent study explored the phenomenon of multiple diagnoses by examining the supposed conflict between Hickam’s dictum and Occam’s razor, as well as the ambiguities in how they are interpreted and used by physicians in clinical reasoning.

Part 1: Researchers identified articles on PubMed related to Hickam’s dictum or conflicting with Occam’s razor, categorizing instances into four models of Hickam’s dictum:

1. Incidentaloma: An asymptomatic condition discovered accidentally.

2. Preexisting diagnosis: A known condition in the patient’s medical history.

3. Causally related disease: A complication, association, epiphenomenon, or underlying cause connected to the primary diagnosis.

4. Coincidental and independent disease: A symptomatic condition unrelated to the primary diagnosis.

Part 2: Researchers analyzed 220 case records from Massachusetts General Hospital, Boston, and clinical problem-solving reports published in The New England Journal of Medicine between 2017 and 2023. They found no cases where the final diagnosis was not a unifying one.

Part 3: In an online survey of 265 physicians, 79% identified coincidental symptomatic conditions (category 4) as the least likely type of multiple diagnoses. Preexisting conditions (category 2) emerged as the most common, reflecting the tendency to add new diagnoses to a patient’s existing health profile. Almost one third of instances referencing Hickam’s dictum or violations of Occam’s razor fell into category 2.

Causally related diseases (category 3) were probabilistically dependent, meaning that the presence of one condition increased the likelihood of the other, based on the strength (often unknown) of the causal relationship.

 

Practical Insights

The significant finding of this work was that multiple diagnoses occur in predictable patterns, informed by causal connections between conditions, symptom onset timing, and likelihood. The principle of common causation supports the search for a unifying diagnosis for coincidental symptoms. It is not surprising that causally related phenomena often co-occur, as reflected by the fact that 40% of multiple diagnoses in the study’s first part were causally linked.

Thus, understanding multiple diagnoses goes beyond Hickam’s dictum and Occam’s razor. It requires not only identifying diseases but also examining their causal relationships and the timing of symptom onset. A unifying diagnosis is not equivalent to a single diagnosis; rather, it represents a causal pathway linking underlying pathologic changes to acute presentations.

 

This story was translated from Univadis Italy using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

The principle of parsimony, often referred to as “Occam’s razor,” favors a unifying explanation over multiple ones, as long as both explain the data equally well. This heuristic, widely used in medical practice, advocates for simpler explanations rather than complex theories. However, its application in modern medicine has sparked debate.

“Hickam’s dictum,” a counterargument to Occam’s razor, asserts that patients — especially as populations grow older and more fragile — can simultaneously have multiple, unrelated diagnoses. These contrasting perspectives on clinical reasoning, balancing diagnostic simplicity and complexity, are both used in daily medical practice.

But are these two axioms truly in conflict, or is this a false dichotomy?

 

Occam’s Razor and Simple Diagnoses

Interpersonal variability in diagnostic approaches, shaped by the subjective nature of many judgments, complicates the formal evaluation of diagnostic parsimony (Occam’s razor). Indirect evidence suggests that prioritizing simplicity in diagnosis can result in under-detection of secondary conditions, particularly in patients with chronic illnesses.

For example, older patients with a known chronic illness were found to have a 30%-60% lower likelihood of being treated for an unrelated secondary diagnosis than matched peers without the chronic condition. Other studies indicate that a readily available, simple diagnosis can lead clinicians to prematurely close their diagnostic reasoning, overlooking other significant illnesses.

 

Beyond Hickam’s Dictum and Occam’s Razor

A recent study explored the phenomenon of multiple diagnoses by examining the supposed conflict between Hickam’s dictum and Occam’s razor, as well as the ambiguities in how they are interpreted and used by physicians in clinical reasoning.

Part 1: Researchers identified articles on PubMed related to Hickam’s dictum or conflicting with Occam’s razor, categorizing instances into four models of Hickam’s dictum:

1. Incidentaloma: An asymptomatic condition discovered accidentally.

2. Preexisting diagnosis: A known condition in the patient’s medical history.

3. Causally related disease: A complication, association, epiphenomenon, or underlying cause connected to the primary diagnosis.

4. Coincidental and independent disease: A symptomatic condition unrelated to the primary diagnosis.

Part 2: Researchers analyzed 220 case records from Massachusetts General Hospital, Boston, and clinical problem-solving reports published in The New England Journal of Medicine between 2017 and 2023. They found no cases where the final diagnosis was not a unifying one.

Part 3: In an online survey of 265 physicians, 79% identified coincidental symptomatic conditions (category 4) as the least likely type of multiple diagnoses. Preexisting conditions (category 2) emerged as the most common, reflecting the tendency to add new diagnoses to a patient’s existing health profile. Almost one third of instances referencing Hickam’s dictum or violations of Occam’s razor fell into category 2.

Causally related diseases (category 3) were probabilistically dependent, meaning that the presence of one condition increased the likelihood of the other, based on the strength (often unknown) of the causal relationship.

 

Practical Insights

The significant finding of this work was that multiple diagnoses occur in predictable patterns, informed by causal connections between conditions, symptom onset timing, and likelihood. The principle of common causation supports the search for a unifying diagnosis for coincidental symptoms. It is not surprising that causally related phenomena often co-occur, as reflected by the fact that 40% of multiple diagnoses in the study’s first part were causally linked.

Thus, understanding multiple diagnoses goes beyond Hickam’s dictum and Occam’s razor. It requires not only identifying diseases but also examining their causal relationships and the timing of symptom onset. A unifying diagnosis is not equivalent to a single diagnosis; rather, it represents a causal pathway linking underlying pathologic changes to acute presentations.

 

This story was translated from Univadis Italy using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

The causes of shoulder pain may be as common as a traumatic injury or as rare as a systemic inflammatory condition, according to the American Academy of Orthopaedic Surgeons. The combination of joints, tendons, and muscles that make up the shoulder can present diagnostic and clinical challenges, but several experts shared their tips for management.

Evaluation and Diagnosis

Rotator cuff tendinopathy/tendinitis and subacromial bursitis are typically the most common causes of shoulder pain presenting to a primary care provider, said Jason Kolfenbach, MD, a rheumatologist at UC Health, Denver, Colorado, in an interview. “Other causes of shoulder pain may include acromioclavicular osteoarthritis, biceps tendinitis (often a secondary process in the setting of rotator cuff disease), and true glenohumeral joint osteoarthritis,” he said.

Experts estimate that as much as 80% of shoulder pain involves the muscles, tendons, and ligaments surrounding the joint, rather than true arthritis, said Kolfenbach, who was a co-author of a Medscape slideshow on evaluating shoulder pain. In the slideshow, the authors noted that proper evaluation is needed for successful pain management. Some patients may do well with nonsteroidal anti-inflammatory drugs (NSAIDs), rest, ice, and physical therapy, but more serious conditions may require steroids, disease-modifying antirheumatic drugs, or surgery.

If a patient’s joint pain with active range of motion is relieved when an examiner supports the affected limb (passive range of motion), the cause is more likely related to muscles, tendons, or ligaments, Kolfenbach said.

Primary care providers may not be familiar with examination maneuvers to diagnose shoulder pain, although they are often tasked with evaluating and managing these patients, said Kolfenbach.

Education focused on practical aspects of these maneuvers may help improve primary care confidence in utilizing them and lead to more appropriate ordering of imaging testing and better pain management plans for patients, he said.

However, “If there is concern for a true intra-articular process, plain radiographs are recommended to determine if there is loss of cartilage space and/or other anatomic drivers of pain,” he noted. “Even in conditions of documented intra-articular arthritis, such as osteoarthritis, weakness, and atrophy of the surrounding musculature can contribute to joint disability and pain,” he said. For these patients, referral to physical therapy for periarticular strengthening can provide pain relief, he added.

 

Pinning Down the Pain Point

The many different structures within the shoulder that can cause pain make diagnosis a challenge, Nicole Angelo, DO, MS, a physiatrist at the Hospital for Special Surgery, New York City, said in an interview.

Potential sources of pain include the joint of the shoulder itself, the structures within it (labrum, capsule, and ligaments), and the surrounding rotator cuff muscles and tendons, she said. Patients also may experience overlapping pain referred from the neck (cervical spine) related to nerve irritation (cervical radiculopathy) or arthritis, she noted.

“A patient’s history, including mechanism and acuity of injury, as well as exam, specifically weakness in certain movements,” can help determine whether advanced imaging and surgical intervention may be required,” Angelo told this news organization.

Frozen shoulder is the most missed diagnosis of shoulder pain in primary care, Brian Feeley, MD, chief of sports medicine and shoulder surgery at the University of California, San Francisco (UCSF), said in an interview.

Frozen shoulder, also known as adhesive capsulitis, can mimic many other conditions including rotator cuff problems, shoulder arthritis, and biceps problems, Feeley said. “When people have a loss of active and passive range of motion and no evidence of arthritis on x-rays, their diagnosis is most likely frozen shoulder,” he said.

Another challenge for primary care providers is identifying the severity of rotator cuff problems, Feeley said. “I like to think of rotator cuff problems along a spectrum — impingement is inflammation above the rotator cuff and suggests an imbalance between rotator cuff strength and deltoid strength,” said Feeley. “Partial thickness tears are often normal age-related problems but can be a source of pain,” he added.

However, full-thickness tears encompass a range of problems, from very small asymptomatic holes in the rotator cuff to massive tears that require shoulder replacement, Feeley explained. “Tendinopathy, or changes in the collagen organization in the tendon of the rotator cuff, sounds problematic, but most often is either incidental or part of aging,” he added.

 

When Shoulder Pain Isn’t Caused by the Shoulder

Primary care patients presenting with shoulder pain may in fact have a neck or spine problem instead, Feeley told this news organization. “Pain that is in the shoulder blade area or down the arm and into the fingers is usually coming from the neck/cervical spine,” he said.

In some cases, shoulder pain stems from the joints below the shoulder, including the elbow, because of arthritis, tennis elbow (lateral epicondylopathy), or golfer’s elbow (medial epicondylopathy), said Angelo. “Conditions of the elbow and neck can also affect shoulder mechanics or cause someone to use the joint more or less frequently,” she said. The interconnections between the neck and joints of the upper extremity, including referral patterns, complicate the diagnosis of shoulder pain; therefore, careful history-taking and examination of joints both above and below the shoulder are essential, she added.

 

Conservative Care

Shoulder problems often can be managed conservatively with therapeutic exercise focused on maintaining range of motion of the shoulder and strengthening the musculature around the shoulder, Angelo said. “Often, working with a physical therapist to address the mechanics of how the shoulder is moving and how the muscles are firing can help decrease pain and help patients meet their functional goals,” said Angelo. “Injections into the joint, the bursa adjacent to the rotator cuff, and, at times, into the tendons themselves can also be beneficial in relieving pain and improving function,” she said.

In some cases, a short, consistent course of anti-inflammatory medications can be part of a conservative strategy for the management of shoulder pain, Angelo noted.

“Utilizing these medications on an as-needed basis can also help patients improve their ability to sleep, perform their daily activities, and participate in physical therapy,” she said. A course of physical therapy that promotes maintaining shoulder range of motion, strengthening of the rotator cuff musculature, and working on the mechanics between the scapula and humerus is a good first step for most shoulder conditions, Angelo told this news organization.

“If there is concern due to recent trauma, significant weakness, or new/persistent numbness, referral to a specialist should be considered,” she said. If conservative measures including analgesics and exercise have failed to improve shoulder pain, advanced imaging and further interventional treatment may be necessary, Angelo added.

Most shoulder problems can and should be managed nonoperatively, Feeley said. Surgery should be reserved for patients whose shoulder pain has not improved with nonoperative care in most situations, he said. “It is often surprising for patients to hear, but most things in the shoulder actually get better without surgery, and changes on MRI are often normal for age,” Feeley noted. For example, more than 80% of individuals older than 50 will show signs of a labral tear or arthritis in the acromioclavicular joint, he said. “These are incidental findings that don’t need treatment,” he added.

More research is needed to develop more medications to manage pain for all musculoskeletal conditions, including shoulder pain, said Feeley. “But for now, for patients with shoulder pain, I tend to recommend a combination of Tylenol and an NSAID to improve inflammation and reduce pain, and a guided [physical] therapy program at home or in person. The combination of both usually will be successful,” he said.

 

Postsurgical Shoulder Pain

“For patients who have shoulder surgery, the techniques to manage pain around surgery have improved tremendously over the last decade, particularly with multimodal pain management and nerve blocks,” Feeley told this news organization. These advances have tremendously reduced the need for narcotics for pain management beyond the first 72 hours after surgery, he said. “I strongly recommend patients and primary care doctors to stop all narcotics as soon as possible after shoulder surgery, since they are not nearly as effective for management of pain after the first few days, and they should never be used as a sleep aid,” he emphasized.

Managing pain during recovery from shoulder surgery also involves about 6 weeks in a sling to protect the repair, followed by 6 weeks of active motion but no strengthening, then 3 months of strengthening exercises, he said.

Shoulder pain resources for patients: https://www.hss.edu/condition-list_shoulder-pain-causes.asp

Feeley’s 10-minute video on shoulder examination and pain assessment at the UCSF 14th Annual Primary Care Sports Medicine Conference, 2019: Video on the Essential Shoulder Exam

Kolfenbach disclosed receiving royalties from Elsevier for being the editor of Rheumatology Secrets and Wolters Kluwer for authoring several articles on UpToDate. Feeley and Angelo had no relevant financial conflicts to disclose.

 

A version of this article appeared on Medscape.com.

The causes of shoulder pain may be as common as a traumatic injury or as rare as a systemic inflammatory condition, according to the American Academy of Orthopaedic Surgeons. The combination of joints, tendons, and muscles that make up the shoulder can present diagnostic and clinical challenges, but several experts shared their tips for management.

Evaluation and Diagnosis

Rotator cuff tendinopathy/tendinitis and subacromial bursitis are typically the most common causes of shoulder pain presenting to a primary care provider, said Jason Kolfenbach, MD, a rheumatologist at UC Health, Denver, Colorado, in an interview. “Other causes of shoulder pain may include acromioclavicular osteoarthritis, biceps tendinitis (often a secondary process in the setting of rotator cuff disease), and true glenohumeral joint osteoarthritis,” he said.

Experts estimate that as much as 80% of shoulder pain involves the muscles, tendons, and ligaments surrounding the joint, rather than true arthritis, said Kolfenbach, who was a co-author of a Medscape slideshow on evaluating shoulder pain. In the slideshow, the authors noted that proper evaluation is needed for successful pain management. Some patients may do well with nonsteroidal anti-inflammatory drugs (NSAIDs), rest, ice, and physical therapy, but more serious conditions may require steroids, disease-modifying antirheumatic drugs, or surgery.

If a patient’s joint pain with active range of motion is relieved when an examiner supports the affected limb (passive range of motion), the cause is more likely related to muscles, tendons, or ligaments, Kolfenbach said.

Primary care providers may not be familiar with examination maneuvers to diagnose shoulder pain, although they are often tasked with evaluating and managing these patients, said Kolfenbach.

Education focused on practical aspects of these maneuvers may help improve primary care confidence in utilizing them and lead to more appropriate ordering of imaging testing and better pain management plans for patients, he said.

However, “If there is concern for a true intra-articular process, plain radiographs are recommended to determine if there is loss of cartilage space and/or other anatomic drivers of pain,” he noted. “Even in conditions of documented intra-articular arthritis, such as osteoarthritis, weakness, and atrophy of the surrounding musculature can contribute to joint disability and pain,” he said. For these patients, referral to physical therapy for periarticular strengthening can provide pain relief, he added.

 

Pinning Down the Pain Point

The many different structures within the shoulder that can cause pain make diagnosis a challenge, Nicole Angelo, DO, MS, a physiatrist at the Hospital for Special Surgery, New York City, said in an interview.

Potential sources of pain include the joint of the shoulder itself, the structures within it (labrum, capsule, and ligaments), and the surrounding rotator cuff muscles and tendons, she said. Patients also may experience overlapping pain referred from the neck (cervical spine) related to nerve irritation (cervical radiculopathy) or arthritis, she noted.

“A patient’s history, including mechanism and acuity of injury, as well as exam, specifically weakness in certain movements,” can help determine whether advanced imaging and surgical intervention may be required,” Angelo told this news organization.

Frozen shoulder is the most missed diagnosis of shoulder pain in primary care, Brian Feeley, MD, chief of sports medicine and shoulder surgery at the University of California, San Francisco (UCSF), said in an interview.

Frozen shoulder, also known as adhesive capsulitis, can mimic many other conditions including rotator cuff problems, shoulder arthritis, and biceps problems, Feeley said. “When people have a loss of active and passive range of motion and no evidence of arthritis on x-rays, their diagnosis is most likely frozen shoulder,” he said.

Another challenge for primary care providers is identifying the severity of rotator cuff problems, Feeley said. “I like to think of rotator cuff problems along a spectrum — impingement is inflammation above the rotator cuff and suggests an imbalance between rotator cuff strength and deltoid strength,” said Feeley. “Partial thickness tears are often normal age-related problems but can be a source of pain,” he added.

However, full-thickness tears encompass a range of problems, from very small asymptomatic holes in the rotator cuff to massive tears that require shoulder replacement, Feeley explained. “Tendinopathy, or changes in the collagen organization in the tendon of the rotator cuff, sounds problematic, but most often is either incidental or part of aging,” he added.

 

When Shoulder Pain Isn’t Caused by the Shoulder

Primary care patients presenting with shoulder pain may in fact have a neck or spine problem instead, Feeley told this news organization. “Pain that is in the shoulder blade area or down the arm and into the fingers is usually coming from the neck/cervical spine,” he said.

In some cases, shoulder pain stems from the joints below the shoulder, including the elbow, because of arthritis, tennis elbow (lateral epicondylopathy), or golfer’s elbow (medial epicondylopathy), said Angelo. “Conditions of the elbow and neck can also affect shoulder mechanics or cause someone to use the joint more or less frequently,” she said. The interconnections between the neck and joints of the upper extremity, including referral patterns, complicate the diagnosis of shoulder pain; therefore, careful history-taking and examination of joints both above and below the shoulder are essential, she added.

 

Conservative Care

Shoulder problems often can be managed conservatively with therapeutic exercise focused on maintaining range of motion of the shoulder and strengthening the musculature around the shoulder, Angelo said. “Often, working with a physical therapist to address the mechanics of how the shoulder is moving and how the muscles are firing can help decrease pain and help patients meet their functional goals,” said Angelo. “Injections into the joint, the bursa adjacent to the rotator cuff, and, at times, into the tendons themselves can also be beneficial in relieving pain and improving function,” she said.

In some cases, a short, consistent course of anti-inflammatory medications can be part of a conservative strategy for the management of shoulder pain, Angelo noted.

“Utilizing these medications on an as-needed basis can also help patients improve their ability to sleep, perform their daily activities, and participate in physical therapy,” she said. A course of physical therapy that promotes maintaining shoulder range of motion, strengthening of the rotator cuff musculature, and working on the mechanics between the scapula and humerus is a good first step for most shoulder conditions, Angelo told this news organization.

“If there is concern due to recent trauma, significant weakness, or new/persistent numbness, referral to a specialist should be considered,” she said. If conservative measures including analgesics and exercise have failed to improve shoulder pain, advanced imaging and further interventional treatment may be necessary, Angelo added.

Most shoulder problems can and should be managed nonoperatively, Feeley said. Surgery should be reserved for patients whose shoulder pain has not improved with nonoperative care in most situations, he said. “It is often surprising for patients to hear, but most things in the shoulder actually get better without surgery, and changes on MRI are often normal for age,” Feeley noted. For example, more than 80% of individuals older than 50 will show signs of a labral tear or arthritis in the acromioclavicular joint, he said. “These are incidental findings that don’t need treatment,” he added.

More research is needed to develop more medications to manage pain for all musculoskeletal conditions, including shoulder pain, said Feeley. “But for now, for patients with shoulder pain, I tend to recommend a combination of Tylenol and an NSAID to improve inflammation and reduce pain, and a guided [physical] therapy program at home or in person. The combination of both usually will be successful,” he said.

 

Postsurgical Shoulder Pain

“For patients who have shoulder surgery, the techniques to manage pain around surgery have improved tremendously over the last decade, particularly with multimodal pain management and nerve blocks,” Feeley told this news organization. These advances have tremendously reduced the need for narcotics for pain management beyond the first 72 hours after surgery, he said. “I strongly recommend patients and primary care doctors to stop all narcotics as soon as possible after shoulder surgery, since they are not nearly as effective for management of pain after the first few days, and they should never be used as a sleep aid,” he emphasized.

Managing pain during recovery from shoulder surgery also involves about 6 weeks in a sling to protect the repair, followed by 6 weeks of active motion but no strengthening, then 3 months of strengthening exercises, he said.

Shoulder pain resources for patients: https://www.hss.edu/condition-list_shoulder-pain-causes.asp

Feeley’s 10-minute video on shoulder examination and pain assessment at the UCSF 14th Annual Primary Care Sports Medicine Conference, 2019: Video on the Essential Shoulder Exam

Kolfenbach disclosed receiving royalties from Elsevier for being the editor of Rheumatology Secrets and Wolters Kluwer for authoring several articles on UpToDate. Feeley and Angelo had no relevant financial conflicts to disclose.

 

A version of this article appeared on Medscape.com.

The causes of shoulder pain may be as common as a traumatic injury or as rare as a systemic inflammatory condition, according to the American Academy of Orthopaedic Surgeons. The combination of joints, tendons, and muscles that make up the shoulder can present diagnostic and clinical challenges, but several experts shared their tips for management.

Evaluation and Diagnosis

Rotator cuff tendinopathy/tendinitis and subacromial bursitis are typically the most common causes of shoulder pain presenting to a primary care provider, said Jason Kolfenbach, MD, a rheumatologist at UC Health, Denver, Colorado, in an interview. “Other causes of shoulder pain may include acromioclavicular osteoarthritis, biceps tendinitis (often a secondary process in the setting of rotator cuff disease), and true glenohumeral joint osteoarthritis,” he said.

Experts estimate that as much as 80% of shoulder pain involves the muscles, tendons, and ligaments surrounding the joint, rather than true arthritis, said Kolfenbach, who was a co-author of a Medscape slideshow on evaluating shoulder pain. In the slideshow, the authors noted that proper evaluation is needed for successful pain management. Some patients may do well with nonsteroidal anti-inflammatory drugs (NSAIDs), rest, ice, and physical therapy, but more serious conditions may require steroids, disease-modifying antirheumatic drugs, or surgery.

If a patient’s joint pain with active range of motion is relieved when an examiner supports the affected limb (passive range of motion), the cause is more likely related to muscles, tendons, or ligaments, Kolfenbach said.

Primary care providers may not be familiar with examination maneuvers to diagnose shoulder pain, although they are often tasked with evaluating and managing these patients, said Kolfenbach.

Education focused on practical aspects of these maneuvers may help improve primary care confidence in utilizing them and lead to more appropriate ordering of imaging testing and better pain management plans for patients, he said.

However, “If there is concern for a true intra-articular process, plain radiographs are recommended to determine if there is loss of cartilage space and/or other anatomic drivers of pain,” he noted. “Even in conditions of documented intra-articular arthritis, such as osteoarthritis, weakness, and atrophy of the surrounding musculature can contribute to joint disability and pain,” he said. For these patients, referral to physical therapy for periarticular strengthening can provide pain relief, he added.

