Family Practice News

Cutaneous melanoma is a type of skin cancer typically associated with significant ultraviolet radiation exposure. Melanoma arises from melanocytes, cells found within the lower portion of the epidermis that make the pigment melanin.

While much less common than squamous cell carcinoma or basal cell carcinoma, melanoma is responsible for most deaths from skin cancer. In 2024, there will be more than 100,000 new cases of melanoma and over 8,000 melanoma-related deaths.¹ If localized at the time of diagnosis, survival rates are excellent. Cutaneous melanomas are more common in those with fair complexions or who have had long periods of exposure to natural or artificial sunlight.

Melanoma can also occur in mucous membranes. Mucosal melanoma is much less common than cutaneous melanoma and accounts for only a very small percentage of all new melanoma diagnoses. Unlike their cutaneous counterparts, risk factors for mucosal melanomas have yet to be identified. Although there is some disagreement on whether vulvar melanomas represent cutaneous or mucous melanomas, vulvovaginal melanomas have historically been considered to be mucosal melanomas.

Vulvovaginal melanomas are characterized by a high mortality rate, diagnostic challenges, and lack of awareness, making early detection and intervention crucial to improving patient outcomes. The 5-year overall survival rate for vulvar melanoma is 36% and for vaginal melanoma ranges between 5% and 25%.² Survival rates for vulvovaginal melanomas are lower than for other types of vulvar cancers (72%) or for cutaneous melanomas (72%-81%).²

Racial disparities in survival rates for mucosal and cutaneous melanomas were highlighted in a retrospective study using the Surveillance Epidemiology and End Results (SEER) database. Although the number of Black patients included was small, the median overall survival in that population was less than that in non-Black patients with vulvovaginal melanoma (16 vs. 39 months). Similar findings were noted in Black patients with cutaneous melanoma, compared with non-Black patients (median overall survival, 124 vs 319 months).³

One of the most significant obstacles in the diagnosis of vulvar and vaginal melanoma is its rarity. Both patients and clinicians alike may fail to recognize early warning signs. In a world where skin cancer is heavily publicized, melanoma in the genital area is not as frequently discussed or understood. Postmenopausal patients may have less regular gynecologic care, and unless they present with specific symptoms prompting an exam, melanomas can grow undetected, progressing to more advanced stages before they are discovered.

The median age of patients diagnosed with vulvar and vaginal melanomas is 67-68.^4,5 Symptoms can be subtle and nonspecific. Women with vulvar melanoma may experience symptoms that are similar to other vulvar cancers including pruritus, irritation, pain, bleeding, or a new or growing mass. While vaginal melanoma can be asymptomatic, patients frequently present with vaginal bleeding, discharge, and/or pain (including dyspareunia).

Vulvovaginal melanomas may present differently than cutaneous melanomas. Vulvar melanomas are often pigmented and frequently present as ulcerated lesions. In some cases, though, they appear amelanotic (lacking pigment), making them even harder to identify. The ABCDEs of skin cancer (asymmetry, border, color, diameter, evolving) should be applied to these lesions. Change in the size, shape, or pigment of preexisting melanosis (areas of hyperpigmentation caused by increased melanin), should raise concern for possible malignant transformation. 

Most vaginal melanomas occur within the distal third of the vagina, frequently along the anterior vaginal wall.⁶ They can be polypoid or nodular in appearance and may be ulcerated. While biopsy of any suspicious, enlarging/changing, or symptomatic lesion should be performed, it may be prudent to pause prior to biopsy of a vaginal lesion depending on its appearance. Although rare, gestational trophoblastic neoplasia (GTN) can present with vaginal metastases, and these lesions are frequently very vascular and pose a high bleeding risk if biopsied. They may look dark blue or black. If there is any concern for metastatic GTN on vaginal exam, a beta-