 

Pinning Down the Pain Point

The many different structures within the shoulder that can cause pain make diagnosis a challenge, Nicole Angelo, DO, MS, a physiatrist at the Hospital for Special Surgery, New York City, said in an interview.

Potential sources of pain include the joint of the shoulder itself, the structures within it (labrum, capsule, and ligaments), and the surrounding rotator cuff muscles and tendons, she said. Patients also may experience overlapping pain referred from the neck (cervical spine) related to nerve irritation (cervical radiculopathy) or arthritis, she noted.

“A patient’s history, including mechanism and acuity of injury, as well as exam, specifically weakness in certain movements,” can help determine whether advanced imaging and surgical intervention may be required,” Angelo told this news organization.

Frozen shoulder is the most missed diagnosis of shoulder pain in primary care, Brian Feeley, MD, chief of sports medicine and shoulder surgery at the University of California, San Francisco (UCSF), said in an interview.

Frozen shoulder, also known as adhesive capsulitis, can mimic many other conditions including rotator cuff problems, shoulder arthritis, and biceps problems, Feeley said. “When people have a loss of active and passive range of motion and no evidence of arthritis on x-rays, their diagnosis is most likely frozen shoulder,” he said.

Another challenge for primary care providers is identifying the severity of rotator cuff problems, Feeley said. “I like to think of rotator cuff problems along a spectrum — impingement is inflammation above the rotator cuff and suggests an imbalance between rotator cuff strength and deltoid strength,” said Feeley. “Partial thickness tears are often normal age-related problems but can be a source of pain,” he added.

However, full-thickness tears encompass a range of problems, from very small asymptomatic holes in the rotator cuff to massive tears that require shoulder replacement, Feeley explained. “Tendinopathy, or changes in the collagen organization in the tendon of the rotator cuff, sounds problematic, but most often is either incidental or part of aging,” he added.

 

When Shoulder Pain Isn’t Caused by the Shoulder

Primary care patients presenting with shoulder pain may in fact have a neck or spine problem instead, Feeley told this news organization. “Pain that is in the shoulder blade area or down the arm and into the fingers is usually coming from the neck/cervical spine,” he said.

In some cases, shoulder pain stems from the joints below the shoulder, including the elbow, because of arthritis, tennis elbow (lateral epicondylopathy), or golfer’s elbow (medial epicondylopathy), said Angelo. “Conditions of the elbow and neck can also affect shoulder mechanics or cause someone to use the joint more or less frequently,” she said. The interconnections between the neck and joints of the upper extremity, including referral patterns, complicate the diagnosis of shoulder pain; therefore, careful history-taking and examination of joints both above and below the shoulder are essential, she added.

 

Conservative Care

Shoulder problems often can be managed conservatively with therapeutic exercise focused on maintaining range of motion of the shoulder and strengthening the musculature around the shoulder, Angelo said. “Often, working with a physical therapist to address the mechanics of how the shoulder is moving and how the muscles are firing can help decrease pain and help patients meet their functional goals,” said Angelo. “Injections into the joint, the bursa adjacent to the rotator cuff, and, at times, into the tendons themselves can also be beneficial in relieving pain and improving function,” she said.

In some cases, a short, consistent course of anti-inflammatory medications can be part of a conservative strategy for the management of shoulder pain, Angelo noted.

“Utilizing these medications on an as-needed basis can also help patients improve their ability to sleep, perform their daily activities, and participate in physical therapy,” she said. A course of physical therapy that promotes maintaining shoulder range of motion, strengthening of the rotator cuff musculature, and working on the mechanics between the scapula and humerus is a good first step for most shoulder conditions, Angelo told this news organization.

“If there is concern due to recent trauma, significant weakness, or new/persistent numbness, referral to a specialist should be considered,” she said. If conservative measures including analgesics and exercise have failed to improve shoulder pain, advanced imaging and further interventional treatment may be necessary, Angelo added.

Most shoulder problems can and should be managed nonoperatively, Feeley said. Surgery should be reserved for patients whose shoulder pain has not improved with nonoperative care in most situations, he said. “It is often surprising for patients to hear, but most things in the shoulder actually get better without surgery, and changes on MRI are often normal for age,” Feeley noted. For example, more than 80% of individuals older than 50 will show signs of a labral tear or arthritis in the acromioclavicular joint, he said. “These are incidental findings that don’t need treatment,” he added.

More research is needed to develop more medications to manage pain for all musculoskeletal conditions, including shoulder pain, said Feeley. “But for now, for patients with shoulder pain, I tend to recommend a combination of Tylenol and an NSAID to improve inflammation and reduce pain, and a guided [physical] therapy program at home or in person. The combination of both usually will be successful,” he said.

 

Postsurgical Shoulder Pain

“For patients who have shoulder surgery, the techniques to manage pain around surgery have improved tremendously over the last decade, particularly with multimodal pain management and nerve blocks,” Feeley told this news organization. These advances have tremendously reduced the need for narcotics for pain management beyond the first 72 hours after surgery, he said. “I strongly recommend patients and primary care doctors to stop all narcotics as soon as possible after shoulder surgery, since they are not nearly as effective for management of pain after the first few days, and they should never be used as a sleep aid,” he emphasized.

Managing pain during recovery from shoulder surgery also involves about 6 weeks in a sling to protect the repair, followed by 6 weeks of active motion but no strengthening, then 3 months of strengthening exercises, he said.

Shoulder pain resources for patients: https://www.hss.edu/condition-list_shoulder-pain-causes.asp

Feeley’s 10-minute video on shoulder examination and pain assessment at the UCSF 14th Annual Primary Care Sports Medicine Conference, 2019: Video on the Essential Shoulder Exam

Kolfenbach disclosed receiving royalties from Elsevier for being the editor of Rheumatology Secrets and Wolters Kluwer for authoring several articles on UpToDate. Feeley and Angelo had no relevant financial conflicts to disclose.

 

A version of this article appeared on Medscape.com.

It was 1996, and Masashi Yanagisawa was on the brink of his next discovery.

The Japanese scientist had arrived at the University of Texas Southwestern in Dallas 5 years earlier, setting up his own lab at age 31. After earning his medical degree, he’d gained notoriety as a PhD student when he discovered endothelin, the body’s most potent vasoconstrictor.

Yanagisawa was about to prove this wasn’t a first-timer’s fluke.

His focus was G-protein–coupled receptors (GPCRs), cell surface receptors that respond to a range of molecules and a popular target for drug discovery. The Human Genome Project had just revealed a slew of newly discovered receptors, or “orphan” GPCRs, and identifying an activating molecule could yield a new drug. (That vasoconstrictor endothelin was one such success story, leading to four new drug approvals in the United States over the past quarter century.) 

Yanagisawa and his team created 50 cell lines, each expressing one orphan receptor. They applied animal tissue to every line, along with a calcium-sensitive dye. If the cells glowed under the microscope, they had a hit.

“He was basically doing an elaborate fishing expedition,” said Jon Willie, MD, PhD, an associate professor of neurosurgery at Washington University School of Medicine in St. Louis, Missouri, who would later join Yanagisawa’s team.

It wasn’t long before the neon-green fluorescence signaled a match. After isolating the activating molecule, the scientists realized they were dealing with two neuropeptides.

No one had ever seen these proteins before. And no one knew their discovery would set off a decades-long journey that would finally solve a century-old medical mystery — and may even fix one of the biggest health crises of our time, as revealed by research published earlier in 2024. It’s a story of strange coincidences, serendipitous discoveries, and quirky details. Most of all, it’s a fascinating example of how basic science can revolutionize medicine — and how true breakthroughs happen over time and in real time.

 

But That’s Basic Science for You

Most basic science studies — the early, foundational research that provides the building blocks for science that follows — don’t lead to medical breakthroughs. But some do, often in surprising ways.

Also called curiosity-driven research, basic science aims to fill knowledge gaps to keep science moving, even if the trajectory isn’t always clear.

“The people working on the basic research that led to discoveries that transformed the modern world had no idea at the time,” said Isobel Ronai, PhD, a postdoctoral fellow in life sciences at Harvard University, Cambridge, Massachusetts. “Often, these stories can only be seen in hindsight,” sometimes decades later.

Case in point: For molecular biology techniques — things like DNA sequencing and gene targeting — the lag between basic science and breakthrough is, on average, 23 years. While many of the resulting techniques have received Nobel Prizes, few of the foundational discoveries have been awarded such accolades.

“The scientific glory is more often associated with the downstream applications,” said Ronai. “The importance of basic research can get lost. But it is the foundation for any future application, such as drug development.”

As funding is increasingly funneled toward applied research, basic science can require a certain persistence. What this under-appreciation can obscure is the pathway to discovery — which is often as compelling as the end result, full of unpredictable twists, turns, and even interpersonal intrigue.

And then there’s the fascinating — and definitely complicated — phenomenon of multiple independent discoveries.

As in: What happens when two independent teams discover the same thing at the same time?

 

Back to Yanagisawa’s Lab ...

... where he and his team learned a few things about those new neuropeptides. Rat brain studies pinpointed the lateral hypothalamus as the peptides’ area of activity — a region often called the brain’s feeding center.

“If you destroy that part of the brain, animals lose appetite,” said Yanagisawa. So these peptides must control feeding, the scientists thought.

Sure enough, injecting the proteins into rat brains led the rodents to start eating.

Satisfied, the team named them “orexin-A” and “orexin-B,” for the Greek word “orexis,” meaning appetite. The brain receptors became “orexin-1” and “orexin-2.” The team prepared to publish its findings in Cell.

But another group beat them to it.

 

Introducing the ‘Hypocretins’

In early January 1998, a team of Scripps Research Institute scientists, led by J. Gregor Sutcliffe, PhD, released a paper in the journal PNAS. They described a gene encoding for the precursor to two neuropeptides

As the peptides were in the hypothalamus and structurally like secretin (a gut hormone), they called them “hypocretins.” The hypocretin peptides excited neurons in the hypothalamus, and later that year, the scientists discovered that the neurons’ branches extended, tentacle-like, throughout the brain. “Many of the connected areas were involved in sleep-wake control,” said Thomas Kilduff, PhD, who joined the Sutcliffe lab just weeks before the hypocretin discovery. At the time, however, the significance of this finding was not yet clear.

Weeks later, in February 1998, Yanagisawa’s paper came out.

Somehow, two groups, over 1000 miles apart, had stumbled on the same neuropeptides at the same time.

“I first heard about [Yanagisawa’s] paper on NBC Nightly News,” recalls Kilduff. “I was skiing in the mountains, so I had to wait until Monday to get back to the lab to see what the paper was all about.”

He realized that Yanagisawa’s orexin was his lab’s hypocretin, although the study didn’t mention another team’s discovery.

“There may have been accusations. But as far as I know, it’s because [Yanagisawa] didn’t know [about the other paper],” said Willie. “This was not something he produced in 2 months. This was clearly years of work.” 

 

‘Multiple Discovery’ Happens More Often Than You Think

In the mid-20th century, sociologist Robert Merton described the phenomenon of “multiple discovery,” where many scientific discoveries or inventions are made independently at roughly the same time.

“This happens much more frequently in scientific research than people suppose,” said David Pendlebury, head of research analysis at Clarivate’s Institute for Scientific Information, the analytics company’s research arm. (Last year, Pendlebury flagged the hypocretin/orexin discovery for Clarivate’s prestigious Citations Laureates award, an honor that aims to predict, often successfully, who will go on to win the Nobel Prize.) 

“People have this idea of the lone researcher making a brilliant discovery,” Pendlebury said. “But more and more, teams find things at the same time.” 

While this can — and does — lead to squabbling about who deserves credit, the desire to be first can also be highly motivating, said Mike Schneider, PhD, an assistant professor of philosophy at the University of Missouri, Columbia, who studies the social dynamics of science, potentially leading to faster scientific advancement.

The downside? If two groups produce the same or similar results, but one publishes first, scientific journals tend to reject the second, citing a lack of novelty.

Yet duplicating research is a key step in confirming the validity of a discovery.

That’s why, in 2018, the journal PLOS Biology created a provision for “scooped” scientists, allowing them to submit their paper within 6 months of the first as a complementary finding. Instead of viewing this as redundancy, the editors believe it adds robustness to the research.

 

‘What the Heck Is This Mouse Doing?’

Even though he’d been scooped, Yanagisawa forged on to the next challenge: Confirming whether orexin regulated feeding.

He began breeding mice missing the orexin gene. His team expected these “knockout” mice to eat less, resulting in a thinner body than other rodents. To the contrary, “they were on average fatter,” said Willie. “They were eating less but weighed more, indicating a slower metabolism.”

The researchers were befuddled. “We were really disappointed, almost desperate about what to do,” said Yanagisawa.

As nocturnal animals eat more at night, he decided they should study the mice after dark. One of his students, Richard Chemelli, MD, bought an infrared video camera from Radio Shack, filming the first 4 hours of the mice’s active period for several nights.

After watching the footage, “Rick called me and said, ‘Let’s get into the lab,’ ” said Willie. “It was four of us on a Saturday looking at these videos, saying, ‘What the heck is this mouse doing?’ ”

While exploring their habitat, the knockout mice would randomly fall over, pop back up after a minute or so, and resume normal activity. This happened over and over — and the scientists were unsure why.

They began monitoring the mice’s brains during these episodes — and made a startling discovery.

The mice weren’t having seizures. They were shifting directly into REM sleep, bypassing the non-REM stage, then quickly toggling back to wake mode.

“That’s when we knew these animals had something akin to narcolepsy,” said Willie.

The team recruited Thomas Scammell, MD, a Harvard neurologist, to investigate whether modafinil — an anti-narcoleptic drug without a clear mechanism — affected orexin neurons.

Two hours after injecting the mice with the medication, the scientists sacrificed them and stained their brains. Remarkably, the number of neurons showing orexin activity had increased ninefold. It seemed modafinil worked by activating the orexin system.

These findings had the potential to crack open the science of narcolepsy, one of the most mysterious sleep disorders.

Unless, of course, another team did it first.

 

The Mystery of Narcolepsy

Yet another multiple discovery, narcolepsy was first described by two scientists — one in Germany, the other in France — within a short span in the late 1800s.

It would be more than a hundred years before anyone understood the disorder’s cause, even though it affects about 1 in 2000 people.

“Patients were often labeled as lazy and malingerers,” said Kilduff, “since they were sleepy all the time and had this weird motor behavior called cataplexy” or the sudden loss of muscle tone.

In the early 1970s, William Dement, MD, PhD — “the father of sleep medicine” — was searching for a narcoleptic cat to study. He couldn’t find a feline, but several colleagues mentioned dogs with narcolepsy-like symptoms.

Dement, who died in 2020, had found his newest research subjects.

In 1973, he started a narcoleptic dog colony at Stanford University in Palo Alto, California. At first, he focused on poodles and beagles. After discovering their narcolepsy wasn’t genetic, he pivoted to dobermans and labradors. Their narcolepsy was inherited, so he could breed them to populate the colony.

Although human narcolepsy is rarely genetic, it’s otherwise a lot like the version in these dogs.

Both involve daytime sleepiness, “pathological” bouts of REM sleep, and the loss of muscle tone in response to emotions, often positive ones.

The researchers hoped the canines could unlock a treatment for human narcolepsy. They began laying out a path of dog kibble, then injecting the dogs with drugs such as selective serotonin reuptake inhibitors. They wanted to see what might help them stay awake as they excitedly chowed down.

Kilduff also started a molecular genetics program, trying to identify the genetic defect behind canine narcolepsy. But after a parvovirus outbreak, Kilduff resigned from the project, drained from the strain of seeing so many dogs die.

A decade after his departure from the dog colony, his work would dramatically intersect with that of his successor, Emmanuel Mignot, MD, PhD.

“I thought I had closed the narcolepsy chapter in my life forever,” said Kilduff. “Then in 1998, we described this novel neuropeptide, hypocretin, that turned out to be the key to understanding the disorder.”

 

Narcoleptic Dogs in California, Mutant Mice in Texas

It was modafinil — the same anti-narcoleptic drug Yanagisawa’s team studied — that brought Emmanuel Mignot to the United States. After training as a pharmacologist in France, his home country sent him to Stanford to study the drug, which was discovered by French scientists, as his required military service.

As Kilduff’s replacement at the dog colony, his goal was to figure out how modafinil worked, hoping to attract a US company to develop the drug.

The plan succeeded. Modafinil became Provigil, a billion-dollar narcolepsy drug, and Mignot became “completely fascinated” with the disorder.

“I realized quickly that there was no way we’d find the cause of narcolepsy by finding the mode of action of this drug,” Mignot said. “Most likely, the drug was acting downstream, not at the cause of the disorder.”

To discover the answer, he needed to become a geneticist. And so began his 11-year odyssey to find the cause of canine narcolepsy.

After mapping the dog genome, Mignot set out to find the smallest stretch of chromosome that the narcoleptic animals had in common. “For a very long time, we were stuck with a relatively large region [of DNA],” he recalls. “It was a no man’s land.” 

Within that region was the gene for the hypocretin/orexin-2 receptor — the same receptor that Yanagisawa had identified in his first orexin paper. Mignot didn’t immediately pursue that gene as a possibility — even though his students suggested it. Why?

“The decision was simply: Should we lose time to test a possible candidate [gene] among many?” Mignot said.

As Mignot studied dog DNA in California, Yanagisawa was creating mutant mice in Texas. Unbeknownst to either scientist, their work was about to converge.

 

What Happened Next Is Somewhat Disputed 

After diagnosing his mice with narcolepsy, Yanagisawa opted not to share this finding with Mignot, though he knew about Mignot’s interest in the condition. Instead, he asked a colleague to find out how far along Mignot was in his genetics research.

According to Yanagisawa, his colleague didn’t realize how quickly DNA sequencing could happen once a target gene was identified. At a sleep meeting, “he showed Emmanuel all of our raw data. Almost accidentally, he disclosed our findings,” he said. “It was a shock for me.” 

Unsure whether he was part of the orexin group, Mignot decided not to reveal that he’d identified the hypocretin/orexin-2 receptor gene as the faulty one in his narcoleptic dogs.

Although he didn’t share this finding, Mignot said he did offer to speak with the lead researcher to see if their findings were the same. If they were, they could jointly submit their articles. But Mignot never heard back.

Meanwhile, back at his lab, Mignot buckled down. While he wasn’t convinced the mouse data proved anything, it did give him the motivation to move faster.

Within weeks, he submitted his findings to Cell, revealing a mutation in the hypocretin/orexin-2 receptor gene as the cause of canine narcolepsy. According to Yanagisawa, the journal’s editor invited him to peer-review the paper, tipping him off to its existence.

“I told him I had a conflict of interest,” said Yanagisawa. “And then we scrambled to finish our manuscript. We wrote up the paper within almost 5 days.”

For a moment, it seemed both papers would be published together in Cell. Instead, on August 6, 1999, Mignot’s study was splashed solo across the journal’s cover.

“At the time, our team was pissed off, but looking back, what else could Emmanuel have done?” said Willie, who was part of Yanagisawa’s team. “The grant he’d been working on for years was at risk. He had it within his power to do the final experiments. Of course he was going to finish.”

Two weeks later, Yanagisawa’s findings followed, also in Cell.

His paper proposed knockout mice as a model for human narcolepsy and orexin as a key regulator of the sleep/wake cycle. With orexin-activated neurons branching into other areas of the brain, the peptide seemed to promote wakefulness by synchronizing several arousal neurotransmitters, such as serotonin, norepinephrine, and histamine.

“If you don’t have orexin, each of those systems can still function, but they’re not as coordinated,” said Willie. “If you have narcolepsy, you’re capable of wakefulness, and you’re capable of sleep. What you can’t do is prevent inappropriately switching between states.”

Together, the two papers painted a clear picture: Narcolepsy was the result of a dysfunction in the hypocretin/orexin system.

After more than a century, the cause of narcolepsy was starting to come into focus.

“This was blockbuster,” said Willie.

By itself, either finding — one in dogs, one in mice — might have been met with skepticism. But in combination, they offered indisputable evidence about narcolepsy’s cause.

 

The Human Brains in Your Fridge Hold Secrets

Jerome Siegel had been searching for the cause of human narcolepsy for years. A PhD and professor at the University of California, Los Angeles, he had managed to acquire four human narcoleptic brains. As laughter is often the trigger for the sudden shift to REM sleep in humans, he focused on the amygdala, an area linked to emotion.

“I looked in the amygdala and didn’t see anything,” he said. “So the brains stayed in my refrigerator for probably 10 years.” 

Then he was invited to review Yanagisawa’s study in Cell. The lightbulb clicked on: Maybe the hypothalamus — not the amygdala — was the area of abnormality. He and his team dug out the decade-old brains.

When they stained the brains, the massive loss of hypocretin-activated neurons was hard to miss: On average, the narcoleptic brains had only about 7000 of the cells versus 70,000 in the average human brain. The scientists also noticed scar tissue in the hypothalamus, indicating that the neurons had at some point died, rather than being absent from birth.

What Siegel didn’t know: Mignot had also acquired a handful of human narcoleptic brains.

Already, he had coauthored a study showing that hypocretin/orexin was undetectable in the cerebrospinal fluid of the majority of the people with narcolepsy his team tested. It seemed clear that the hypocretin/orexin system was flawed — or even broken — in people with the condition.

“It looked like the cause of narcolepsy in humans was indeed this lack of orexin in the brain,” he said. “That was the hypothesis immediately. To me, this is when we established that narcolepsy in humans was due to a lack of orexin. The next thing was to check that the cells were missing.” 

Now he could do exactly that.

As expected, Mignot’s team observed a dramatic loss of hypocretin/orexin cells in the narcoleptic brains. They also noticed that a different cell type in the hypothalamus was unaffected. This implied the damage was specific to the hypocretin-activated cells and supported a hunch they already had: That the deficit was the result not of a genetic defect but of an autoimmune attack. (It’s a hypothesis Mignot has spent the last 15 years proving.)

It wasn’t until a gathering in Hawaii, in late August 2000, that the two realized the overlap of their work.

To celebrate his team’s finding, Mignot had invited a group of researchers to Big Island. With his paper scheduled for publication on September 1, he felt comfortable presenting his findings to his guests, which included Siegel.

Until then, “I didn’t know what he had found, and he didn’t know what I had found, which basically was the same thing,” said Siegel.

In yet another strange twist, the two papers were published just weeks apart, simultaneously revealing that human narcoleptics have a depleted supply of the neurons that bind to hypocretin/orexin. The cause of the disorder was at last a certainty.

“Even if I was first, what does it matter? In the end, you need confirmation,” said Mignot. “You need multiple people to make sure that it’s true. It’s good science when things like this happen.”

 

How All of This Changed Medicine

Since these groundbreaking discoveries, the diagnosis of narcolepsy has become much simpler. Lab tests can now easily measure hypocretin in cerebrospinal fluid, providing a definitive diagnosis.

But the development of narcolepsy treatments has lagged — even though hypocretin/orexin replacement therapy is the obvious answer.

“Almost 25 years have elapsed, and there’s no such therapeutic on the market,” said Kilduff, who now works for SRI International, a non-profit research and development institute.

That’s partly because agonists — drugs that bind to receptors in the brain — are challenging to create, as this requires mimicking the activating molecule’s structure, like copying the grooves of an intricate key.

Antagonists, by comparison, are easier to develop. These act as a gate, blocking access to the receptors. As a result, drugs that promote sleep by thwarting hypocretin/orexin have emerged more quickly, providing a flurry of new options for people with insomnia. The first, suvorexant, was launched in 2014. Two others followed in recent years.

Researchers are hopeful a hypocretin/orexin agonist is on the horizon.

“This is a very hot area of drug development,” said Kilduff. “It’s just a matter of who’s going to get the drug to market first.”

 

One More Hypocretin/Orexin Surprise — and It Could Be The Biggest

Several years ago, Siegel’s lab received what was supposed to be a healthy human brain — one they could use as a comparison for narcoleptic brains. But researcher Thomas Thannickal, PhD, lead author of the UCLA study linking hypocretin loss to human narcolepsy, noticed something strange: This brain had significantly more hypocretin neurons than average.

Was this due to a seizure? A traumatic death? Siegel called the brain bank to request the donor’s records. He was told they were missing.

Years later, Siegel happened to be visiting the brain bank for another project and found himself in a room adjacent to the medical records. “Nobody was there,” he said, “so I just opened a drawer.”

Shuffling through the brain bank’s files, Siegel found the medical records he’d been told were lost. In the file was a note from the donor, explaining that he was a former heroin addict.

“I almost fell out of my chair,” said Siegel. “I realized this guy’s heroin addiction likely had something to do with his very unusual brain.” 

Obviously, opioids affected the orexin system. But how? 

“It’s when people are happy that this peptide is released,” said Siegel. “The hypocretin system is not just related to alertness. It’s related to pleasure.” 

As Yanagisawa observed early on, hypocretin/orexin does indeed play a role in eating — just not the one he initially thought. The peptides prompted pleasure seeking. So the rodents ate. 

In 2018, after acquiring five more brains, Siegel’s group published a study in Translational Medicine showing 54% more detectable hypocretin neurons in the brains of heroin addicts than in those of control individuals.

In 2022, another breakthrough: His team showed that morphine significantly altered the pathways of hypocretin neurons in mice, sending their axons into brain regions associated with addiction. Then, when they removed the mice’s hypocretin neurons and discontinued their daily morphine dose, the rodents showed no symptoms of opioid withdrawal.

This fits the connection with narcolepsy: Among the standard treatments for the condition are amphetamines and other stimulants, which all have addictive potential. Yet, “narcoleptics never abuse these drugs,” Siegel said. “They seem to be uniquely resistant to addiction.”

This could powerfully change the way opioids are administered.

“If you prevent the hypocretin response to opioids, you may be able to prevent opioid addiction,” said Siegel. In other words, blocking the hypocretin system with a drug like those used to treat insomnia may allow patients to experience the pain-relieving benefits of opioids — without the risk for addiction.

His team is currently investigating treatments targeting the hypocretin/orexin system for opioid addiction.

In a study published in July, they found that mice who received suvorexant — the drug for insomnia — didn’t anticipate their daily dose of opioids the way other rodents did. This suggests the medication prevented addiction, without diminishing the pain-relieving effect of opioids.

If it translates to humans, this discovery could potentially save millions of lives.

“I think it’s just us working on this,” said Siegel.

But with hypocretin/orexin, you never know.

A version of this article appeared on Medscape.com.

It was 1996, and Masashi Yanagisawa was on the brink of his next discovery.

The Japanese scientist had arrived at the University of Texas Southwestern in Dallas 5 years earlier, setting up his own lab at age 31. After earning his medical degree, he’d gained notoriety as a PhD student when he discovered endothelin, the body’s most potent vasoconstrictor.

Yanagisawa was about to prove this wasn’t a first-timer’s fluke.

His focus was G-protein–coupled receptors (GPCRs), cell surface receptors that respond to a range of molecules and a popular target for drug discovery. The Human Genome Project had just revealed a slew of newly discovered receptors, or “orphan” GPCRs, and identifying an activating molecule could yield a new drug. (That vasoconstrictor endothelin was one such success story, leading to four new drug approvals in the United States over the past quarter century.) 

Yanagisawa and his team created 50 cell lines, each expressing one orphan receptor. They applied animal tissue to every line, along with a calcium-sensitive dye. If the cells glowed under the microscope, they had a hit.

“He was basically doing an elaborate fishing expedition,” said Jon Willie, MD, PhD, an associate professor of neurosurgery at Washington University School of Medicine in St. Louis, Missouri, who would later join Yanagisawa’s team.

It wasn’t long before the neon-green fluorescence signaled a match. After isolating the activating molecule, the scientists realized they were dealing with two neuropeptides.

No one had ever seen these proteins before. And no one knew their discovery would set off a decades-long journey that would finally solve a century-old medical mystery — and may even fix one of the biggest health crises of our time, as revealed by research published earlier in 2024. It’s a story of strange coincidences, serendipitous discoveries, and quirky details. Most of all, it’s a fascinating example of how basic science can revolutionize medicine — and how true breakthroughs happen over time and in real time.

 

But That’s Basic Science for You

Most basic science studies — the early, foundational research that provides the building blocks for science that follows — don’t lead to medical breakthroughs. But some do, often in surprising ways.

Also called curiosity-driven research, basic science aims to fill knowledge gaps to keep science moving, even if the trajectory isn’t always clear.

“The people working on the basic research that led to discoveries that transformed the modern world had no idea at the time,” said Isobel Ronai, PhD, a postdoctoral fellow in life sciences at Harvard University, Cambridge, Massachusetts. “Often, these stories can only be seen in hindsight,” sometimes decades later.

Case in point: For molecular biology techniques — things like DNA sequencing and gene targeting — the lag between basic science and breakthrough is, on average, 23 years. While many of the resulting techniques have received Nobel Prizes, few of the foundational discoveries have been awarded such accolades.

“The scientific glory is more often associated with the downstream applications,” said Ronai. “The importance of basic research can get lost. But it is the foundation for any future application, such as drug development.”

As funding is increasingly funneled toward applied research, basic science can require a certain persistence. What this under-appreciation can obscure is the pathway to discovery — which is often as compelling as the end result, full of unpredictable twists, turns, and even interpersonal intrigue.

And then there’s the fascinating — and definitely complicated — phenomenon of multiple independent discoveries.

As in: What happens when two independent teams discover the same thing at the same time?

 

Back to Yanagisawa’s Lab ...

... where he and his team learned a few things about those new neuropeptides. Rat brain studies pinpointed the lateral hypothalamus as the peptides’ area of activity — a region often called the brain’s feeding center.

“If you destroy that part of the brain, animals lose appetite,” said Yanagisawa. So these peptides must control feeding, the scientists thought.

Sure enough, injecting the proteins into rat brains led the rodents to start eating.

Satisfied, the team named them “orexin-A” and “orexin-B,” for the Greek word “orexis,” meaning appetite. The brain receptors became “orexin-1” and “orexin-2.” The team prepared to publish its findings in Cell.

But another group beat them to it.

 

Introducing the ‘Hypocretins’

In early January 1998, a team of Scripps Research Institute scientists, led by J. Gregor Sutcliffe, PhD, released a paper in the journal PNAS. They described a gene encoding for the precursor to two neuropeptides

As the peptides were in the hypothalamus and structurally like secretin (a gut hormone), they called them “hypocretins.” The hypocretin peptides excited neurons in the hypothalamus, and later that year, the scientists discovered that the neurons’ branches extended, tentacle-like, throughout the brain. “Many of the connected areas were involved in sleep-wake control,” said Thomas Kilduff, PhD, who joined the Sutcliffe lab just weeks before the hypocretin discovery. At the time, however, the significance of this finding was not yet clear.

Weeks later, in February 1998, Yanagisawa’s paper came out.

Somehow, two groups, over 1000 miles apart, had stumbled on the same neuropeptides at the same time.

“I first heard about [Yanagisawa’s] paper on NBC Nightly News,” recalls Kilduff. “I was skiing in the mountains, so I had to wait until Monday to get back to the lab to see what the paper was all about.”

He realized that Yanagisawa’s orexin was his lab’s hypocretin, although the study didn’t mention another team’s discovery.

“There may have been accusations. But as far as I know, it’s because [Yanagisawa] didn’t know [about the other paper],” said Willie. “This was not something he produced in 2 months. This was clearly years of work.” 

 

‘Multiple Discovery’ Happens More Often Than You Think

In the mid-20th century, sociologist Robert Merton described the phenomenon of “multiple discovery,” where many scientific discoveries or inventions are made independently at roughly the same time.

“This happens much more frequently in scientific research than people suppose,” said David Pendlebury, head of research analysis at Clarivate’s Institute for Scientific Information, the analytics company’s research arm. (Last year, Pendlebury flagged the hypocretin/orexin discovery for Clarivate’s prestigious Citations Laureates award, an honor that aims to predict, often successfully, who will go on to win the Nobel Prize.) 

“People have this idea of the lone researcher making a brilliant discovery,” Pendlebury said. “But more and more, teams find things at the same time.” 

While this can — and does — lead to squabbling about who deserves credit, the desire to be first can also be highly motivating, said Mike Schneider, PhD, an assistant professor of philosophy at the University of Missouri, Columbia, who studies the social dynamics of science, potentially leading to faster scientific advancement.

The downside? If two groups produce the same or similar results, but one publishes first, scientific journals tend to reject the second, citing a lack of novelty.

Yet duplicating research is a key step in confirming the validity of a discovery.

That’s why, in 2018, the journal PLOS Biology created a provision for “scooped” scientists, allowing them to submit their paper within 6 months of the first as a complementary finding. Instead of viewing this as redundancy, the editors believe it adds robustness to the research.

 

‘What the Heck Is This Mouse Doing?’

Even though he’d been scooped, Yanagisawa forged on to the next challenge: Confirming whether orexin regulated feeding.

He began breeding mice missing the orexin gene. His team expected these “knockout” mice to eat less, resulting in a thinner body than other rodents. To the contrary, “they were on average fatter,” said Willie. “They were eating less but weighed more, indicating a slower metabolism.”

The researchers were befuddled. “We were really disappointed, almost desperate about what to do,” said Yanagisawa.

As nocturnal animals eat more at night, he decided they should study the mice after dark. One of his students, Richard Chemelli, MD, bought an infrared video camera from Radio Shack, filming the first 4 hours of the mice’s active period for several nights.

After watching the footage, “Rick called me and said, ‘Let’s get into the lab,’ ” said Willie. “It was four of us on a Saturday looking at these videos, saying, ‘What the heck is this mouse doing?’ ”

While exploring their habitat, the knockout mice would randomly fall over, pop back up after a minute or so, and resume normal activity. This happened over and over — and the scientists were unsure why.

They began monitoring the mice’s brains during these episodes — and made a startling discovery.

The mice weren’t having seizures. They were shifting directly into REM sleep, bypassing the non-REM stage, then quickly toggling back to wake mode.

“That’s when we knew these animals had something akin to narcolepsy,” said Willie.

The team recruited Thomas Scammell, MD, a Harvard neurologist, to investigate whether modafinil — an anti-narcoleptic drug without a clear mechanism — affected orexin neurons.

Two hours after injecting the mice with the medication, the scientists sacrificed them and stained their brains. Remarkably, the number of neurons showing orexin activity had increased ninefold. It seemed modafinil worked by activating the orexin system.

These findings had the potential to crack open the science of narcolepsy, one of the most mysterious sleep disorders.

Unless, of course, another team did it first.

 

The Mystery of Narcolepsy

Yet another multiple discovery, narcolepsy was first described by two scientists — one in Germany, the other in France — within a short span in the late 1800s.

It would be more than a hundred years before anyone understood the disorder’s cause, even though it affects about 1 in 2000 people.

“Patients were often labeled as lazy and malingerers,” said Kilduff, “since they were sleepy all the time and had this weird motor behavior called cataplexy” or the sudden loss of muscle tone.

In the early 1970s, William Dement, MD, PhD — “the father of sleep medicine” — was searching for a narcoleptic cat to study. He couldn’t find a feline, but several colleagues mentioned dogs with narcolepsy-like symptoms.

Dement, who died in 2020, had found his newest research subjects.

In 1973, he started a narcoleptic dog colony at Stanford University in Palo Alto, California. At first, he focused on poodles and beagles. After discovering their narcolepsy wasn’t genetic, he pivoted to dobermans and labradors. Their narcolepsy was inherited, so he could breed them to populate the colony.

Although human narcolepsy is rarely genetic, it’s otherwise a lot like the version in these dogs.

Both involve daytime sleepiness, “pathological” bouts of REM sleep, and the loss of muscle tone in response to emotions, often positive ones.

The researchers hoped the canines could unlock a treatment for human narcolepsy. They began laying out a path of dog kibble, then injecting the dogs with drugs such as selective serotonin reuptake inhibitors. They wanted to see what might help them stay awake as they excitedly chowed down.

Kilduff also started a molecular genetics program, trying to identify the genetic defect behind canine narcolepsy. But after a parvovirus outbreak, Kilduff resigned from the project, drained from the strain of seeing so many dogs die.

A decade after his departure from the dog colony, his work would dramatically intersect with that of his successor, Emmanuel Mignot, MD, PhD.

“I thought I had closed the narcolepsy chapter in my life forever,” said Kilduff. “Then in 1998, we described this novel neuropeptide, hypocretin, that turned out to be the key to understanding the disorder.”

 

Narcoleptic Dogs in California, Mutant Mice in Texas

It was modafinil — the same anti-narcoleptic drug Yanagisawa’s team studied — that brought Emmanuel Mignot to the United States. After training as a pharmacologist in France, his home country sent him to Stanford to study the drug, which was discovered by French scientists, as his required military service.

As Kilduff’s replacement at the dog colony, his goal was to figure out how modafinil worked, hoping to attract a US company to develop the drug.

The plan succeeded. Modafinil became Provigil, a billion-dollar narcolepsy drug, and Mignot became “completely fascinated” with the disorder.

“I realized quickly that there was no way we’d find the cause of narcolepsy by finding the mode of action of this drug,” Mignot said. “Most likely, the drug was acting downstream, not at the cause of the disorder.”

To discover the answer, he needed to become a geneticist. And so began his 11-year odyssey to find the cause of canine narcolepsy.

After mapping the dog genome, Mignot set out to find the smallest stretch of chromosome that the narcoleptic animals had in common. “For a very long time, we were stuck with a relatively large region [of DNA],” he recalls. “It was a no man’s land.” 

Within that region was the gene for the hypocretin/orexin-2 receptor — the same receptor that Yanagisawa had identified in his first orexin paper. Mignot didn’t immediately pursue that gene as a possibility — even though his students suggested it. Why?

“The decision was simply: Should we lose time to test a possible candidate [gene] among many?” Mignot said.

As Mignot studied dog DNA in California, Yanagisawa was creating mutant mice in Texas. Unbeknownst to either scientist, their work was about to converge.

 

What Happened Next Is Somewhat Disputed 

After diagnosing his mice with narcolepsy, Yanagisawa opted not to share this finding with Mignot, though he knew about Mignot’s interest in the condition. Instead, he asked a colleague to find out how far along Mignot was in his genetics research.

According to Yanagisawa, his colleague didn’t realize how quickly DNA sequencing could happen once a target gene was identified. At a sleep meeting, “he showed Emmanuel all of our raw data. Almost accidentally, he disclosed our findings,” he said. “It was a shock for me.” 

Unsure whether he was part of the orexin group, Mignot decided not to reveal that he’d identified the hypocretin/orexin-2 receptor gene as the faulty one in his narcoleptic dogs.

Although he didn’t share this finding, Mignot said he did offer to speak with the lead researcher to see if their findings were the same. If they were, they could jointly submit their articles. But Mignot never heard back.

Meanwhile, back at his lab, Mignot buckled down. While he wasn’t convinced the mouse data proved anything, it did give him the motivation to move faster.

Within weeks, he submitted his findings to Cell, revealing a mutation in the hypocretin/orexin-2 receptor gene as the cause of canine narcolepsy. According to Yanagisawa, the journal’s editor invited him to peer-review the paper, tipping him off to its existence.

“I told him I had a conflict of interest,” said Yanagisawa. “And then we scrambled to finish our manuscript. We wrote up the paper within almost 5 days.”

For a moment, it seemed both papers would be published together in Cell. Instead, on August 6, 1999, Mignot’s study was splashed solo across the journal’s cover.

“At the time, our team was pissed off, but looking back, what else could Emmanuel have done?” said Willie, who was part of Yanagisawa’s team. “The grant he’d been working on for years was at risk. He had it within his power to do the final experiments. Of course he was going to finish.”

Two weeks later, Yanagisawa’s findings followed, also in Cell.

His paper proposed knockout mice as a model for human narcolepsy and orexin as a key regulator of the sleep/wake cycle. With orexin-activated neurons branching into other areas of the brain, the peptide seemed to promote wakefulness by synchronizing several arousal neurotransmitters, such as serotonin, norepinephrine, and histamine.

“If you don’t have orexin, each of those systems can still function, but they’re not as coordinated,” said Willie. “If you have narcolepsy, you’re capable of wakefulness, and you’re capable of sleep. What you can’t do is prevent inappropriately switching between states.”

Together, the two papers painted a clear picture: Narcolepsy was the result of a dysfunction in the hypocretin/orexin system.

After more than a century, the cause of narcolepsy was starting to come into focus.

“This was blockbuster,” said Willie.

By itself, either finding — one in dogs, one in mice — might have been met with skepticism. But in combination, they offered indisputable evidence about narcolepsy’s cause.

 

The Human Brains in Your Fridge Hold Secrets

Jerome Siegel had been searching for the cause of human narcolepsy for years. A PhD and professor at the University of California, Los Angeles, he had managed to acquire four human narcoleptic brains. As laughter is often the trigger for the sudden shift to REM sleep in humans, he focused on the amygdala, an area linked to emotion.

“I looked in the amygdala and didn’t see anything,” he said. “So the brains stayed in my refrigerator for probably 10 years.” 

Then he was invited to review Yanagisawa’s study in Cell. The lightbulb clicked on: Maybe the hypothalamus — not the amygdala — was the area of abnormality. He and his team dug out the decade-old brains.

When they stained the brains, the massive loss of hypocretin-activated neurons was hard to miss: On average, the narcoleptic brains had only about 7000 of the cells versus 70,000 in the average human brain. The scientists also noticed scar tissue in the hypothalamus, indicating that the neurons had at some point died, rather than being absent from birth.

What Siegel didn’t know: Mignot had also acquired a handful of human narcoleptic brains.

Already, he had coauthored a study showing that hypocretin/orexin was undetectable in the cerebrospinal fluid of the majority of the people with narcolepsy his team tested. It seemed clear that the hypocretin/orexin system was flawed — or even broken — in people with the condition.

“It looked like the cause of narcolepsy in humans was indeed this lack of orexin in the brain,” he said. “That was the hypothesis immediately. To me, this is when we established that narcolepsy in humans was due to a lack of orexin. The next thing was to check that the cells were missing.” 

Now he could do exactly that.

As expected, Mignot’s team observed a dramatic loss of hypocretin/orexin cells in the narcoleptic brains. They also noticed that a different cell type in the hypothalamus was unaffected. This implied the damage was specific to the hypocretin-activated cells and supported a hunch they already had: That the deficit was the result not of a genetic defect but of an autoimmune attack. (It’s a hypothesis Mignot has spent the last 15 years proving.)

It wasn’t until a gathering in Hawaii, in late August 2000, that the two realized the overlap of their work.

To celebrate his team’s finding, Mignot had invited a group of researchers to Big Island. With his paper scheduled for publication on September 1, he felt comfortable presenting his findings to his guests, which included Siegel.

Until then, “I didn’t know what he had found, and he didn’t know what I had found, which basically was the same thing,” said Siegel.

In yet another strange twist, the two papers were published just weeks apart, simultaneously revealing that human narcoleptics have a depleted supply of the neurons that bind to hypocretin/orexin. The cause of the disorder was at last a certainty.

“Even if I was first, what does it matter? In the end, you need confirmation,” said Mignot. “You need multiple people to make sure that it’s true. It’s good science when things like this happen.”

 

How All of This Changed Medicine

Since these groundbreaking discoveries, the diagnosis of narcolepsy has become much simpler. Lab tests can now easily measure hypocretin in cerebrospinal fluid, providing a definitive diagnosis.

But the development of narcolepsy treatments has lagged — even though hypocretin/orexin replacement therapy is the obvious answer.

“Almost 25 years have elapsed, and there’s no such therapeutic on the market,” said Kilduff, who now works for SRI International, a non-profit research and development institute.

That’s partly because agonists — drugs that bind to receptors in the brain — are challenging to create, as this requires mimicking the activating molecule’s structure, like copying the grooves of an intricate key.

Antagonists, by comparison, are easier to develop. These act as a gate, blocking access to the receptors. As a result, drugs that promote sleep by thwarting hypocretin/orexin have emerged more quickly, providing a flurry of new options for people with insomnia. The first, suvorexant, was launched in 2014. Two others followed in recent years.

Researchers are hopeful a hypocretin/orexin agonist is on the horizon.

“This is a very hot area of drug development,” said Kilduff. “It’s just a matter of who’s going to get the drug to market first.”

 

One More Hypocretin/Orexin Surprise — and It Could Be The Biggest

Several years ago, Siegel’s lab received what was supposed to be a healthy human brain — one they could use as a comparison for narcoleptic brains. But researcher Thomas Thannickal, PhD, lead author of the UCLA study linking hypocretin loss to human narcolepsy, noticed something strange: This brain had significantly more hypocretin neurons than average.

Was this due to a seizure? A traumatic death? Siegel called the brain bank to request the donor’s records. He was told they were missing.

Years later, Siegel happened to be visiting the brain bank for another project and found himself in a room adjacent to the medical records. “Nobody was there,” he said, “so I just opened a drawer.”

Shuffling through the brain bank’s files, Siegel found the medical records he’d been told were lost. In the file was a note from the donor, explaining that he was a former heroin addict.

“I almost fell out of my chair,” said Siegel. “I realized this guy’s heroin addiction likely had something to do with his very unusual brain.” 

Obviously, opioids affected the orexin system. But how? 

“It’s when people are happy that this peptide is released,” said Siegel. “The hypocretin system is not just related to alertness. It’s related to pleasure.” 

As Yanagisawa observed early on, hypocretin/orexin does indeed play a role in eating — just not the one he initially thought. The peptides prompted pleasure seeking. So the rodents ate. 

In 2018, after acquiring five more brains, Siegel’s group published a study in Translational Medicine showing 54% more detectable hypocretin neurons in the brains of heroin addicts than in those of control individuals.

In 2022, another breakthrough: His team showed that morphine significantly altered the pathways of hypocretin neurons in mice, sending their axons into brain regions associated with addiction. Then, when they removed the mice’s hypocretin neurons and discontinued their daily morphine dose, the rodents showed no symptoms of opioid withdrawal.

This fits the connection with narcolepsy: Among the standard treatments for the condition are amphetamines and other stimulants, which all have addictive potential. Yet, “narcoleptics never abuse these drugs,” Siegel said. “They seem to be uniquely resistant to addiction.”

This could powerfully change the way opioids are administered.

“If you prevent the hypocretin response to opioids, you may be able to prevent opioid addiction,” said Siegel. In other words, blocking the hypocretin system with a drug like those used to treat insomnia may allow patients to experience the pain-relieving benefits of opioids — without the risk for addiction.

His team is currently investigating treatments targeting the hypocretin/orexin system for opioid addiction.

In a study published in July, they found that mice who received suvorexant — the drug for insomnia — didn’t anticipate their daily dose of opioids the way other rodents did. This suggests the medication prevented addiction, without diminishing the pain-relieving effect of opioids.

If it translates to humans, this discovery could potentially save millions of lives.

“I think it’s just us working on this,” said Siegel.

But with hypocretin/orexin, you never know.

A version of this article appeared on Medscape.com.

It was 1996, and Masashi Yanagisawa was on the brink of his next discovery.

The Japanese scientist had arrived at the University of Texas Southwestern in Dallas 5 years earlier, setting up his own lab at age 31. After earning his medical degree, he’d gained notoriety as a PhD student when he discovered endothelin, the body’s most potent vasoconstrictor.

Yanagisawa was about to prove this wasn’t a first-timer’s fluke.

His focus was G-protein–coupled receptors (GPCRs), cell surface receptors that respond to a range of molecules and a popular target for drug discovery. The Human Genome Project had just revealed a slew of newly discovered receptors, or “orphan” GPCRs, and identifying an activating molecule could yield a new drug. (That vasoconstrictor endothelin was one such success story, leading to four new drug approvals in the United States over the past quarter century.) 

Yanagisawa and his team created 50 cell lines, each expressing one orphan receptor. They applied animal tissue to every line, along with a calcium-sensitive dye. If the cells glowed under the microscope, they had a hit.

“He was basically doing an elaborate fishing expedition,” said Jon Willie, MD, PhD, an associate professor of neurosurgery at Washington University School of Medicine in St. Louis, Missouri, who would later join Yanagisawa’s team.

It wasn’t long before the neon-green fluorescence signaled a match. After isolating the activating molecule, the scientists realized they were dealing with two neuropeptides.

No one had ever seen these proteins before. And no one knew their discovery would set off a decades-long journey that would finally solve a century-old medical mystery — and may even fix one of the biggest health crises of our time, as revealed by research published earlier in 2024. It’s a story of strange coincidences, serendipitous discoveries, and quirky details. Most of all, it’s a fascinating example of how basic science can revolutionize medicine — and how true breakthroughs happen over time and in real time.

 

But That’s Basic Science for You

Most basic science studies — the early, foundational research that provides the building blocks for science that follows — don’t lead to medical breakthroughs. But some do, often in surprising ways.

Also called curiosity-driven research, basic science aims to fill knowledge gaps to keep science moving, even if the trajectory isn’t always clear.

“The people working on the basic research that led to discoveries that transformed the modern world had no idea at the time,” said Isobel Ronai, PhD, a postdoctoral fellow in life sciences at Harvard University, Cambridge, Massachusetts. “Often, these stories can only be seen in hindsight,” sometimes decades later.

Case in point: For molecular biology techniques — things like DNA sequencing and gene targeting — the lag between basic science and breakthrough is, on average, 23 years. While many of the resulting techniques have received Nobel Prizes, few of the foundational discoveries have been awarded such accolades.

“The scientific glory is more often associated with the downstream applications,” said Ronai. “The importance of basic research can get lost. But it is the foundation for any future application, such as drug development.”

As funding is increasingly funneled toward applied research, basic science can require a certain persistence. What this under-appreciation can obscure is the pathway to discovery — which is often as compelling as the end result, full of unpredictable twists, turns, and even interpersonal intrigue.

And then there’s the fascinating — and definitely complicated — phenomenon of multiple independent discoveries.

As in: What happens when two independent teams discover the same thing at the same time?

 

Back to Yanagisawa’s Lab ...

... where he and his team learned a few things about those new neuropeptides. Rat brain studies pinpointed the lateral hypothalamus as the peptides’ area of activity — a region often called the brain’s feeding center.

“If you destroy that part of the brain, animals lose appetite,” said Yanagisawa. So these peptides must control feeding, the scientists thought.

Sure enough, injecting the proteins into rat brains led the rodents to start eating.

Satisfied, the team named them “orexin-A” and “orexin-B,” for the Greek word “orexis,” meaning appetite. The brain receptors became “orexin-1” and “orexin-2.” The team prepared to publish its findings in Cell.

But another group beat them to it.

 

Introducing the ‘Hypocretins’

In early January 1998, a team of Scripps Research Institute scientists, led by J. Gregor Sutcliffe, PhD, released a paper in the journal PNAS. They described a gene encoding for the precursor to two neuropeptides

As the peptides were in the hypothalamus and structurally like secretin (a gut hormone), they called them “hypocretins.” The hypocretin peptides excited neurons in the hypothalamus, and later that year, the scientists discovered that the neurons’ branches extended, tentacle-like, throughout the brain. “Many of the connected areas were involved in sleep-wake control,” said Thomas Kilduff, PhD, who joined the Sutcliffe lab just weeks before the hypocretin discovery. At the time, however, the significance of this finding was not yet clear.

Weeks later, in February 1998, Yanagisawa’s paper came out.

Somehow, two groups, over 1000 miles apart, had stumbled on the same neuropeptides at the same time.

“I first heard about [Yanagisawa’s] paper on NBC Nightly News,” recalls Kilduff. “I was skiing in the mountains, so I had to wait until Monday to get back to the lab to see what the paper was all about.”

He realized that Yanagisawa’s orexin was his lab’s hypocretin, although the study didn’t mention another team’s discovery.

“There may have been accusations. But as far as I know, it’s because [Yanagisawa] didn’t know [about the other paper],” said Willie. “This was not something he produced in 2 months. This was clearly years of work.” 

 

‘Multiple Discovery’ Happens More Often Than You Think

In the mid-20th century, sociologist Robert Merton described the phenomenon of “multiple discovery,” where many scientific discoveries or inventions are made independently at roughly the same time.

“This happens much more frequently in scientific research than people suppose,” said David Pendlebury, head of research analysis at Clarivate’s Institute for Scientific Information, the analytics company’s research arm. (Last year, Pendlebury flagged the hypocretin/orexin discovery for Clarivate’s prestigious Citations Laureates award, an honor that aims to predict, often successfully, who will go on to win the Nobel Prize.) 

“People have this idea of the lone researcher making a brilliant discovery,” Pendlebury said. “But more and more, teams find things at the same time.” 

While this can — and does — lead to squabbling about who deserves credit, the desire to be first can also be highly motivating, said Mike Schneider, PhD, an assistant professor of philosophy at the University of Missouri, Columbia, who studies the social dynamics of science, potentially leading to faster scientific advancement.

The downside? If two groups produce the same or similar results, but one publishes first, scientific journals tend to reject the second, citing a lack of novelty.

Yet duplicating research is a key step in confirming the validity of a discovery.

That’s why, in 2018, the journal PLOS Biology created a provision for “scooped” scientists, allowing them to submit their paper within 6 months of the first as a complementary finding. Instead of viewing this as redundancy, the editors believe it adds robustness to the research.

 

‘What the Heck Is This Mouse Doing?’

Even though he’d been scooped, Yanagisawa forged on to the next challenge: Confirming whether orexin regulated feeding.

He began breeding mice missing the orexin gene. His team expected these “knockout” mice to eat less, resulting in a thinner body than other rodents. To the contrary, “they were on average fatter,” said Willie. “They were eating less but weighed more, indicating a slower metabolism.”

The researchers were befuddled. “We were really disappointed, almost desperate about what to do,” said Yanagisawa.

As nocturnal animals eat more at night, he decided they should study the mice after dark. One of his students, Richard Chemelli, MD, bought an infrared video camera from Radio Shack, filming the first 4 hours of the mice’s active period for several nights.

After watching the footage, “Rick called me and said, ‘Let’s get into the lab,’ ” said Willie. “It was four of us on a Saturday looking at these videos, saying, ‘What the heck is this mouse doing?’ ”

While exploring their habitat, the knockout mice would randomly fall over, pop back up after a minute or so, and resume normal activity. This happened over and over — and the scientists were unsure why.

They began monitoring the mice’s brains during these episodes — and made a startling discovery.

The mice weren’t having seizures. They were shifting directly into REM sleep, bypassing the non-REM stage, then quickly toggling back to wake mode.

“That’s when we knew these animals had something akin to narcolepsy,” said Willie.

The team recruited Thomas Scammell, MD, a Harvard neurologist, to investigate whether modafinil — an anti-narcoleptic drug without a clear mechanism — affected orexin neurons.

Two hours after injecting the mice with the medication, the scientists sacrificed them and stained their brains. Remarkably, the number of neurons showing orexin activity had increased ninefold. It seemed modafinil worked by activating the orexin system.

These findings had the potential to crack open the science of narcolepsy, one of the most mysterious sleep disorders.

Unless, of course, another team did it first.

 

The Mystery of Narcolepsy

Yet another multiple discovery, narcolepsy was first described by two scientists — one in Germany, the other in France — within a short span in the late 1800s.

It would be more than a hundred years before anyone understood the disorder’s cause, even though it affects about 1 in 2000 people.

“Patients were often labeled as lazy and malingerers,” said Kilduff, “since they were sleepy all the time and had this weird motor behavior called cataplexy” or the sudden loss of muscle tone.

In the early 1970s, William Dement, MD, PhD — “the father of sleep medicine” — was searching for a narcoleptic cat to study. He couldn’t find a feline, but several colleagues mentioned dogs with narcolepsy-like symptoms.

Dement, who died in 2020, had found his newest research subjects.

In 1973, he started a narcoleptic dog colony at Stanford University in Palo Alto, California. At first, he focused on poodles and beagles. After discovering their narcolepsy wasn’t genetic, he pivoted to dobermans and labradors. Their narcolepsy was inherited, so he could breed them to populate the colony.

Although human narcolepsy is rarely genetic, it’s otherwise a lot like the version in these dogs.

Both involve daytime sleepiness, “pathological” bouts of REM sleep, and the loss of muscle tone in response to emotions, often positive ones.

The researchers hoped the canines could unlock a treatment for human narcolepsy. They began laying out a path of dog kibble, then injecting the dogs with drugs such as selective serotonin reuptake inhibitors. They wanted to see what might help them stay awake as they excitedly chowed down.

Kilduff also started a molecular genetics program, trying to identify the genetic defect behind canine narcolepsy. But after a parvovirus outbreak, Kilduff resigned from the project, drained from the strain of seeing so many dogs die.

A decade after his departure from the dog colony, his work would dramatically intersect with that of his successor, Emmanuel Mignot, MD, PhD.

“I thought I had closed the narcolepsy chapter in my life forever,” said Kilduff. “Then in 1998, we described this novel neuropeptide, hypocretin, that turned out to be the key to understanding the disorder.”

 

Narcoleptic Dogs in California, Mutant Mice in Texas

It was modafinil — the same anti-narcoleptic drug Yanagisawa’s team studied — that brought Emmanuel Mignot to the United States. After training as a pharmacologist in France, his home country sent him to Stanford to study the drug, which was discovered by French scientists, as his required military service.

As Kilduff’s replacement at the dog colony, his goal was to figure out how modafinil worked, hoping to attract a US company to develop the drug.

The plan succeeded. Modafinil became Provigil, a billion-dollar narcolepsy drug, and Mignot became “completely fascinated” with the disorder.

“I realized quickly that there was no way we’d find the cause of narcolepsy by finding the mode of action of this drug,” Mignot said. “Most likely, the drug was acting downstream, not at the cause of the disorder.”

To discover the answer, he needed to become a geneticist. And so began his 11-year odyssey to find the cause of canine narcolepsy.

After mapping the dog genome, Mignot set out to find the smallest stretch of chromosome that the narcoleptic animals had in common. “For a very long time, we were stuck with a relatively large region [of DNA],” he recalls. “It was a no man’s land.” 

Within that region was the gene for the hypocretin/orexin-2 receptor — the same receptor that Yanagisawa had identified in his first orexin paper. Mignot didn’t immediately pursue that gene as a possibility — even though his students suggested it. Why?

“The decision was simply: Should we lose time to test a possible candidate [gene] among many?” Mignot said.

As Mignot studied dog DNA in California, Yanagisawa was creating mutant mice in Texas. Unbeknownst to either scientist, their work was about to converge.

 

What Happened Next Is Somewhat Disputed 

After diagnosing his mice with narcolepsy, Yanagisawa opted not to share this finding with Mignot, though he knew about Mignot’s interest in the condition. Instead, he asked a colleague to find out how far along Mignot was in his genetics research.

According to Yanagisawa, his colleague didn’t realize how quickly DNA sequencing could happen once a target gene was identified. At a sleep meeting, “he showed Emmanuel all of our raw data. Almost accidentally, he disclosed our findings,” he said. “It was a shock for me.” 

Unsure whether he was part of the orexin group, Mignot decided not to reveal that he’d identified the hypocretin/orexin-2 receptor gene as the faulty one in his narcoleptic dogs.

Although he didn’t share this finding, Mignot said he did offer to speak with the lead researcher to see if their findings were the same. If they were, they could jointly submit their articles. But Mignot never heard back.

Meanwhile, back at his lab, Mignot buckled down. While he wasn’t convinced the mouse data proved anything, it did give him the motivation to move faster.

Within weeks, he submitted his findings to Cell, revealing a mutation in the hypocretin/orexin-2 receptor gene as the cause of canine narcolepsy. According to Yanagisawa, the journal’s editor invited him to peer-review the paper, tipping him off to its existence.

“I told him I had a conflict of interest,” said Yanagisawa. “And then we scrambled to finish our manuscript. We wrote up the paper within almost 5 days.”

For a moment, it seemed both papers would be published together in Cell. Instead, on August 6, 1999, Mignot’s study was splashed solo across the journal’s cover.

“At the time, our team was pissed off, but looking back, what else could Emmanuel have done?” said Willie, who was part of Yanagisawa’s team. “The grant he’d been working on for years was at risk. He had it within his power to do the final experiments. Of course he was going to finish.”

Two weeks later, Yanagisawa’s findings followed, also in Cell.

His paper proposed knockout mice as a model for human narcolepsy and orexin as a key regulator of the sleep/wake cycle. With orexin-activated neurons branching into other areas of the brain, the peptide seemed to promote wakefulness by synchronizing several arousal neurotransmitters, such as serotonin, norepinephrine, and histamine.

“If you don’t have orexin, each of those systems can still function, but they’re not as coordinated,” said Willie. “If you have narcolepsy, you’re capable of wakefulness, and you’re capable of sleep. What you can’t do is prevent inappropriately switching between states.”

Together, the two papers painted a clear picture: Narcolepsy was the result of a dysfunction in the hypocretin/orexin system.

After more than a century, the cause of narcolepsy was starting to come into focus.

“This was blockbuster,” said Willie.

By itself, either finding — one in dogs, one in mice — might have been met with skepticism. But in combination, they offered indisputable evidence about narcolepsy’s cause.

 

The Human Brains in Your Fridge Hold Secrets

Jerome Siegel had been searching for the cause of human narcolepsy for years. A PhD and professor at the University of California, Los Angeles, he had managed to acquire four human narcoleptic brains. As laughter is often the trigger for the sudden shift to REM sleep in humans, he focused on the amygdala, an area linked to emotion.

“I looked in the amygdala and didn’t see anything,” he said. “So the brains stayed in my refrigerator for probably 10 years.” 

Then he was invited to review Yanagisawa’s study in Cell. The lightbulb clicked on: Maybe the hypothalamus — not the amygdala — was the area of abnormality. He and his team dug out the decade-old brains.

When they stained the brains, the massive loss of hypocretin-activated neurons was hard to miss: On average, the narcoleptic brains had only about 7000 of the cells versus 70,000 in the average human brain. The scientists also noticed scar tissue in the hypothalamus, indicating that the neurons had at some point died, rather than being absent from birth.

What Siegel didn’t know: Mignot had also acquired a handful of human narcoleptic brains.

Already, he had coauthored a study showing that hypocretin/orexin was undetectable in the cerebrospinal fluid of the majority of the people with narcolepsy his team tested. It seemed clear that the hypocretin/orexin system was flawed — or even broken — in people with the condition.

“It looked like the cause of narcolepsy in humans was indeed this lack of orexin in the brain,” he said. “That was the hypothesis immediately. To me, this is when we established that narcolepsy in humans was due to a lack of orexin. The next thing was to check that the cells were missing.” 

Now he could do exactly that.

As expected, Mignot’s team observed a dramatic loss of hypocretin/orexin cells in the narcoleptic brains. They also noticed that a different cell type in the hypothalamus was unaffected. This implied the damage was specific to the hypocretin-activated cells and supported a hunch they already had: That the deficit was the result not of a genetic defect but of an autoimmune attack. (It’s a hypothesis Mignot has spent the last 15 years proving.)

It wasn’t until a gathering in Hawaii, in late August 2000, that the two realized the overlap of their work.

To celebrate his team’s finding, Mignot had invited a group of researchers to Big Island. With his paper scheduled for publication on September 1, he felt comfortable presenting his findings to his guests, which included Siegel.

Until then, “I didn’t know what he had found, and he didn’t know what I had found, which basically was the same thing,” said Siegel.

In yet another strange twist, the two papers were published just weeks apart, simultaneously revealing that human narcoleptics have a depleted supply of the neurons that bind to hypocretin/orexin. The cause of the disorder was at last a certainty.

“Even if I was first, what does it matter? In the end, you need confirmation,” said Mignot. “You need multiple people to make sure that it’s true. It’s good science when things like this happen.”

 

How All of This Changed Medicine

Since these groundbreaking discoveries, the diagnosis of narcolepsy has become much simpler. Lab tests can now easily measure hypocretin in cerebrospinal fluid, providing a definitive diagnosis.

But the development of narcolepsy treatments has lagged — even though hypocretin/orexin replacement therapy is the obvious answer.

“Almost 25 years have elapsed, and there’s no such therapeutic on the market,” said Kilduff, who now works for SRI International, a non-profit research and development institute.

That’s partly because agonists — drugs that bind to receptors in the brain — are challenging to create, as this requires mimicking the activating molecule’s structure, like copying the grooves of an intricate key.

Antagonists, by comparison, are easier to develop. These act as a gate, blocking access to the receptors. As a result, drugs that promote sleep by thwarting hypocretin/orexin have emerged more quickly, providing a flurry of new options for people with insomnia. The first, suvorexant, was launched in 2014. Two others followed in recent years.

Researchers are hopeful a hypocretin/orexin agonist is on the horizon.

“This is a very hot area of drug development,” said Kilduff. “It’s just a matter of who’s going to get the drug to market first.”

 

One More Hypocretin/Orexin Surprise — and It Could Be The Biggest

Several years ago, Siegel’s lab received what was supposed to be a healthy human brain — one they could use as a comparison for narcoleptic brains. But researcher Thomas Thannickal, PhD, lead author of the UCLA study linking hypocretin loss to human narcolepsy, noticed something strange: This brain had significantly more hypocretin neurons than average.

Was this due to a seizure? A traumatic death? Siegel called the brain bank to request the donor’s records. He was told they were missing.

Years later, Siegel happened to be visiting the brain bank for another project and found himself in a room adjacent to the medical records. “Nobody was there,” he said, “so I just opened a drawer.”

Shuffling through the brain bank’s files, Siegel found the medical records he’d been told were lost. In the file was a note from the donor, explaining that he was a former heroin addict.

“I almost fell out of my chair,” said Siegel. “I realized this guy’s heroin addiction likely had something to do with his very unusual brain.” 

Obviously, opioids affected the orexin system. But how? 

“It’s when people are happy that this peptide is released,” said Siegel. “The hypocretin system is not just related to alertness. It’s related to pleasure.” 

As Yanagisawa observed early on, hypocretin/orexin does indeed play a role in eating — just not the one he initially thought. The peptides prompted pleasure seeking. So the rodents ate. 

In 2018, after acquiring five more brains, Siegel’s group published a study in Translational Medicine showing 54% more detectable hypocretin neurons in the brains of heroin addicts than in those of control individuals.

In 2022, another breakthrough: His team showed that morphine significantly altered the pathways of hypocretin neurons in mice, sending their axons into brain regions associated with addiction. Then, when they removed the mice’s hypocretin neurons and discontinued their daily morphine dose, the rodents showed no symptoms of opioid withdrawal.

This fits the connection with narcolepsy: Among the standard treatments for the condition are amphetamines and other stimulants, which all have addictive potential. Yet, “narcoleptics never abuse these drugs,” Siegel said. “They seem to be uniquely resistant to addiction.”

This could powerfully change the way opioids are administered.

“If you prevent the hypocretin response to opioids, you may be able to prevent opioid addiction,” said Siegel. In other words, blocking the hypocretin system with a drug like those used to treat insomnia may allow patients to experience the pain-relieving benefits of opioids — without the risk for addiction.

His team is currently investigating treatments targeting the hypocretin/orexin system for opioid addiction.

In a study published in July, they found that mice who received suvorexant — the drug for insomnia — didn’t anticipate their daily dose of opioids the way other rodents did. This suggests the medication prevented addiction, without diminishing the pain-relieving effect of opioids.

If it translates to humans, this discovery could potentially save millions of lives.

“I think it’s just us working on this,” said Siegel.

But with hypocretin/orexin, you never know.

A version of this article appeared on Medscape.com.

Patients who discontinue treatment with the osteoporosis drug denosumab, despite transitioning to zoledronate, show significant losses in lumbar spine bone mineral density (BMD) within a year, according to the latest findings to show that the rapid rebound of bone loss after denosumab discontinuation is not easily prevented with other therapies — even bisphosphonates.

“When initiating denosumab for osteoporosis treatment, it is recommended to engage in thorough shared decision-making with the patient to ensure they understand the potential risks associated with discontinuing the medication,” senior author Shau-Huai Fu, MD, PhD, Department of Orthopedics, National Taiwan University Hospital Yunlin Branch, Douliu, told this news organization.

Furthermore, “integrating a case manager system is crucial to support long-term adherence and compliance,” he added.

The results are from the Denosumab Sequential Therapy prospective, open-label, parallel-group randomized clinical trial, published online in JAMA Network Open.

In the study, 101 patients were recruited between April 2019 and May 2021 at a referral center and two hospitals in Taiwan. The patients, including postmenopausal women and men over the age of 50, had been treated with regular denosumab for at least 2 years and had no previous exposure to other anti-osteoporosis medication.

They were randomized to treatment either with continuous denosumab at the standard dose of 60 mg twice yearly or to discontinue denosumab and receive the standard intravenous dose of the bisphosphonate zoledronate at 5 mg at the time when the next dose of denosumab would have been administered.

There were no differences between the two groups in serum bone turnover markers at baseline.

The current results, reflecting the first year of the 2-year study, show that, overall, those receiving zoledronate (n = 76), had a significant decrease in lumbar spine BMD, compared with a slight increase in the denosumab continuation group (–0.68% vs 1.30%, respectively; P = .03).

No significant differences were observed between the groups in terms of the study’s other measures of total hip BMD (median, 0% vs 1.12%; P = .24), and femoral neck BMD (median, 0.18% vs 0.17%; P = .71).

Additional findings from multivariable analyses in the study also supported results from previous studies showing that a longer duration of denosumab use is associated with a more substantial rebound effect: Among 15 of the denosumab users in the study who had ≥ 3 prior years of the drug, the reduction in lumbar spine BMD was even greater with zoledronate compared with denosumab continuation (–3.20% vs 1.30%; P = .003).

Though the lack of losses in the other measures of total hip and femoral neck BMD may seem encouraging, evidence from the bulk of other studies suggests cautious interpretation of those findings, Fu said.

“Although our study did not observe a noticeable decline in total hip or femoral neck BMD, other randomized controlled trials with longer durations of denosumab use have reported significant reductions in these areas,” Fu said. “Therefore, it cannot be assumed that non-lumbar spine regions are entirely safe.”

 

Fracture Risk Is the Overriding Concern

Meanwhile, the loss of lumbar spine BMD is of particular concern because of its role in what amounts to the broader, overriding concern of denosumab discontinuation — the risk for fracture, Fu noted.

“Real-world observations indicate that fractures caused by or associated with discontinuation of denosumab primarily occur in the spine,” he explained.

Previous research underscores the risk for fracture with denosumab discontinuation — and the greater risk with longer-term denosumab use, showing an 11.8% annual incidence of vertebral fracture after discontinuation of denosumab used for less than 2 years, increasing to 16.0% upon discontinuation after more than 2 years of treatment.

Randomized trials have shown sequential zoledronate to have some benefit in offsetting that risk, reducing first-year fracture risk by 3%-4% in some studies.

In the current study, 3 of 76 participants experienced a vertebral fracture in the first year of discontinuation, all involving women, including 2 who had been receiving denosumab for ≥ 4 years before medication transition.

If a transition to a bisphosphonate is anticipated, the collective findings suggest doing it as early on in denosumab treatment as possible, Fu and his colleagues noted in the study.

“When medication transition from denosumab is expected or when long-term denosumab treatment may not be suitable, earlier medication transition with potent sequential therapy should be considered,” they wrote.

 

Dosing Adjustments?

The findings add to the evidence that “patients who gain the most with denosumab are likely to lose the most with zoledronate,” Nelson Watts, MD, who authored an editorial accompanying the study, told this news organization.

Furthermore, “denosumab and other medications seem to do more [and faster] for BMD in the spine, so we expect more loss in the spine than in the hip,” said Watts, who is director of Mercy Health Osteoporosis and Bone Health Services, Bon Secours Mercy Health in Cincinnati, Ohio.

“Studies are needed but not yet done to see if a higher dose or more frequent zoledronate would be better for BMD than the ‘usual’ yearly dose,” Watts added.

The only published clinical recommendations on the matter are discussed in a position paper from the European Calcified Tissue Society (ECTS).

“Pending additional robust data, a pragmatic approach is to begin treatment with zoledronate 6 months after the last denosumab injection and monitor the effect with bone turnover markers, for example, 3 and 6 months after the zoledronate infusion,” they recommended.

In cases of increased bone turnover markers, including above the mean found in age- and sex-matched cohorts, “repeated infusion of zoledronate should be considered,” the society added.

If bone turnover markers are not available for monitoring the patients, “a pragmatic approach could be administrating a second infusion of zoledronate 6 months after the first infusion,” they wrote.

 

Clinicians Need to Be Proactive From the Start

Bente Langdahl, MD, of the Medical Department of Endocrinology, Aarhus University Hospital in Denmark, who was a coauthor on the ECTS position statement, told this news organization that clinicians should also be proactive on the other side of treatment — before it begins — to prevent problems with discontinuation.

“I think denosumab is a very good treatment for some patients with high fracture risk and very low BMD, but both patients and clinicians should know that this treatment is either lifelong or there needs to be a plan for discontinuation,” Langdahl said.

Langdahl noted that denosumab is coming off patent soon; hence, issues with cost could become more manageable.

But until then, “I think [cost] should be considered before starting treatment because if patients cannot afford denosumab, they should have been started on zoledronate from the beginning.”

 

Discontinuation Reasons Vary

Research indicates that, broadly, adherence to denosumab ranges from about 45% to 72% at 2 years, with some reasons for discontinuation including the need for dental treatment or cost, Fu and colleagues reported.

Fu added, however, that other reasons for discontinuing denosumab “are not due to ‘need’ but rather factors such as relocating, missing follow-up appointments, or poor adherence.”

Lorenz Hofbauer, MD, who is head of the Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III at the Technical University Medical Center in Dresden, Germany, noted that another issue contributing to some hesitation by patients about remaining on, or even initiating denosumab, is the known risk for osteonecrosis of the jaw (ONJ).

Though reported as being rare, research continuing to stir concern for ONJ with denosumab use includes one recent study of patients with breast cancer showing those treated with denosumab had a fivefold higher risk for ONJ vs those on bisphosphonates.

“About 20% of my patients have ONJ concerns or other questions, which may delay treatment with denosumab or other therapies,” Hofbauer told this news organization.

“There is a high need to discuss risk versus benefits toward a shared decision-making,” he said.

Conversely, however, Hofbauer noted that adherence to denosumab at his center is fairly high — at 90%, which he says is largely credited to an electronically supported recall system in place at the center.

Denosumab maker Amgen also offers patient reminders via email, text, or phone through its Bone Matters patient support system, which also provides access to a call center for questions or to update treatment appointment information.

In terms of the ongoing question of how to best prevent fracture risk when patients do wind up discontinuing denosumab, Watts concluded in his editorial that more robust studies are needed.

“The dilemma is what to do with longer-term users who stop, and the real question is not what happens to BMD, but what happens to fracture risk,” he wrote.

“It is unlikely that the fracture risk question can be answered due to ethical limitations, but finding the best option, [whether it is] oral or intravenous bisphosphonate, timing, dose, and frequency, to minimize bone loss and the rebound increase in bone resorption after stopping long-term denosumab requires larger and longer studies of better design.”

The authors had no disclosures to report. Watts has been an investigator, consultant, and speaker for Amgen outside of the published editorial. Hofbauer is on advisory boards for Alexion Pharmaceuticals, Amolyt Pharma, Amgen, and UCB. Langdahl has been a primary investigator on previous and ongoing clinical trials involving denosumab.

A version of this article appeared on Medscape.com.

Patients who discontinue treatment with the osteoporosis drug denosumab, despite transitioning to zoledronate, show significant losses in lumbar spine bone mineral density (BMD) within a year, according to the latest findings to show that the rapid rebound of bone loss after denosumab discontinuation is not easily prevented with other therapies — even bisphosphonates.

“When initiating denosumab for osteoporosis treatment, it is recommended to engage in thorough shared decision-making with the patient to ensure they understand the potential risks associated with discontinuing the medication,” senior author Shau-Huai Fu, MD, PhD, Department of Orthopedics, National Taiwan University Hospital Yunlin Branch, Douliu, told this news organization.

Furthermore, “integrating a case manager system is crucial to support long-term adherence and compliance,” he added.

The results are from the Denosumab Sequential Therapy prospective, open-label, parallel-group randomized clinical trial, published online in JAMA Network Open.

In the study, 101 patients were recruited between April 2019 and May 2021 at a referral center and two hospitals in Taiwan. The patients, including postmenopausal women and men over the age of 50, had been treated with regular denosumab for at least 2 years and had no previous exposure to other anti-osteoporosis medication.

They were randomized to treatment either with continuous denosumab at the standard dose of 60 mg twice yearly or to discontinue denosumab and receive the standard intravenous dose of the bisphosphonate zoledronate at 5 mg at the time when the next dose of denosumab would have been administered.

There were no differences between the two groups in serum bone turnover markers at baseline.

The current results, reflecting the first year of the 2-year study, show that, overall, those receiving zoledronate (n = 76), had a significant decrease in lumbar spine BMD, compared with a slight increase in the denosumab continuation group (–0.68% vs 1.30%, respectively; P = .03).

No significant differences were observed between the groups in terms of the study’s other measures of total hip BMD (median, 0% vs 1.12%; P = .24), and femoral neck BMD (median, 0.18% vs 0.17%; P = .71).

Additional findings from multivariable analyses in the study also supported results from previous studies showing that a longer duration of denosumab use is associated with a more substantial rebound effect: Among 15 of the denosumab users in the study who had ≥ 3 prior years of the drug, the reduction in lumbar spine BMD was even greater with zoledronate compared with denosumab continuation (–3.20% vs 1.30%; P = .003).

Though the lack of losses in the other measures of total hip and femoral neck BMD may seem encouraging, evidence from the bulk of other studies suggests cautious interpretation of those findings, Fu said.

“Although our study did not observe a noticeable decline in total hip or femoral neck BMD, other randomized controlled trials with longer durations of denosumab use have reported significant reductions in these areas,” Fu said. “Therefore, it cannot be assumed that non-lumbar spine regions are entirely safe.”

 

Fracture Risk Is the Overriding Concern

Meanwhile, the loss of lumbar spine BMD is of particular concern because of its role in what amounts to the broader, overriding concern of denosumab discontinuation — the risk for fracture, Fu noted.

“Real-world observations indicate that fractures caused by or associated with discontinuation of denosumab primarily occur in the spine,” he explained.

Previous research underscores the risk for fracture with denosumab discontinuation — and the greater risk with longer-term denosumab use, showing an 11.8% annual incidence of vertebral fracture after discontinuation of denosumab used for less than 2 years, increasing to 16.0% upon discontinuation after more than 2 years of treatment.

Randomized trials have shown sequential zoledronate to have some benefit in offsetting that risk, reducing first-year fracture risk by 3%-4% in some studies.

In the current study, 3 of 76 participants experienced a vertebral fracture in the first year of discontinuation, all involving women, including 2 who had been receiving denosumab for ≥ 4 years before medication transition.

If a transition to a bisphosphonate is anticipated, the collective findings suggest doing it as early on in denosumab treatment as possible, Fu and his colleagues noted in the study.

“When medication transition from denosumab is expected or when long-term denosumab treatment may not be suitable, earlier medication transition with potent sequential therapy should be considered,” they wrote.

 

Dosing Adjustments?

The findings add to the evidence that “patients who gain the most with denosumab are likely to lose the most with zoledronate,” Nelson Watts, MD, who authored an editorial accompanying the study, told this news organization.

Furthermore, “denosumab and other medications seem to do more [and faster] for BMD in the spine, so we expect more loss in the spine than in the hip,” said Watts, who is director of Mercy Health Osteoporosis and Bone Health Services, Bon Secours Mercy Health in Cincinnati, Ohio.

“Studies are needed but not yet done to see if a higher dose or more frequent zoledronate would be better for BMD than the ‘usual’ yearly dose,” Watts added.

The only published clinical recommendations on the matter are discussed in a position paper from the European Calcified Tissue Society (ECTS).

“Pending additional robust data, a pragmatic approach is to begin treatment with zoledronate 6 months after the last denosumab injection and monitor the effect with bone turnover markers, for example, 3 and 6 months after the zoledronate infusion,” they recommended.

In cases of increased bone turnover markers, including above the mean found in age- and sex-matched cohorts, “repeated infusion of zoledronate should be considered,” the society added.

If bone turnover markers are not available for monitoring the patients, “a pragmatic approach could be administrating a second infusion of zoledronate 6 months after the first infusion,” they wrote.

 

Clinicians Need to Be Proactive From the Start

Bente Langdahl, MD, of the Medical Department of Endocrinology, Aarhus University Hospital in Denmark, who was a coauthor on the ECTS position statement, told this news organization that clinicians should also be proactive on the other side of treatment — before it begins — to prevent problems with discontinuation.

“I think denosumab is a very good treatment for some patients with high fracture risk and very low BMD, but both patients and clinicians should know that this treatment is either lifelong or there needs to be a plan for discontinuation,” Langdahl said.

Langdahl noted that denosumab is coming off patent soon; hence, issues with cost could become more manageable.

But until then, “I think [cost] should be considered before starting treatment because if patients cannot afford denosumab, they should have been started on zoledronate from the beginning.”

 

Discontinuation Reasons Vary

Research indicates that, broadly, adherence to denosumab ranges from about 45% to 72% at 2 years, with some reasons for discontinuation including the need for dental treatment or cost, Fu and colleagues reported.

Fu added, however, that other reasons for discontinuing denosumab “are not due to ‘need’ but rather factors such as relocating, missing follow-up appointments, or poor adherence.”

Lorenz Hofbauer, MD, who is head of the Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III at the Technical University Medical Center in Dresden, Germany, noted that another issue contributing to some hesitation by patients about remaining on, or even initiating denosumab, is the known risk for osteonecrosis of the jaw (ONJ).

Though reported as being rare, research continuing to stir concern for ONJ with denosumab use includes one recent study of patients with breast cancer showing those treated with denosumab had a fivefold higher risk for ONJ vs those on bisphosphonates.

“About 20% of my patients have ONJ concerns or other questions, which may delay treatment with denosumab or other therapies,” Hofbauer told this news organization.

“There is a high need to discuss risk versus benefits toward a shared decision-making,” he said.

Conversely, however, Hofbauer noted that adherence to denosumab at his center is fairly high — at 90%, which he says is largely credited to an electronically supported recall system in place at the center.

Denosumab maker Amgen also offers patient reminders via email, text, or phone through its Bone Matters patient support system, which also provides access to a call center for questions or to update treatment appointment information.

In terms of the ongoing question of how to best prevent fracture risk when patients do wind up discontinuing denosumab, Watts concluded in his editorial that more robust studies are needed.

“The dilemma is what to do with longer-term users who stop, and the real question is not what happens to BMD, but what happens to fracture risk,” he wrote.

“It is unlikely that the fracture risk question can be answered due to ethical limitations, but finding the best option, [whether it is] oral or intravenous bisphosphonate, timing, dose, and frequency, to minimize bone loss and the rebound increase in bone resorption after stopping long-term denosumab requires larger and longer studies of better design.”

The authors had no disclosures to report. Watts has been an investigator, consultant, and speaker for Amgen outside of the published editorial. Hofbauer is on advisory boards for Alexion Pharmaceuticals, Amolyt Pharma, Amgen, and UCB. Langdahl has been a primary investigator on previous and ongoing clinical trials involving denosumab.

A version of this article appeared on Medscape.com.

Patients who discontinue treatment with the osteoporosis drug denosumab, despite transitioning to zoledronate, show significant losses in lumbar spine bone mineral density (BMD) within a year, according to the latest findings to show that the rapid rebound of bone loss after denosumab discontinuation is not easily prevented with other therapies — even bisphosphonates.

“When initiating denosumab for osteoporosis treatment, it is recommended to engage in thorough shared decision-making with the patient to ensure they understand the potential risks associated with discontinuing the medication,” senior author Shau-Huai Fu, MD, PhD, Department of Orthopedics, National Taiwan University Hospital Yunlin Branch, Douliu, told this news organization.

Furthermore, “integrating a case manager system is crucial to support long-term adherence and compliance,” he added.

The results are from the Denosumab Sequential Therapy prospective, open-label, parallel-group randomized clinical trial, published online in JAMA Network Open.

In the study, 101 patients were recruited between April 2019 and May 2021 at a referral center and two hospitals in Taiwan. The patients, including postmenopausal women and men over the age of 50, had been treated with regular denosumab for at least 2 years and had no previous exposure to other anti-osteoporosis medication.

They were randomized to treatment either with continuous denosumab at the standard dose of 60 mg twice yearly or to discontinue denosumab and receive the standard intravenous dose of the bisphosphonate zoledronate at 5 mg at the time when the next dose of denosumab would have been administered.

There were no differences between the two groups in serum bone turnover markers at baseline.

The current results, reflecting the first year of the 2-year study, show that, overall, those receiving zoledronate (n = 76), had a significant decrease in lumbar spine BMD, compared with a slight increase in the denosumab continuation group (–0.68% vs 1.30%, respectively; P = .03).

No significant differences were observed between the groups in terms of the study’s other measures of total hip BMD (median, 0% vs 1.12%; P = .24), and femoral neck BMD (median, 0.18% vs 0.17%; P = .71).

Additional findings from multivariable analyses in the study also supported results from previous studies showing that a longer duration of denosumab use is associated with a more substantial rebound effect: Among 15 of the denosumab users in the study who had ≥ 3 prior years of the drug, the reduction in lumbar spine BMD was even greater with zoledronate compared with denosumab continuation (–3.20% vs 1.30%; P = .003).

Though the lack of losses in the other measures of total hip and femoral neck BMD may seem encouraging, evidence from the bulk of other studies suggests cautious interpretation of those findings, Fu said.

“Although our study did not observe a noticeable decline in total hip or femoral neck BMD, other randomized controlled trials with longer durations of denosumab use have reported significant reductions in these areas,” Fu said. “Therefore, it cannot be assumed that non-lumbar spine regions are entirely safe.”

 

Fracture Risk Is the Overriding Concern

Meanwhile, the loss of lumbar spine BMD is of particular concern because of its role in what amounts to the broader, overriding concern of denosumab discontinuation — the risk for fracture, Fu noted.

“Real-world observations indicate that fractures caused by or associated with discontinuation of denosumab primarily occur in the spine,” he explained.

Previous research underscores the risk for fracture with denosumab discontinuation — and the greater risk with longer-term denosumab use, showing an 11.8% annual incidence of vertebral fracture after discontinuation of denosumab used for less than 2 years, increasing to 16.0% upon discontinuation after more than 2 years of treatment.

Randomized trials have shown sequential zoledronate to have some benefit in offsetting that risk, reducing first-year fracture risk by 3%-4% in some studies.

In the current study, 3 of 76 participants experienced a vertebral fracture in the first year of discontinuation, all involving women, including 2 who had been receiving denosumab for ≥ 4 years before medication transition.

If a transition to a bisphosphonate is anticipated, the collective findings suggest doing it as early on in denosumab treatment as possible, Fu and his colleagues noted in the study.

“When medication transition from denosumab is expected or when long-term denosumab treatment may not be suitable, earlier medication transition with potent sequential therapy should be considered,” they wrote.

 

Dosing Adjustments?

The findings add to the evidence that “patients who gain the most with denosumab are likely to lose the most with zoledronate,” Nelson Watts, MD, who authored an editorial accompanying the study, told this news organization.

Furthermore, “denosumab and other medications seem to do more [and faster] for BMD in the spine, so we expect more loss in the spine than in the hip,” said Watts, who is director of Mercy Health Osteoporosis and Bone Health Services, Bon Secours Mercy Health in Cincinnati, Ohio.

“Studies are needed but not yet done to see if a higher dose or more frequent zoledronate would be better for BMD than the ‘usual’ yearly dose,” Watts added.

The only published clinical recommendations on the matter are discussed in a position paper from the European Calcified Tissue Society (ECTS).

“Pending additional robust data, a pragmatic approach is to begin treatment with zoledronate 6 months after the last denosumab injection and monitor the effect with bone turnover markers, for example, 3 and 6 months after the zoledronate infusion,” they recommended.

In cases of increased bone turnover markers, including above the mean found in age- and sex-matched cohorts, “repeated infusion of zoledronate should be considered,” the society added.

If bone turnover markers are not available for monitoring the patients, “a pragmatic approach could be administrating a second infusion of zoledronate 6 months after the first infusion,” they wrote.

 

Clinicians Need to Be Proactive From the Start

Bente Langdahl, MD, of the Medical Department of Endocrinology, Aarhus University Hospital in Denmark, who was a coauthor on the ECTS position statement, told this news organization that clinicians should also be proactive on the other side of treatment — before it begins — to prevent problems with discontinuation.

“I think denosumab is a very good treatment for some patients with high fracture risk and very low BMD, but both patients and clinicians should know that this treatment is either lifelong or there needs to be a plan for discontinuation,” Langdahl said.

Langdahl noted that denosumab is coming off patent soon; hence, issues with cost could become more manageable.

But until then, “I think [cost] should be considered before starting treatment because if patients cannot afford denosumab, they should have been started on zoledronate from the beginning.”

 

Discontinuation Reasons Vary

Research indicates that, broadly, adherence to denosumab ranges from about 45% to 72% at 2 years, with some reasons for discontinuation including the need for dental treatment or cost, Fu and colleagues reported.

Fu added, however, that other reasons for discontinuing denosumab “are not due to ‘need’ but rather factors such as relocating, missing follow-up appointments, or poor adherence.”

Lorenz Hofbauer, MD, who is head of the Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III at the Technical University Medical Center in Dresden, Germany, noted that another issue contributing to some hesitation by patients about remaining on, or even initiating denosumab, is the known risk for osteonecrosis of the jaw (ONJ).

Though reported as being rare, research continuing to stir concern for ONJ with denosumab use includes one recent study of patients with breast cancer showing those treated with denosumab had a fivefold higher risk for ONJ vs those on bisphosphonates.

“About 20% of my patients have ONJ concerns or other questions, which may delay treatment with denosumab or other therapies,” Hofbauer told this news organization.

“There is a high need to discuss risk versus benefits toward a shared decision-making,” he said.

Conversely, however, Hofbauer noted that adherence to denosumab at his center is fairly high — at 90%, which he says is largely credited to an electronically supported recall system in place at the center.

Denosumab maker Amgen also offers patient reminders via email, text, or phone through its Bone Matters patient support system, which also provides access to a call center for questions or to update treatment appointment information.

In terms of the ongoing question of how to best prevent fracture risk when patients do wind up discontinuing denosumab, Watts concluded in his editorial that more robust studies are needed.

“The dilemma is what to do with longer-term users who stop, and the real question is not what happens to BMD, but what happens to fracture risk,” he wrote.

“It is unlikely that the fracture risk question can be answered due to ethical limitations, but finding the best option, [whether it is] oral or intravenous bisphosphonate, timing, dose, and frequency, to minimize bone loss and the rebound increase in bone resorption after stopping long-term denosumab requires larger and longer studies of better design.”

The authors had no disclosures to report. Watts has been an investigator, consultant, and speaker for Amgen outside of the published editorial. Hofbauer is on advisory boards for Alexion Pharmaceuticals, Amolyt Pharma, Amgen, and UCB. Langdahl has been a primary investigator on previous and ongoing clinical trials involving denosumab.

A version of this article appeared on Medscape.com.

Nursing is a competitive field. In 2022, nursing schools rejected more than 78,000 qualified applications, and the students whose applications were accepted faced demanding schedules and rigorous academics and clinical rotations. Is this a recipe for depression?

In 2024, 38% of nursing students experienced depression — a 9.3% increase over 2019, according to research from higher education research group Degreechoices. Catherine A. Stubin, PhD, RN, assistant professor of nursing at Rutgers University–Camden in New Jersey, calls it “a mental health crisis in nursing.”

“Nursing is a very rigorous, difficult, psychologically and physically demanding profession,” she said. “If students don’t have the tools and resources to adequately deal with these stressors in nursing school, it’s going to carry over to their professional practice.”

A growing recognition of the toll that nursing programs may have on students’ mental health has led schools to launch initiatives to better support the next generation of nurses.

 

Diagnosing the Problem

Higher than average rates of depression among nursing students are not new. Nursing students often work long shifts with limited breaks. The academic rigors and clinical demands of caring for patients with acute and chronic conditions while instructors evaluate and watch for mistakes can cause high levels of stress, Stubin told this news organization. “Eventually, something has to give, and it’s usually their mental health.”

Clinical practicums often start when nursing students are still freshmen, and asking 18-year-old students to provide patient care in often-chaotic clinical environments is “overwhelming,” according to Stubin. The COVID-19 pandemic further exacerbated the issue.

During lockdown, more than half the nursing students reported moderate to severe symptoms of anxiety and depression, which was attributed to the transition to online learning, fear of infection, burnout, and the psychological distress of lockdown.

“The pandemic exacerbated existing mental health problems in undergraduate nursing students,” said Stubin. “In the wake of it ... a lot of [registered nurses] have mental health issues and are leaving the profession.”

 

Helping Nurses Heal

A significant shift in the willingness to talk about mental health and seek treatment could help. In 2011, just one third of students participated in the treatment for a mental health disorder. The latest data show that 61% of students experiencing symptoms of depression or anxiety take medication or seek therapy or counseling.

Incoming health sciences students at Ohio State University (OSU), Columbus, are screened for depression, anxiety, and suicidal ideation and directed to campus health services as needed. Bernadette Mazurek Melnyk, PhD, APRN-CNP, OSU’s chief wellness officer and former dean in the College of Nursing, believes it’s an essential step in supporting students, adding, “If you don’t screen, you don’t know the students are suffering, and we’re able to get help to the students who need it quickly.”

 

Prioritizing Solutions

Counseling services available through campus health centers are just one part of a multipronged approach that nursing schools have taken to improve the health and well-being of students. Nursing programs have also introduced initiatives to lower stress, prevent burnout, and relieve emotional trauma.

“In nursing education, we have to lay the groundwork for the self-care, wellness, and resilience practices that can, hopefully, be carried over into their professional practices,” Stubin said.

At Rutgers University–Camden, the wellness center provides counseling services, and the Student Nursing Association offers a pet therapy program. Stubin also incorporates self-care, resilience-building strategies, and wellness programming into the curriculum.

During the pandemic, the University of Colorado College of Nursing, Aurora, created a class called Stress Impact and Care for COVID-19 to provide content, exercises, and support groups for nursing students. The class was so popular that it was adapted and integrated into the curriculum.

The University of Vermont, Burlington, introduced the Benson-Henry Institute Stress Management and Resiliency Training program in 2021. The 8-week program was designed to teach nursing students coping strategies to reduce stress.

Offering stress management programs to first-year nursing students has been linked to improved problem-solving skills and fewer emotional and social behavioral symptoms. However, for programs to be effective, Melnyk believes that they need to be integrated into the curriculum, not offered as electives.

“We know mindfulness works, we know cognitive behavior skills-building works, and these types of evidence-based programs with such efficacy behind them should not be optional,” she said. “Students are overwhelmed just with their coursework, so if these programs exist for extra credit, students won’t take them.”

 

Creating a Culture of Wellness

Teaching nursing students how to manage stress and providing the resources to combat depression and anxiety is just the first step in building a healthy, resilient nursing workforce.

Prioritizing wellness in nursing isn’t just essential for addressing the nationwide nursing shortage. Burnout in the medical field costs the United States healthcare system $4.6 billion per year, and preventable medical errors are the third leading cause of death in the United States.

“There is a nice movement across the United States to reduce these mental health issues because they’re so costly,” Melnyk said.

There are also national efforts to address the issue. The National Academy of Medicine introduced the Action Collaborative on Clinician Well-Being and Resilience, which has grown to include more than 200 organizations committed to reversing burnout and improving mental health in the clinical workforce. The American Nurses Foundation created The Nurse Well-Being: Building Peer and Leadership Support Program to provide resources and peer support to help nurses manage stress.

Health systems and hospitals also need to prioritize clinical well-being to reduce stress and burnout — and these efforts must be ongoing.

“These resources have to be extended into the working world ... and not just once a year for Nurses Week in May, but on a regular continued basis,” said Stubin. “Healthcare corporations and hospitals have to continue these resources and this help; it has to be a priority.”

Until the culture changes, Stubin fears that nursing students will continue facing barriers to completing their programs and maintaining nursing careers. Currently, 43% of college students considered leaving their program for mental health reasons, and 21.7% of nurses reported suicidal ideation.

“There’s a nursing shortage, and the acuity of patient care is increasing, so the stressors in the clinical area aren’t going to decrease,” Stubin said. “We as nursing faculty must teach our students how to manage these stressors to build a resilient, mentally and physically healthy workforce.”

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

Nursing is a competitive field. In 2022, nursing schools rejected more than 78,000 qualified applications, and the students whose applications were accepted faced demanding schedules and rigorous academics and clinical rotations. Is this a recipe for depression?

In 2024, 38% of nursing students experienced depression — a 9.3% increase over 2019, according to research from higher education research group Degreechoices. Catherine A. Stubin, PhD, RN, assistant professor of nursing at Rutgers University–Camden in New Jersey, calls it “a mental health crisis in nursing.”

“Nursing is a very rigorous, difficult, psychologically and physically demanding profession,” she said. “If students don’t have the tools and resources to adequately deal with these stressors in nursing school, it’s going to carry over to their professional practice.”

A growing recognition of the toll that nursing programs may have on students’ mental health has led schools to launch initiatives to better support the next generation of nurses.

 

Diagnosing the Problem

Higher than average rates of depression among nursing students are not new. Nursing students often work long shifts with limited breaks. The academic rigors and clinical demands of caring for patients with acute and chronic conditions while instructors evaluate and watch for mistakes can cause high levels of stress, Stubin told this news organization. “Eventually, something has to give, and it’s usually their mental health.”

Clinical practicums often start when nursing students are still freshmen, and asking 18-year-old students to provide patient care in often-chaotic clinical environments is “overwhelming,” according to Stubin. The COVID-19 pandemic further exacerbated the issue.

During lockdown, more than half the nursing students reported moderate to severe symptoms of anxiety and depression, which was attributed to the transition to online learning, fear of infection, burnout, and the psychological distress of lockdown.

“The pandemic exacerbated existing mental health problems in undergraduate nursing students,” said Stubin. “In the wake of it ... a lot of [registered nurses] have mental health issues and are leaving the profession.”

 

Helping Nurses Heal

A significant shift in the willingness to talk about mental health and seek treatment could help. In 2011, just one third of students participated in the treatment for a mental health disorder. The latest data show that 61% of students experiencing symptoms of depression or anxiety take medication or seek therapy or counseling.

Incoming health sciences students at Ohio State University (OSU), Columbus, are screened for depression, anxiety, and suicidal ideation and directed to campus health services as needed. Bernadette Mazurek Melnyk, PhD, APRN-CNP, OSU’s chief wellness officer and former dean in the College of Nursing, believes it’s an essential step in supporting students, adding, “If you don’t screen, you don’t know the students are suffering, and we’re able to get help to the students who need it quickly.”

 

Prioritizing Solutions

Counseling services available through campus health centers are just one part of a multipronged approach that nursing schools have taken to improve the health and well-being of students. Nursing programs have also introduced initiatives to lower stress, prevent burnout, and relieve emotional trauma.

“In nursing education, we have to lay the groundwork for the self-care, wellness, and resilience practices that can, hopefully, be carried over into their professional practices,” Stubin said.

At Rutgers University–Camden, the wellness center provides counseling services, and the Student Nursing Association offers a pet therapy program. Stubin also incorporates self-care, resilience-building strategies, and wellness programming into the curriculum.

During the pandemic, the University of Colorado College of Nursing, Aurora, created a class called Stress Impact and Care for COVID-19 to provide content, exercises, and support groups for nursing students. The class was so popular that it was adapted and integrated into the curriculum.

The University of Vermont, Burlington, introduced the Benson-Henry Institute Stress Management and Resiliency Training program in 2021. The 8-week program was designed to teach nursing students coping strategies to reduce stress.

Offering stress management programs to first-year nursing students has been linked to improved problem-solving skills and fewer emotional and social behavioral symptoms. However, for programs to be effective, Melnyk believes that they need to be integrated into the curriculum, not offered as electives.

“We know mindfulness works, we know cognitive behavior skills-building works, and these types of evidence-based programs with such efficacy behind them should not be optional,” she said. “Students are overwhelmed just with their coursework, so if these programs exist for extra credit, students won’t take them.”

 

Creating a Culture of Wellness

Teaching nursing students how to manage stress and providing the resources to combat depression and anxiety is just the first step in building a healthy, resilient nursing workforce.

Prioritizing wellness in nursing isn’t just essential for addressing the nationwide nursing shortage. Burnout in the medical field costs the United States healthcare system $4.6 billion per year, and preventable medical errors are the third leading cause of death in the United States.

“There is a nice movement across the United States to reduce these mental health issues because they’re so costly,” Melnyk said.

There are also national efforts to address the issue. The National Academy of Medicine introduced the Action Collaborative on Clinician Well-Being and Resilience, which has grown to include more than 200 organizations committed to reversing burnout and improving mental health in the clinical workforce. The American Nurses Foundation created The Nurse Well-Being: Building Peer and Leadership Support Program to provide resources and peer support to help nurses manage stress.

Health systems and hospitals also need to prioritize clinical well-being to reduce stress and burnout — and these efforts must be ongoing.

“These resources have to be extended into the working world ... and not just once a year for Nurses Week in May, but on a regular continued basis,” said Stubin. “Healthcare corporations and hospitals have to continue these resources and this help; it has to be a priority.”

Until the culture changes, Stubin fears that nursing students will continue facing barriers to completing their programs and maintaining nursing careers. Currently, 43% of college students considered leaving their program for mental health reasons, and 21.7% of nurses reported suicidal ideation.

“There’s a nursing shortage, and the acuity of patient care is increasing, so the stressors in the clinical area aren’t going to decrease,” Stubin said. “We as nursing faculty must teach our students how to manage these stressors to build a resilient, mentally and physically healthy workforce.”

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

Nursing is a competitive field. In 2022, nursing schools rejected more than 78,000 qualified applications, and the students whose applications were accepted faced demanding schedules and rigorous academics and clinical rotations. Is this a recipe for depression?

In 2024, 38% of nursing students experienced depression — a 9.3% increase over 2019, according to research from higher education research group Degreechoices. Catherine A. Stubin, PhD, RN, assistant professor of nursing at Rutgers University–Camden in New Jersey, calls it “a mental health crisis in nursing.”

“Nursing is a very rigorous, difficult, psychologically and physically demanding profession,” she said. “If students don’t have the tools and resources to adequately deal with these stressors in nursing school, it’s going to carry over to their professional practice.”

A growing recognition of the toll that nursing programs may have on students’ mental health has led schools to launch initiatives to better support the next generation of nurses.

 

Diagnosing the Problem

Higher than average rates of depression among nursing students are not new. Nursing students often work long shifts with limited breaks. The academic rigors and clinical demands of caring for patients with acute and chronic conditions while instructors evaluate and watch for mistakes can cause high levels of stress, Stubin told this news organization. “Eventually, something has to give, and it’s usually their mental health.”

Clinical practicums often start when nursing students are still freshmen, and asking 18-year-old students to provide patient care in often-chaotic clinical environments is “overwhelming,” according to Stubin. The COVID-19 pandemic further exacerbated the issue.

During lockdown, more than half the nursing students reported moderate to severe symptoms of anxiety and depression, which was attributed to the transition to online learning, fear of infection, burnout, and the psychological distress of lockdown.

“The pandemic exacerbated existing mental health problems in undergraduate nursing students,” said Stubin. “In the wake of it ... a lot of [registered nurses] have mental health issues and are leaving the profession.”

 

Helping Nurses Heal

A significant shift in the willingness to talk about mental health and seek treatment could help. In 2011, just one third of students participated in the treatment for a mental health disorder. The latest data show that 61% of students experiencing symptoms of depression or anxiety take medication or seek therapy or counseling.

Incoming health sciences students at Ohio State University (OSU), Columbus, are screened for depression, anxiety, and suicidal ideation and directed to campus health services as needed. Bernadette Mazurek Melnyk, PhD, APRN-CNP, OSU’s chief wellness officer and former dean in the College of Nursing, believes it’s an essential step in supporting students, adding, “If you don’t screen, you don’t know the students are suffering, and we’re able to get help to the students who need it quickly.”

 

Prioritizing Solutions

Counseling services available through campus health centers are just one part of a multipronged approach that nursing schools have taken to improve the health and well-being of students. Nursing programs have also introduced initiatives to lower stress, prevent burnout, and relieve emotional trauma.

“In nursing education, we have to lay the groundwork for the self-care, wellness, and resilience practices that can, hopefully, be carried over into their professional practices,” Stubin said.

At Rutgers University–Camden, the wellness center provides counseling services, and the Student Nursing Association offers a pet therapy program. Stubin also incorporates self-care, resilience-building strategies, and wellness programming into the curriculum.

During the pandemic, the University of Colorado College of Nursing, Aurora, created a class called Stress Impact and Care for COVID-19 to provide content, exercises, and support groups for nursing students. The class was so popular that it was adapted and integrated into the curriculum.

The University of Vermont, Burlington, introduced the Benson-Henry Institute Stress Management and Resiliency Training program in 2021. The 8-week program was designed to teach nursing students coping strategies to reduce stress.

Offering stress management programs to first-year nursing students has been linked to improved problem-solving skills and fewer emotional and social behavioral symptoms. However, for programs to be effective, Melnyk believes that they need to be integrated into the curriculum, not offered as electives.

“We know mindfulness works, we know cognitive behavior skills-building works, and these types of evidence-based programs with such efficacy behind them should not be optional,” she said. “Students are overwhelmed just with their coursework, so if these programs exist for extra credit, students won’t take them.”

 

Creating a Culture of Wellness

Teaching nursing students how to manage stress and providing the resources to combat depression and anxiety is just the first step in building a healthy, resilient nursing workforce.

Prioritizing wellness in nursing isn’t just essential for addressing the nationwide nursing shortage. Burnout in the medical field costs the United States healthcare system $4.6 billion per year, and preventable medical errors are the third leading cause of death in the United States.

“There is a nice movement across the United States to reduce these mental health issues because they’re so costly,” Melnyk said.

There are also national efforts to address the issue. The National Academy of Medicine introduced the Action Collaborative on Clinician Well-Being and Resilience, which has grown to include more than 200 organizations committed to reversing burnout and improving mental health in the clinical workforce. The American Nurses Foundation created The Nurse Well-Being: Building Peer and Leadership Support Program to provide resources and peer support to help nurses manage stress.

Health systems and hospitals also need to prioritize clinical well-being to reduce stress and burnout — and these efforts must be ongoing.

“These resources have to be extended into the working world ... and not just once a year for Nurses Week in May, but on a regular continued basis,” said Stubin. “Healthcare corporations and hospitals have to continue these resources and this help; it has to be a priority.”

Until the culture changes, Stubin fears that nursing students will continue facing barriers to completing their programs and maintaining nursing careers. Currently, 43% of college students considered leaving their program for mental health reasons, and 21.7% of nurses reported suicidal ideation.

“There’s a nursing shortage, and the acuity of patient care is increasing, so the stressors in the clinical area aren’t going to decrease,” Stubin said. “We as nursing faculty must teach our students how to manage these stressors to build a resilient, mentally and physically healthy workforce.”

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

Sarah Cigna, MD, sees patients every week with vulvovaginal pain and vulvar dermatoses. She’s an ob.gyn. with a focus on sexual health — often the first physician seen by patients with vulvar pain or itch — and she believes collaboration with dermatologists is essential, especially for complex cases in what she calls a neglected, data-poor area of medicine.

She also recommends that dermatologists have a good understanding of the vestibule, “one of the most important structures in vulvar medicine,” and that they become equipped to recognize generalized and localized causes of vulvar pain and/or itch.

“The problem is, we don’t talk about [vulvovaginal pain and itch] ... it’s taboo and we’re not taught about it in medical school,” Cigna, assistant professor of obstetrics and gynecology at The George Washington University (GWU), Washington, DC, said in a grand rounds lecture held recently at the GWU School of Medicine and Health Sciences Department of Dermatology.

“There are dermatologists who don’t have much training in vulvar dermatology, and a lot of gyns don’t get as much training” as they should, she said in an interview after the lecture. “So who’s looking at people’s vulvar skin and figuring out what’s going on and giving them effective treatments and evidence-based education?”

Cigna and dermatologist Emily Murphy, MD, will be co-directors of a joint ob.gyn-dermatology Vulvar Dermatology Clinic at GWU that will be launched in 2025, with monthly clinics for particularly challenging cases where the etiology is unclear or treatment is ineffective. “We want to collaborate in a more systematic way and put our heads together and think creatively about what will improve patient care,” Cigna said in the interview.

Dermatologists have valuable expertise in the immunology and genetic factors involved in skin disorders, Cigna said. Moreover, Murphy, assistant professor of dermatology and director of the Vulvar Health Program at GWU, said in an interview, dermatologists “are comfortable in going to off-label systemic medications that ob.gyns may not use that often” and bring to the table expertise in various types of procedures.

Murphy recently trained with Melissa Mauskar, MD, associate of dermatology and obstetrics and gynecology at the University of Texas Southwestern, Dallas, and founder and director of the Gynecologic Dermatology Clinic there. “It’s so important for dermatologists to be involved. It just takes some extra training that residents aren’t getting right now,” said Murphy, a member of the newly formed Vulvar Dermatoses Research Consortium.

In her grand rounds lecture, Cigna offered pearls to dermatologists for approaching a history and exam and covered highlights of the diagnosis and treatment of various problems, from vulvar Candida infections and lichen simplex chronicus to vulvar lichen sclerosus (LS), vulvar lichen planus (LP), vulvar Crohn’s disease, pudendal neuralgia, and pelvic floor muscle spasm, as well as the role of mast cell proliferation in vulvar issues.

 

Approaching the History and Exam

A comprehensive history covers the start, duration, and location of pain and/or itching as well as a detailed timeline (such as timing of potential causes, including injuries or births) and symptoms (such as burning, cutting, aching, and stinging). The question of whether pain “is on the outside, at the entrance, or deeper inside” is “crucial, especially for those in dermatology,” Cigna emphasized.

“And if you’re seeing a patient for a vulvar condition, please ask them about sex. Ask, is this affecting your sexual or intimate life with your partner because this can also give you a clue about what’s going on and how you can help them,” she told the audience of dermatologists.

Queries about trauma history (physical and emotional/verbal), competitive sports (such as daily cycling, equestrian, and heavy weight lifting), endometriosis/gynecologic surgery, connective tissue disorders (such as Ehler-Danlos syndrome), and irritable bowel syndrome are all potentially important to consider. It is important to ask about anxiety, depression, and obsessive-compulsive disorder, which do not cause — but are highly associated with — vulvar dermatoses, she said.

A surprisingly large number of people with vulvovaginal issues are being diagnosed with Ehler-Danlos syndrome, so “I’m always asking, are you hypermobile because this might be affecting the musculoskeletal system, which might be affecting the pelvis,” Cigna said. “Anything that affects the pelvis can affect the vulva as well.”

The pelvic examination should be “offered” rather than assumed to be part of the exam, as part of a trauma-informed approach that is crucial for earning trust, she advised. “Just saying, ‘we’re going to talk, and then I can offer you an exam if you like’…patients like it. It helps them feel safer and more open.”

Many diagnoses are differentiated by eliciting pain on the anterior vs the posterior half of the vulvar vestibule — the part of the vulva that lies between the labia minora and is composed of nonkeratinized tissue with embryonic origins in the endoderm. “If you touch on the keratinized skin (of the vulva) and they don’t have pain, but on the vestibule they do have pain, and there is no pain inside the vagina, this suggests there is a vestibular problem,” said Cigna.

Pain/tenderness isolated to the posterior half of the vestibule suggests a muscular cause, and pain in both the posterior and anterior parts of the vestibule suggests a cause that is more systemic or diffuse, which could be a result of a hormonal issue such as one related to oral contraceptives or decreased testosterone, or a nerve-related process.

Cigna uses gentle swipes of a Q-tip moistened with water or gel to examine the vulva rather than a poke or touch, with the exception being the posterior vestibule, which overlies muscle insertion sites. “Make sure to get a baseline in remote areas such as the inner thigh, and always distinguish between ‘scratchy/sensitive’ sensations and pain,” she said, noting the value of having the patient hold a mirror on her inner thigh.

 

Causes of Vulvar Itch: Infectious and Noninfectious

With vulvar candidiasis, a common infectious cause of vulvar itch, “you have to ask if they’re also itching on the inside because if you treat them with a topical and you don’t treat the vaginal yeast infection that may be co-occurring, they’ll keep reseeding their vulvar skin,” Cigna said, “and it will never be fully treated.”

Candida albicans is the most common cause of vulvar or vulvovaginal candidiasis, and resistance to antifungals has been rising. Non-albicans Candida “tends to have even higher resistance rates,” she said. Ordering a sensitivity panel along with the culture is helpful, but “comprehensive vaginal biome” panels are generally not useful. “It’s hard to correlate the information clinically,” she said, “and there’s not always a lot of information about susceptibilities, which is what I really like to know.”

Cigna’s treatments for vaginal infections include miconazole, terconazole, and fluconazole (and occasionally, itraconazole or voriconazole — a “decision we don’t take lightly”). Vulvar treatments include nystatin ointment, clotrimazole cream, and miconazole cream. Often, optimal treatment involves addressing “both inside and out,” she said, noting the importance of also killing yeast in undergarment fabric.

“In my experience, Diflucan [oral fluconazole] doesn’t treat persistent vulvar cutaneous skin yeast well, so while I might try Diflucan, I typically use something topical as well,” she said. “And with vaginal yeast, we do use boric acid from time to time, especially for non-albicans species because it tends to be a little more effective.”

Noninfectious causes of vulvar itch include allergic, neuropathic, and muscular causes, as well as autoimmune dermatoses and mast cell activation syndrome. Well known in dermatology are acute contact dermatitis and lichen simplex chronicus — both characterized by induration, thickening, and a “puffy” erythematous appearance, and worsening of pruritus at night. What may be less appreciated is the long list of implicated allergens , including Always menstrual pads made of a plastic-containing “dry weave” material, Cigna said. There are at least several cotton-only, low-preservative feminine products available on the market, she noted.

 

Common Autoimmune Vulvar Dermatoses: LS and LP

Vulvar LS has traditionally been thought to affect mainly prepubertal and postmenopausal women, but the autoimmune condition is now known to affect more reproductive-age people with vulvas than previously appreciated, Cigna said.

And notably, in an observational web-based study of premenopausal women (aged 18-50 years) with biopsy-confirmed vulvar LS, the leading symptom was not itch but dyspareunia and tearing with intercourse. This means “we’re missing people,” said Cigna, an author of the study. “We think the reason we’re not seeing itch as commonly in this population is that itch is likely mediated by the low estrogen state of pre- and postmenopausal people.”

Vulvar LS also occurs in pregnancy, with symptoms that are either stable or decrease during pregnancy and increase in the postpartum period, as demonstrated in a recently published online survey.

Patients with vulvar LS can present with hypopigmentation, lichenification, and scarring and architectural changes, the latter of which can involve clitoral phimosis, labial resorption, and narrowing of the introitus. (The vaginal mucosa is unaffected.) The presentation can be subtle, especially in premenopausal women, and differentiation between LS, vitiligo, and yeast is sometimes necessary.

A timely biopsy-driven definitive diagnosis is important because vulvar LS increases the risk for cancer if it’s not adequately treated and because long-term steroid use can affect the accuracy of pathology reports. “We really care about keeping this disease in remission as much as possible,” Cigna said. Experts in the field recommend long-term maintenance therapy with a mid-ultra-potent steroid one to three times/week or an alternative. “I’ve just started using ruxolitinib cream, a Janus kinase (JAK) inhibitor, and tacrolimus, a calcineurin inhibitor,” she said.

With vulvar LP, based on current evidence, the risk for malignant transformation is low, but “it crosses into the vagina and can cause vaginal adhesions, so if you’re diagnosing someone with lichen planus, you need to make sure you’re talking with them about dilators, and if you’re not comfortable, send them to [gyn],” she said.

The use of vulvoscopy is important for one’s ability to see the fine Wickham’s striae that often characterize vulvar LP, she noted. Medical treatments for vulvar LP include topical calcineurin inhibitors, high-potency steroids, and JAK inhibitors.

Surgical treatment of vulvar granuloma fissuratum caused by vulvar LS is possible (when the patient is in complete remission, to prevent koebnerization), with daily post-op application of clobetasol and retraction of tissues, noted Cigna, the author of a study on vulvar lysis of adhesions.

With both LS and LP, Cigna said, “don’t forget (consideration of) hormones” as an adjunctive treatment, especially in postmenopausal women. “Patients in a low hormone state will have more flares.”

 

Vulvar Crohn’s

“We all have to know how to look for this,” Cigna said. “Unilateral or asymmetric swelling is classic, but don’t rule out the diagnosis if you see symmetric swelling.” Patients also typically have linear “knife-like” fissures or ulcerations, the vulva “is very indurated,” and “swelling is so intense, the patients are miserable,” she said.

Vulvar Crohn’s disease may precede intestinal disease in 20%-30% of patients, so referral to a gastroenterologist — and ideally subsequent collaboration — is important, as vulvar manifestations are treated with systemic medications typical for Crohn’s.

A biopsy is required for diagnosis, and the pathologist should be advised to look for lichenified squamous mucosa with the Touton giant cell reaction. “Vulvar Crohn’s is a rare enough disorder that if you don’t have an experienced or informed pathologist looking at your specimen, they may miss it because they won’t be looking for it,” Cigna added in the interview. “You should be really clear about what you’re looking for.”

 

Neuropathic Itch, Pelvic Floor Muscle Spasm

Patients with pudendal neuralgia — caused by an injured, entrapped, or irritated pudendal nerve (originating from S2-S4) — typically present with chronic vulvar and pelvic pain that is often unprovoked and worsens with sitting. Itching upon touch is often another symptom, and some patients describe a foreign body sensation. The cause is often trauma (such as an accident or childbirth-related) as opposed to myofascial irritation, Cigna explained in her lecture.

“Your exam will be largely normal, with no skin findings, so patients will get sent away if you don’t know to look for pudendal neuralgia by pressing on the pudendal nerve or doing (or referring for) a diagnostic nerve block,” Cigna added in the interview.

Persistent genital arousal disorder (PGAD) is “more global” in that it can also originate not only from the pudendal nerve but also from nerve roots higher in the spine or even from the brain. “People feel a sense of arousal, but some describe it as an itch,” Cigna said in her lecture, referring to a 2021 consensus document on PGAD/genito-pelvic dysesthesia by the International Society for the Study of Women’s Sexual Health as a valuable resource for understanding and managing the condition.

Diagnosis and treatment usually start with a pudendal nerve block with a combination of steroid and anesthetic. If this does not relieve arousal/itching, the next step may be an MRI to look higher in the spine.

 

Pelvic Floor Muscle Spasm

Vulvar pain, skin itching, and irritation can be symptoms of pelvic floor muscle spasm. “Oftentimes people come to me and say, ‘I have a dermatologic problem,’” Cigna said. “The skin may look red and erythematous, but it’s probably more likely a muscle problem when you’re not finding anything, and no amount of steroid will help the itch go away when the problem lies underneath.”

Co-occurring symptoms can include vaginal dryness, clitoral pain, urethral discomfort, bladder pain/irritation, increased urgency, constipation, and anal fissures. The first-line treatment approach is pelvic floor therapy.

“Pelvic floor therapy is not just for incontinence. It’s also for pain and discomfort from muscles,” she said, noting that most patients with vulvar disorders are referred for pelvic floor therapy. “Almost all of them end up having pelvic floor dysfunction because the pelvic floor muscles spasm whenever there’s pain or inflammation.”

 

A Cautionary Word on Vulvodynia, and a Mast Cell Paradigm to Explore

Vulvodynia is defined as persistent pain of at least 3 months’ duration with no clear cause. “These are the patients with no skin findings,” Cigna said. But in most cases, she said, careful investigation identifies causes that are musculoskeletal, hormonal, or nerve-related.

“It’s a term that’s thrown around a lot — it’s kind of a catchall. Yet it should be a small minority of patients who truly have a diagnosis of vulvodynia,” she said.

In the early stages of investigation is the idea that mast cell proliferation and mast cell activation may play a role in some cases of vulvar and vestibular pain and itching. “We see that some patients with vulvodynia and vestibulodynia have mast cells that are increased in number in the epithelium and beneath the epithelium, and nerve staining shows an increased number of nerve endings traveling into the epithelium,” Cigna said.

“We do diagnose some people clinically” based on urticaria and other symptoms suggestive of mast cell proliferation/activation (such as flushing, abdominal cramping, diarrhea, hypotensive syncope or near syncope, and tachycardia), and “then we send them to the allergist for testing,” Cigna said.

Cigna and Murphy have no relevant financial disclosures.

 

A version of this article appeared on Medscape.com.

Sarah Cigna, MD, sees patients every week with vulvovaginal pain and vulvar dermatoses. She’s an ob.gyn. with a focus on sexual health — often the first physician seen by patients with vulvar pain or itch — and she believes collaboration with dermatologists is essential, especially for complex cases in what she calls a neglected, data-poor area of medicine.

She also recommends that dermatologists have a good understanding of the vestibule, “one of the most important structures in vulvar medicine,” and that they become equipped to recognize generalized and localized causes of vulvar pain and/or itch.

“The problem is, we don’t talk about [vulvovaginal pain and itch] ... it’s taboo and we’re not taught about it in medical school,” Cigna, assistant professor of obstetrics and gynecology at The George Washington University (GWU), Washington, DC, said in a grand rounds lecture held recently at the GWU School of Medicine and Health Sciences Department of Dermatology.

“There are dermatologists who don’t have much training in vulvar dermatology, and a lot of gyns don’t get as much training” as they should, she said in an interview after the lecture. “So who’s looking at people’s vulvar skin and figuring out what’s going on and giving them effective treatments and evidence-based education?”

Cigna and dermatologist Emily Murphy, MD, will be co-directors of a joint ob.gyn-dermatology Vulvar Dermatology Clinic at GWU that will be launched in 2025, with monthly clinics for particularly challenging cases where the etiology is unclear or treatment is ineffective. “We want to collaborate in a more systematic way and put our heads together and think creatively about what will improve patient care,” Cigna said in the interview.

Dermatologists have valuable expertise in the immunology and genetic factors involved in skin disorders, Cigna said. Moreover, Murphy, assistant professor of dermatology and director of the Vulvar Health Program at GWU, said in an interview, dermatologists “are comfortable in going to off-label systemic medications that ob.gyns may not use that often” and bring to the table expertise in various types of procedures.

Murphy recently trained with Melissa Mauskar, MD, associate of dermatology and obstetrics and gynecology at the University of Texas Southwestern, Dallas, and founder and director of the Gynecologic Dermatology Clinic there. “It’s so important for dermatologists to be involved. It just takes some extra training that residents aren’t getting right now,” said Murphy, a member of the newly formed Vulvar Dermatoses Research Consortium.

In her grand rounds lecture, Cigna offered pearls to dermatologists for approaching a history and exam and covered highlights of the diagnosis and treatment of various problems, from vulvar Candida infections and lichen simplex chronicus to vulvar lichen sclerosus (LS), vulvar lichen planus (LP), vulvar Crohn’s disease, pudendal neuralgia, and pelvic floor muscle spasm, as well as the role of mast cell proliferation in vulvar issues.

 

Approaching the History and Exam

A comprehensive history covers the start, duration, and location of pain and/or itching as well as a detailed timeline (such as timing of potential causes, including injuries or births) and symptoms (such as burning, cutting, aching, and stinging). The question of whether pain “is on the outside, at the entrance, or deeper inside” is “crucial, especially for those in dermatology,” Cigna emphasized.

“And if you’re seeing a patient for a vulvar condition, please ask them about sex. Ask, is this affecting your sexual or intimate life with your partner because this can also give you a clue about what’s going on and how you can help them,” she told the audience of dermatologists.

Queries about trauma history (physical and emotional/verbal), competitive sports (such as daily cycling, equestrian, and heavy weight lifting), endometriosis/gynecologic surgery, connective tissue disorders (such as Ehler-Danlos syndrome), and irritable bowel syndrome are all potentially important to consider. It is important to ask about anxiety, depression, and obsessive-compulsive disorder, which do not cause — but are highly associated with — vulvar dermatoses, she said.

A surprisingly large number of people with vulvovaginal issues are being diagnosed with Ehler-Danlos syndrome, so “I’m always asking, are you hypermobile because this might be affecting the musculoskeletal system, which might be affecting the pelvis,” Cigna said. “Anything that affects the pelvis can affect the vulva as well.”

The pelvic examination should be “offered” rather than assumed to be part of the exam, as part of a trauma-informed approach that is crucial for earning trust, she advised. “Just saying, ‘we’re going to talk, and then I can offer you an exam if you like’…patients like it. It helps them feel safer and more open.”

Many diagnoses are differentiated by eliciting pain on the anterior vs the posterior half of the vulvar vestibule — the part of the vulva that lies between the labia minora and is composed of nonkeratinized tissue with embryonic origins in the endoderm. “If you touch on the keratinized skin (of the vulva) and they don’t have pain, but on the vestibule they do have pain, and there is no pain inside the vagina, this suggests there is a vestibular problem,” said Cigna.

Pain/tenderness isolated to the posterior half of the vestibule suggests a muscular cause, and pain in both the posterior and anterior parts of the vestibule suggests a cause that is more systemic or diffuse, which could be a result of a hormonal issue such as one related to oral contraceptives or decreased testosterone, or a nerve-related process.

Cigna uses gentle swipes of a Q-tip moistened with water or gel to examine the vulva rather than a poke or touch, with the exception being the posterior vestibule, which overlies muscle insertion sites. “Make sure to get a baseline in remote areas such as the inner thigh, and always distinguish between ‘scratchy/sensitive’ sensations and pain,” she said, noting the value of having the patient hold a mirror on her inner thigh.

 

Causes of Vulvar Itch: Infectious and Noninfectious

With vulvar candidiasis, a common infectious cause of vulvar itch, “you have to ask if they’re also itching on the inside because if you treat them with a topical and you don’t treat the vaginal yeast infection that may be co-occurring, they’ll keep reseeding their vulvar skin,” Cigna said, “and it will never be fully treated.”

Candida albicans is the most common cause of vulvar or vulvovaginal candidiasis, and resistance to antifungals has been rising. Non-albicans Candida “tends to have even higher resistance rates,” she said. Ordering a sensitivity panel along with the culture is helpful, but “comprehensive vaginal biome” panels are generally not useful. “It’s hard to correlate the information clinically,” she said, “and there’s not always a lot of information about susceptibilities, which is what I really like to know.”

Cigna’s treatments for vaginal infections include miconazole, terconazole, and fluconazole (and occasionally, itraconazole or voriconazole — a “decision we don’t take lightly”). Vulvar treatments include nystatin ointment, clotrimazole cream, and miconazole cream. Often, optimal treatment involves addressing “both inside and out,” she said, noting the importance of also killing yeast in undergarment fabric.

“In my experience, Diflucan [oral fluconazole] doesn’t treat persistent vulvar cutaneous skin yeast well, so while I might try Diflucan, I typically use something topical as well,” she said. “And with vaginal yeast, we do use boric acid from time to time, especially for non-albicans species because it tends to be a little more effective.”

Noninfectious causes of vulvar itch include allergic, neuropathic, and muscular causes, as well as autoimmune dermatoses and mast cell activation syndrome. Well known in dermatology are acute contact dermatitis and lichen simplex chronicus — both characterized by induration, thickening, and a “puffy” erythematous appearance, and worsening of pruritus at night. What may be less appreciated is the long list of implicated allergens , including Always menstrual pads made of a plastic-containing “dry weave” material, Cigna said. There are at least several cotton-only, low-preservative feminine products available on the market, she noted.

 

Common Autoimmune Vulvar Dermatoses: LS and LP

Vulvar LS has traditionally been thought to affect mainly prepubertal and postmenopausal women, but the autoimmune condition is now known to affect more reproductive-age people with vulvas than previously appreciated, Cigna said.

And notably, in an observational web-based study of premenopausal women (aged 18-50 years) with biopsy-confirmed vulvar LS, the leading symptom was not itch but dyspareunia and tearing with intercourse. This means “we’re missing people,” said Cigna, an author of the study. “We think the reason we’re not seeing itch as commonly in this population is that itch is likely mediated by the low estrogen state of pre- and postmenopausal people.”

Vulvar LS also occurs in pregnancy, with symptoms that are either stable or decrease during pregnancy and increase in the postpartum period, as demonstrated in a recently published online survey.

Patients with vulvar LS can present with hypopigmentation, lichenification, and scarring and architectural changes, the latter of which can involve clitoral phimosis, labial resorption, and narrowing of the introitus. (The vaginal mucosa is unaffected.) The presentation can be subtle, especially in premenopausal women, and differentiation between LS, vitiligo, and yeast is sometimes necessary.

A timely biopsy-driven definitive diagnosis is important because vulvar LS increases the risk for cancer if it’s not adequately treated and because long-term steroid use can affect the accuracy of pathology reports. “We really care about keeping this disease in remission as much as possible,” Cigna said. Experts in the field recommend long-term maintenance therapy with a mid-ultra-potent steroid one to three times/week or an alternative. “I’ve just started using ruxolitinib cream, a Janus kinase (JAK) inhibitor, and tacrolimus, a calcineurin inhibitor,” she said.

With vulvar LP, based on current evidence, the risk for malignant transformation is low, but “it crosses into the vagina and can cause vaginal adhesions, so if you’re diagnosing someone with lichen planus, you need to make sure you’re talking with them about dilators, and if you’re not comfortable, send them to [gyn],” she said.

The use of vulvoscopy is important for one’s ability to see the fine Wickham’s striae that often characterize vulvar LP, she noted. Medical treatments for vulvar LP include topical calcineurin inhibitors, high-potency steroids, and JAK inhibitors.

Surgical treatment of vulvar granuloma fissuratum caused by vulvar LS is possible (when the patient is in complete remission, to prevent koebnerization), with daily post-op application of clobetasol and retraction of tissues, noted Cigna, the author of a study on vulvar lysis of adhesions.

With both LS and LP, Cigna said, “don’t forget (consideration of) hormones” as an adjunctive treatment, especially in postmenopausal women. “Patients in a low hormone state will have more flares.”

 

Vulvar Crohn’s

“We all have to know how to look for this,” Cigna said. “Unilateral or asymmetric swelling is classic, but don’t rule out the diagnosis if you see symmetric swelling.” Patients also typically have linear “knife-like” fissures or ulcerations, the vulva “is very indurated,” and “swelling is so intense, the patients are miserable,” she said.

Vulvar Crohn’s disease may precede intestinal disease in 20%-30% of patients, so referral to a gastroenterologist — and ideally subsequent collaboration — is important, as vulvar manifestations are treated with systemic medications typical for Crohn’s.

A biopsy is required for diagnosis, and the pathologist should be advised to look for lichenified squamous mucosa with the Touton giant cell reaction. “Vulvar Crohn’s is a rare enough disorder that if you don’t have an experienced or informed pathologist looking at your specimen, they may miss it because they won’t be looking for it,” Cigna added in the interview. “You should be really clear about what you’re looking for.”

 

Neuropathic Itch, Pelvic Floor Muscle Spasm

Patients with pudendal neuralgia — caused by an injured, entrapped, or irritated pudendal nerve (originating from S2-S4) — typically present with chronic vulvar and pelvic pain that is often unprovoked and worsens with sitting. Itching upon touch is often another symptom, and some patients describe a foreign body sensation. The cause is often trauma (such as an accident or childbirth-related) as opposed to myofascial irritation, Cigna explained in her lecture.

“Your exam will be largely normal, with no skin findings, so patients will get sent away if you don’t know to look for pudendal neuralgia by pressing on the pudendal nerve or doing (or referring for) a diagnostic nerve block,” Cigna added in the interview.

Persistent genital arousal disorder (PGAD) is “more global” in that it can also originate not only from the pudendal nerve but also from nerve roots higher in the spine or even from the brain. “People feel a sense of arousal, but some describe it as an itch,” Cigna said in her lecture, referring to a 2021 consensus document on PGAD/genito-pelvic dysesthesia by the International Society for the Study of Women’s Sexual Health as a valuable resource for understanding and managing the condition.

Diagnosis and treatment usually start with a pudendal nerve block with a combination of steroid and anesthetic. If this does not relieve arousal/itching, the next step may be an MRI to look higher in the spine.

 

Pelvic Floor Muscle Spasm

Vulvar pain, skin itching, and irritation can be symptoms of pelvic floor muscle spasm. “Oftentimes people come to me and say, ‘I have a dermatologic problem,’” Cigna said. “The skin may look red and erythematous, but it’s probably more likely a muscle problem when you’re not finding anything, and no amount of steroid will help the itch go away when the problem lies underneath.”

Co-occurring symptoms can include vaginal dryness, clitoral pain, urethral discomfort, bladder pain/irritation, increased urgency, constipation, and anal fissures. The first-line treatment approach is pelvic floor therapy.

“Pelvic floor therapy is not just for incontinence. It’s also for pain and discomfort from muscles,” she said, noting that most patients with vulvar disorders are referred for pelvic floor therapy. “Almost all of them end up having pelvic floor dysfunction because the pelvic floor muscles spasm whenever there’s pain or inflammation.”

 

A Cautionary Word on Vulvodynia, and a Mast Cell Paradigm to Explore

Vulvodynia is defined as persistent pain of at least 3 months’ duration with no clear cause. “These are the patients with no skin findings,” Cigna said. But in most cases, she said, careful investigation identifies causes that are musculoskeletal, hormonal, or nerve-related.

“It’s a term that’s thrown around a lot — it’s kind of a catchall. Yet it should be a small minority of patients who truly have a diagnosis of vulvodynia,” she said.

In the early stages of investigation is the idea that mast cell proliferation and mast cell activation may play a role in some cases of vulvar and vestibular pain and itching. “We see that some patients with vulvodynia and vestibulodynia have mast cells that are increased in number in the epithelium and beneath the epithelium, and nerve staining shows an increased number of nerve endings traveling into the epithelium,” Cigna said.

“We do diagnose some people clinically” based on urticaria and other symptoms suggestive of mast cell proliferation/activation (such as flushing, abdominal cramping, diarrhea, hypotensive syncope or near syncope, and tachycardia), and “then we send them to the allergist for testing,” Cigna said.

Cigna and Murphy have no relevant financial disclosures.

 

A version of this article appeared on Medscape.com.

Sarah Cigna, MD, sees patients every week with vulvovaginal pain and vulvar dermatoses. She’s an ob.gyn. with a focus on sexual health — often the first physician seen by patients with vulvar pain or itch — and she believes collaboration with dermatologists is essential, especially for complex cases in what she calls a neglected, data-poor area of medicine.

She also recommends that dermatologists have a good understanding of the vestibule, “one of the most important structures in vulvar medicine,” and that they become equipped to recognize generalized and localized causes of vulvar pain and/or itch.

“The problem is, we don’t talk about [vulvovaginal pain and itch] ... it’s taboo and we’re not taught about it in medical school,” Cigna, assistant professor of obstetrics and gynecology at The George Washington University (GWU), Washington, DC, said in a grand rounds lecture held recently at the GWU School of Medicine and Health Sciences Department of Dermatology.

“There are dermatologists who don’t have much training in vulvar dermatology, and a lot of gyns don’t get as much training” as they should, she said in an interview after the lecture. “So who’s looking at people’s vulvar skin and figuring out what’s going on and giving them effective treatments and evidence-based education?”

Cigna and dermatologist Emily Murphy, MD, will be co-directors of a joint ob.gyn-dermatology Vulvar Dermatology Clinic at GWU that will be launched in 2025, with monthly clinics for particularly challenging cases where the etiology is unclear or treatment is ineffective. “We want to collaborate in a more systematic way and put our heads together and think creatively about what will improve patient care,” Cigna said in the interview.

Dermatologists have valuable expertise in the immunology and genetic factors involved in skin disorders, Cigna said. Moreover, Murphy, assistant professor of dermatology and director of the Vulvar Health Program at GWU, said in an interview, dermatologists “are comfortable in going to off-label systemic medications that ob.gyns may not use that often” and bring to the table expertise in various types of procedures.

Murphy recently trained with Melissa Mauskar, MD, associate of dermatology and obstetrics and gynecology at the University of Texas Southwestern, Dallas, and founder and director of the Gynecologic Dermatology Clinic there. “It’s so important for dermatologists to be involved. It just takes some extra training that residents aren’t getting right now,” said Murphy, a member of the newly formed Vulvar Dermatoses Research Consortium.

In her grand rounds lecture, Cigna offered pearls to dermatologists for approaching a history and exam and covered highlights of the diagnosis and treatment of various problems, from vulvar Candida infections and lichen simplex chronicus to vulvar lichen sclerosus (LS), vulvar lichen planus (LP), vulvar Crohn’s disease, pudendal neuralgia, and pelvic floor muscle spasm, as well as the role of mast cell proliferation in vulvar issues.

 

Approaching the History and Exam

A comprehensive history covers the start, duration, and location of pain and/or itching as well as a detailed timeline (such as timing of potential causes, including injuries or births) and symptoms (such as burning, cutting, aching, and stinging). The question of whether pain “is on the outside, at the entrance, or deeper inside” is “crucial, especially for those in dermatology,” Cigna emphasized.

“And if you’re seeing a patient for a vulvar condition, please ask them about sex. Ask, is this affecting your sexual or intimate life with your partner because this can also give you a clue about what’s going on and how you can help them,” she told the audience of dermatologists.

Queries about trauma history (physical and emotional/verbal), competitive sports (such as daily cycling, equestrian, and heavy weight lifting), endometriosis/gynecologic surgery, connective tissue disorders (such as Ehler-Danlos syndrome), and irritable bowel syndrome are all potentially important to consider. It is important to ask about anxiety, depression, and obsessive-compulsive disorder, which do not cause — but are highly associated with — vulvar dermatoses, she said.

A surprisingly large number of people with vulvovaginal issues are being diagnosed with Ehler-Danlos syndrome, so “I’m always asking, are you hypermobile because this might be affecting the musculoskeletal system, which might be affecting the pelvis,” Cigna said. “Anything that affects the pelvis can affect the vulva as well.”

The pelvic examination should be “offered” rather than assumed to be part of the exam, as part of a trauma-informed approach that is crucial for earning trust, she advised. “Just saying, ‘we’re going to talk, and then I can offer you an exam if you like’…patients like it. It helps them feel safer and more open.”

Many diagnoses are differentiated by eliciting pain on the anterior vs the posterior half of the vulvar vestibule — the part of the vulva that lies between the labia minora and is composed of nonkeratinized tissue with embryonic origins in the endoderm. “If you touch on the keratinized skin (of the vulva) and they don’t have pain, but on the vestibule they do have pain, and there is no pain inside the vagina, this suggests there is a vestibular problem,” said Cigna.

Pain/tenderness isolated to the posterior half of the vestibule suggests a muscular cause, and pain in both the posterior and anterior parts of the vestibule suggests a cause that is more systemic or diffuse, which could be a result of a hormonal issue such as one related to oral contraceptives or decreased testosterone, or a nerve-related process.

Cigna uses gentle swipes of a Q-tip moistened with water or gel to examine the vulva rather than a poke or touch, with the exception being the posterior vestibule, which overlies muscle insertion sites. “Make sure to get a baseline in remote areas such as the inner thigh, and always distinguish between ‘scratchy/sensitive’ sensations and pain,” she said, noting the value of having the patient hold a mirror on her inner thigh.

 

Causes of Vulvar Itch: Infectious and Noninfectious

With vulvar candidiasis, a common infectious cause of vulvar itch, “you have to ask if they’re also itching on the inside because if you treat them with a topical and you don’t treat the vaginal yeast infection that may be co-occurring, they’ll keep reseeding their vulvar skin,” Cigna said, “and it will never be fully treated.”

Candida albicans is the most common cause of vulvar or vulvovaginal candidiasis, and resistance to antifungals has been rising. Non-albicans Candida “tends to have even higher resistance rates,” she said. Ordering a sensitivity panel along with the culture is helpful, but “comprehensive vaginal biome” panels are generally not useful. “It’s hard to correlate the information clinically,” she said, “and there’s not always a lot of information about susceptibilities, which is what I really like to know.”

Cigna’s treatments for vaginal infections include miconazole, terconazole, and fluconazole (and occasionally, itraconazole or voriconazole — a “decision we don’t take lightly”). Vulvar treatments include nystatin ointment, clotrimazole cream, and miconazole cream. Often, optimal treatment involves addressing “both inside and out,” she said, noting the importance of also killing yeast in undergarment fabric.

“In my experience, Diflucan [oral fluconazole] doesn’t treat persistent vulvar cutaneous skin yeast well, so while I might try Diflucan, I typically use something topical as well,” she said. “And with vaginal yeast, we do use boric acid from time to time, especially for non-albicans species because it tends to be a little more effective.”

Noninfectious causes of vulvar itch include allergic, neuropathic, and muscular causes, as well as autoimmune dermatoses and mast cell activation syndrome. Well known in dermatology are acute contact dermatitis and lichen simplex chronicus — both characterized by induration, thickening, and a “puffy” erythematous appearance, and worsening of pruritus at night. What may be less appreciated is the long list of implicated allergens , including Always menstrual pads made of a plastic-containing “dry weave” material, Cigna said. There are at least several cotton-only, low-preservative feminine products available on the market, she noted.

 

Common Autoimmune Vulvar Dermatoses: LS and LP

Vulvar LS has traditionally been thought to affect mainly prepubertal and postmenopausal women, but the autoimmune condition is now known to affect more reproductive-age people with vulvas than previously appreciated, Cigna said.

And notably, in an observational web-based study of premenopausal women (aged 18-50 years) with biopsy-confirmed vulvar LS, the leading symptom was not itch but dyspareunia and tearing with intercourse. This means “we’re missing people,” said Cigna, an author of the study. “We think the reason we’re not seeing itch as commonly in this population is that itch is likely mediated by the low estrogen state of pre- and postmenopausal people.”

Vulvar LS also occurs in pregnancy, with symptoms that are either stable or decrease during pregnancy and increase in the postpartum period, as demonstrated in a recently published online survey.

Patients with vulvar LS can present with hypopigmentation, lichenification, and scarring and architectural changes, the latter of which can involve clitoral phimosis, labial resorption, and narrowing of the introitus. (The vaginal mucosa is unaffected.) The presentation can be subtle, especially in premenopausal women, and differentiation between LS, vitiligo, and yeast is sometimes necessary.

A timely biopsy-driven definitive diagnosis is important because vulvar LS increases the risk for cancer if it’s not adequately treated and because long-term steroid use can affect the accuracy of pathology reports. “We really care about keeping this disease in remission as much as possible,” Cigna said. Experts in the field recommend long-term maintenance therapy with a mid-ultra-potent steroid one to three times/week or an alternative. “I’ve just started using ruxolitinib cream, a Janus kinase (JAK) inhibitor, and tacrolimus, a calcineurin inhibitor,” she said.

With vulvar LP, based on current evidence, the risk for malignant transformation is low, but “it crosses into the vagina and can cause vaginal adhesions, so if you’re diagnosing someone with lichen planus, you need to make sure you’re talking with them about dilators, and if you’re not comfortable, send them to [gyn],” she said.

The use of vulvoscopy is important for one’s ability to see the fine Wickham’s striae that often characterize vulvar LP, she noted. Medical treatments for vulvar LP include topical calcineurin inhibitors, high-potency steroids, and JAK inhibitors.

Surgical treatment of vulvar granuloma fissuratum caused by vulvar LS is possible (when the patient is in complete remission, to prevent koebnerization), with daily post-op application of clobetasol and retraction of tissues, noted Cigna, the author of a study on vulvar lysis of adhesions.

With both LS and LP, Cigna said, “don’t forget (consideration of) hormones” as an adjunctive treatment, especially in postmenopausal women. “Patients in a low hormone state will have more flares.”

 

Vulvar Crohn’s

“We all have to know how to look for this,” Cigna said. “Unilateral or asymmetric swelling is classic, but don’t rule out the diagnosis if you see symmetric swelling.” Patients also typically have linear “knife-like” fissures or ulcerations, the vulva “is very indurated,” and “swelling is so intense, the patients are miserable,” she said.

Vulvar Crohn’s disease may precede intestinal disease in 20%-30% of patients, so referral to a gastroenterologist — and ideally subsequent collaboration — is important, as vulvar manifestations are treated with systemic medications typical for Crohn’s.

A biopsy is required for diagnosis, and the pathologist should be advised to look for lichenified squamous mucosa with the Touton giant cell reaction. “Vulvar Crohn’s is a rare enough disorder that if you don’t have an experienced or informed pathologist looking at your specimen, they may miss it because they won’t be looking for it,” Cigna added in the interview. “You should be really clear about what you’re looking for.”

 

Neuropathic Itch, Pelvic Floor Muscle Spasm

Patients with pudendal neuralgia — caused by an injured, entrapped, or irritated pudendal nerve (originating from S2-S4) — typically present with chronic vulvar and pelvic pain that is often unprovoked and worsens with sitting. Itching upon touch is often another symptom, and some patients describe a foreign body sensation. The cause is often trauma (such as an accident or childbirth-related) as opposed to myofascial irritation, Cigna explained in her lecture.

“Your exam will be largely normal, with no skin findings, so patients will get sent away if you don’t know to look for pudendal neuralgia by pressing on the pudendal nerve or doing (or referring for) a diagnostic nerve block,” Cigna added in the interview.

Persistent genital arousal disorder (PGAD) is “more global” in that it can also originate not only from the pudendal nerve but also from nerve roots higher in the spine or even from the brain. “People feel a sense of arousal, but some describe it as an itch,” Cigna said in her lecture, referring to a 2021 consensus document on PGAD/genito-pelvic dysesthesia by the International Society for the Study of Women’s Sexual Health as a valuable resource for understanding and managing the condition.

Diagnosis and treatment usually start with a pudendal nerve block with a combination of steroid and anesthetic. If this does not relieve arousal/itching, the next step may be an MRI to look higher in the spine.

 

Pelvic Floor Muscle Spasm

Vulvar pain, skin itching, and irritation can be symptoms of pelvic floor muscle spasm. “Oftentimes people come to me and say, ‘I have a dermatologic problem,’” Cigna said. “The skin may look red and erythematous, but it’s probably more likely a muscle problem when you’re not finding anything, and no amount of steroid will help the itch go away when the problem lies underneath.”

Co-occurring symptoms can include vaginal dryness, clitoral pain, urethral discomfort, bladder pain/irritation, increased urgency, constipation, and anal fissures. The first-line treatment approach is pelvic floor therapy.

“Pelvic floor therapy is not just for incontinence. It’s also for pain and discomfort from muscles,” she said, noting that most patients with vulvar disorders are referred for pelvic floor therapy. “Almost all of them end up having pelvic floor dysfunction because the pelvic floor muscles spasm whenever there’s pain or inflammation.”

 

A Cautionary Word on Vulvodynia, and a Mast Cell Paradigm to Explore

Vulvodynia is defined as persistent pain of at least 3 months’ duration with no clear cause. “These are the patients with no skin findings,” Cigna said. But in most cases, she said, careful investigation identifies causes that are musculoskeletal, hormonal, or nerve-related.

“It’s a term that’s thrown around a lot — it’s kind of a catchall. Yet it should be a small minority of patients who truly have a diagnosis of vulvodynia,” she said.

In the early stages of investigation is the idea that mast cell proliferation and mast cell activation may play a role in some cases of vulvar and vestibular pain and itching. “We see that some patients with vulvodynia and vestibulodynia have mast cells that are increased in number in the epithelium and beneath the epithelium, and nerve staining shows an increased number of nerve endings traveling into the epithelium,” Cigna said.

“We do diagnose some people clinically” based on urticaria and other symptoms suggestive of mast cell proliferation/activation (such as flushing, abdominal cramping, diarrhea, hypotensive syncope or near syncope, and tachycardia), and “then we send them to the allergist for testing,” Cigna said.

Cigna and Murphy have no relevant financial disclosures.

 

A version of this article appeared on Medscape.com.

Overtreatment of men with prostate cancer and limited life expectancy (LE) has persisted in the era of active surveillance and worsened in some instances, according to a new study.

“Overtreatment of men with limited longevity for intermediate- and high-risk tumors has not only failed to improve but has actually worsened over the last 20 years,” Timothy Daskivich, MD, MSHPM, with Cedars-Sinai Medical Center, Los Angeles, said in an interview.

“Many doctors assume that the increase in uptake of active surveillance for low-risk prostate cancers has solved the problem of overtreatment, but this trend has not affected overtreatment of men with low likelihood of living long enough to benefit from treatment who have higher-risk tumors,” Daskivich said.

The study was published online on November 11 in JAMA Internal Medicine.

‘Concerning’ Real-World Data

For men with low- and intermediate-risk prostate cancer expected to live fewer than 10 years, prostate cancer screening and aggressive treatment are not recommended.

Daskivich and colleagues analyzed data on 243,928 men (mean age, 66 years) in the Veterans Affairs (VA) Health System with clinically localized prostate cancer diagnosed between 2000 and 2019.

About 21% had LE < 10 years, and about 4% had LE < 5 years, according to the validated age-adjusted Prostate Cancer Comorbidity Index.

Overtreatment was defined as aggressive treatment (surgery or radiation) in those with LE < 10 years and low- to intermediate-risk disease and in those with LE < 5 years and high-risk disease, in line with current guidelines.

Among men with LE < 10 years, the proportion of men overtreated with surgery or radiotherapy for low-risk disease decreased 22% but increased 22% for intermediate-risk disease during the study period.

Among men with LE < 5 years, the proportion of men treated with definitive treatment for high-risk disease increased 29%.

“While lower-risk tumors are treated less aggressively across the board, including in men with limited longevity, it seems that we are more indiscriminately treating men with higher-risk disease without considering their expected longevity,” Daskivich said in an interview.

 

Is This Happening in the General US Population?

Daskivich noted that the sample included a large sample of men diagnosed with localized prostate cancer in the VA Health System.

“Rates of overtreatment are likely to be lower in the VA [Health System], so the problem may be worse in the community setting. The VA [Health System] has been exemplary in its uptake of active surveillance for low-risk cancers, leading the effort to reduce overtreatment of men with low-risk cancers. However, the problem of overtreatment of men with limited longevity persists in the VA [Health System], underscoring the pervasiveness of this problem,” he explained.

“We don’t have a perfect head-to-head comparison of overtreatment in the VA setting vs in the community. [However, one study shows] that this is not a VA-specific phenomenon and that there is an increase in overtreatment of men with limited longevity in a Medicare population as well,” Daskivich noted.

 

Is Overtreatment All Bad?

Overtreatment of prostate cancer, especially in cases where the cancer is unlikely to progress or cause symptoms, can lead to significant physical, psychological, and financial harms, Christopher Anderson, MD, urologist with Columbia University Irving Medical Center in New York City, who wasn’t involved in the study, noted in an interview.

In the study by Daskivich and colleagues, over three quarters of the overtreatment was radiation therapy, which carries the risk for urinary, bowel, and sexual issues.

“Overscreening, which can lead to overtreatment, is a core issue,” Anderson said. It’s easy to order a “simple” prostate-specific antigen blood test, but in an older man with limited LE, that can lead to a host of further testing, he said.

Stopping the pipeline of overscreening that then feeds into the cascade of overtreatment is the first step in addressing the problem of prostate cancer overtreatment, Nancy Li Schoenborn, MD, MHS, with Johns Hopkins University School of Medicine, Baltimore, and Louise C. Walter, MD, with University of California San Francisco, wrote in an editorial in JAMA Internal Medicine.

Considering LE during screening decision-making is “fundamental to reducing harms of prostate cancer overdiagnosis and overtreatment” because limited LE increases the likelihood of experiencing “harms all along the diagnostic and treatment cascade following screening,” the editorial writers said.

The time spent diagnosing, monitoring, and treating asymptomatic prostate cancer in men with limited LE distracts from monitoring and treating chronic symptomatic life-limiting illnesses, they noted.

 

Tough to Talk About?

Anderson noted that, in general, doctors are not great at estimating and counseling patients on LE. “It’s sometimes difficult to have that conversation,” he said.

Daskivich said physicians may fail to include average LE when advising patients on treatments because they believe that the patients do not want to discuss this topic. “Yet, in interviews with patients, we found that prostate cancer patients reported they wanted this information,” he continued, in an interview.

Solving the problem of overscreening and overtreatment will require a “multifaceted approach, including improving access to life expectancy data at the point of care for providers, educating providers on how to communicate this information, and improving data sources to predict longevity,” Daskivich said.

He said it’s equally important to note that some men with prostate cancer may choose treatment even if they have a limited longevity.

“Not all patients will choose conservative management, even if it is recommended by guidelines. However, they need to be given the opportunity to make a good decision for themselves with the best possible data,” Daskivich said.

This work was supported in part by a US Department of VA Merit Review. Daskivich reported receiving personal fees from the Medical Education Speakers Network, EDAP, and RAND; research support from Lantheus and Janssen; and a patent pending for a system for healthcare visit quality assessment outside the submitted work. Schoenborn, Walter, and Anderson had no relevant disclosures.

 

A version of this article appeared on Medscape.com.

Overtreatment of men with prostate cancer and limited life expectancy (LE) has persisted in the era of active surveillance and worsened in some instances, according to a new study.

“Overtreatment of men with limited longevity for intermediate- and high-risk tumors has not only failed to improve but has actually worsened over the last 20 years,” Timothy Daskivich, MD, MSHPM, with Cedars-Sinai Medical Center, Los Angeles, said in an interview.

“Many doctors assume that the increase in uptake of active surveillance for low-risk prostate cancers has solved the problem of overtreatment, but this trend has not affected overtreatment of men with low likelihood of living long enough to benefit from treatment who have higher-risk tumors,” Daskivich said.

The study was published online on November 11 in JAMA Internal Medicine.

‘Concerning’ Real-World Data

For men with low- and intermediate-risk prostate cancer expected to live fewer than 10 years, prostate cancer screening and aggressive treatment are not recommended.

Daskivich and colleagues analyzed data on 243,928 men (mean age, 66 years) in the Veterans Affairs (VA) Health System with clinically localized prostate cancer diagnosed between 2000 and 2019.

About 21% had LE < 10 years, and about 4% had LE < 5 years, according to the validated age-adjusted Prostate Cancer Comorbidity Index.

Overtreatment was defined as aggressive treatment (surgery or radiation) in those with LE < 10 years and low- to intermediate-risk disease and in those with LE < 5 years and high-risk disease, in line with current guidelines.

Among men with LE < 10 years, the proportion of men overtreated with surgery or radiotherapy for low-risk disease decreased 22% but increased 22% for intermediate-risk disease during the study period.

Among men with LE < 5 years, the proportion of men treated with definitive treatment for high-risk disease increased 29%.

“While lower-risk tumors are treated less aggressively across the board, including in men with limited longevity, it seems that we are more indiscriminately treating men with higher-risk disease without considering their expected longevity,” Daskivich said in an interview.

 

Is This Happening in the General US Population?

Daskivich noted that the sample included a large sample of men diagnosed with localized prostate cancer in the VA Health System.

“Rates of overtreatment are likely to be lower in the VA [Health System], so the problem may be worse in the community setting. The VA [Health System] has been exemplary in its uptake of active surveillance for low-risk cancers, leading the effort to reduce overtreatment of men with low-risk cancers. However, the problem of overtreatment of men with limited longevity persists in the VA [Health System], underscoring the pervasiveness of this problem,” he explained.

“We don’t have a perfect head-to-head comparison of overtreatment in the VA setting vs in the community. [However, one study shows] that this is not a VA-specific phenomenon and that there is an increase in overtreatment of men with limited longevity in a Medicare population as well,” Daskivich noted.

 

Is Overtreatment All Bad?

Overtreatment of prostate cancer, especially in cases where the cancer is unlikely to progress or cause symptoms, can lead to significant physical, psychological, and financial harms, Christopher Anderson, MD, urologist with Columbia University Irving Medical Center in New York City, who wasn’t involved in the study, noted in an interview.

In the study by Daskivich and colleagues, over three quarters of the overtreatment was radiation therapy, which carries the risk for urinary, bowel, and sexual issues.

“Overscreening, which can lead to overtreatment, is a core issue,” Anderson said. It’s easy to order a “simple” prostate-specific antigen blood test, but in an older man with limited LE, that can lead to a host of further testing, he said.

Stopping the pipeline of overscreening that then feeds into the cascade of overtreatment is the first step in addressing the problem of prostate cancer overtreatment, Nancy Li Schoenborn, MD, MHS, with Johns Hopkins University School of Medicine, Baltimore, and Louise C. Walter, MD, with University of California San Francisco, wrote in an editorial in JAMA Internal Medicine.

Considering LE during screening decision-making is “fundamental to reducing harms of prostate cancer overdiagnosis and overtreatment” because limited LE increases the likelihood of experiencing “harms all along the diagnostic and treatment cascade following screening,” the editorial writers said.

The time spent diagnosing, monitoring, and treating asymptomatic prostate cancer in men with limited LE distracts from monitoring and treating chronic symptomatic life-limiting illnesses, they noted.

 

Tough to Talk About?

Anderson noted that, in general, doctors are not great at estimating and counseling patients on LE. “It’s sometimes difficult to have that conversation,” he said.

Daskivich said physicians may fail to include average LE when advising patients on treatments because they believe that the patients do not want to discuss this topic. “Yet, in interviews with patients, we found that prostate cancer patients reported they wanted this information,” he continued, in an interview.

Solving the problem of overscreening and overtreatment will require a “multifaceted approach, including improving access to life expectancy data at the point of care for providers, educating providers on how to communicate this information, and improving data sources to predict longevity,” Daskivich said.

He said it’s equally important to note that some men with prostate cancer may choose treatment even if they have a limited longevity.

“Not all patients will choose conservative management, even if it is recommended by guidelines. However, they need to be given the opportunity to make a good decision for themselves with the best possible data,” Daskivich said.

This work was supported in part by a US Department of VA Merit Review. Daskivich reported receiving personal fees from the Medical Education Speakers Network, EDAP, and RAND; research support from Lantheus and Janssen; and a patent pending for a system for healthcare visit quality assessment outside the submitted work. Schoenborn, Walter, and Anderson had no relevant disclosures.

 

A version of this article appeared on Medscape.com.

Overtreatment of men with prostate cancer and limited life expectancy (LE) has persisted in the era of active surveillance and worsened in some instances, according to a new study.

“Overtreatment of men with limited longevity for intermediate- and high-risk tumors has not only failed to improve but has actually worsened over the last 20 years,” Timothy Daskivich, MD, MSHPM, with Cedars-Sinai Medical Center, Los Angeles, said in an interview.

“Many doctors assume that the increase in uptake of active surveillance for low-risk prostate cancers has solved the problem of overtreatment, but this trend has not affected overtreatment of men with low likelihood of living long enough to benefit from treatment who have higher-risk tumors,” Daskivich said.

The study was published online on November 11 in JAMA Internal Medicine.

‘Concerning’ Real-World Data

For men with low- and intermediate-risk prostate cancer expected to live fewer than 10 years, prostate cancer screening and aggressive treatment are not recommended.

Daskivich and colleagues analyzed data on 243,928 men (mean age, 66 years) in the Veterans Affairs (VA) Health System with clinically localized prostate cancer diagnosed between 2000 and 2019.

About 21% had LE < 10 years, and about 4% had LE < 5 years, according to the validated age-adjusted Prostate Cancer Comorbidity Index.

Overtreatment was defined as aggressive treatment (surgery or radiation) in those with LE < 10 years and low- to intermediate-risk disease and in those with LE < 5 years and high-risk disease, in line with current guidelines.

Among men with LE < 10 years, the proportion of men overtreated with surgery or radiotherapy for low-risk disease decreased 22% but increased 22% for intermediate-risk disease during the study period.

Among men with LE < 5 years, the proportion of men treated with definitive treatment for high-risk disease increased 29%.

“While lower-risk tumors are treated less aggressively across the board, including in men with limited longevity, it seems that we are more indiscriminately treating men with higher-risk disease without considering their expected longevity,” Daskivich said in an interview.

 

Is This Happening in the General US Population?

Daskivich noted that the sample included a large sample of men diagnosed with localized prostate cancer in the VA Health System.

“Rates of overtreatment are likely to be lower in the VA [Health System], so the problem may be worse in the community setting. The VA [Health System] has been exemplary in its uptake of active surveillance for low-risk cancers, leading the effort to reduce overtreatment of men with low-risk cancers. However, the problem of overtreatment of men with limited longevity persists in the VA [Health System], underscoring the pervasiveness of this problem,” he explained.

“We don’t have a perfect head-to-head comparison of overtreatment in the VA setting vs in the community. [However, one study shows] that this is not a VA-specific phenomenon and that there is an increase in overtreatment of men with limited longevity in a Medicare population as well,” Daskivich noted.

 

Is Overtreatment All Bad?

Overtreatment of prostate cancer, especially in cases where the cancer is unlikely to progress or cause symptoms, can lead to significant physical, psychological, and financial harms, Christopher Anderson, MD, urologist with Columbia University Irving Medical Center in New York City, who wasn’t involved in the study, noted in an interview.

In the study by Daskivich and colleagues, over three quarters of the overtreatment was radiation therapy, which carries the risk for urinary, bowel, and sexual issues.

“Overscreening, which can lead to overtreatment, is a core issue,” Anderson said. It’s easy to order a “simple” prostate-specific antigen blood test, but in an older man with limited LE, that can lead to a host of further testing, he said.

Stopping the pipeline of overscreening that then feeds into the cascade of overtreatment is the first step in addressing the problem of prostate cancer overtreatment, Nancy Li Schoenborn, MD, MHS, with Johns Hopkins University School of Medicine, Baltimore, and Louise C. Walter, MD, with University of California San Francisco, wrote in an editorial in JAMA Internal Medicine.

Considering LE during screening decision-making is “fundamental to reducing harms of prostate cancer overdiagnosis and overtreatment” because limited LE increases the likelihood of experiencing “harms all along the diagnostic and treatment cascade following screening,” the editorial writers said.

The time spent diagnosing, monitoring, and treating asymptomatic prostate cancer in men with limited LE distracts from monitoring and treating chronic symptomatic life-limiting illnesses, they noted.

 

Tough to Talk About?

Anderson noted that, in general, doctors are not great at estimating and counseling patients on LE. “It’s sometimes difficult to have that conversation,” he said.

Daskivich said physicians may fail to include average LE when advising patients on treatments because they believe that the patients do not want to discuss this topic. “Yet, in interviews with patients, we found that prostate cancer patients reported they wanted this information,” he continued, in an interview.

Solving the problem of overscreening and overtreatment will require a “multifaceted approach, including improving access to life expectancy data at the point of care for providers, educating providers on how to communicate this information, and improving data sources to predict longevity,” Daskivich said.

He said it’s equally important to note that some men with prostate cancer may choose treatment even if they have a limited longevity.

“Not all patients will choose conservative management, even if it is recommended by guidelines. However, they need to be given the opportunity to make a good decision for themselves with the best possible data,” Daskivich said.

This work was supported in part by a US Department of VA Merit Review. Daskivich reported receiving personal fees from the Medical Education Speakers Network, EDAP, and RAND; research support from Lantheus and Janssen; and a patent pending for a system for healthcare visit quality assessment outside the submitted work. Schoenborn, Walter, and Anderson had no relevant disclosures.

 

A version of this article appeared on Medscape.com.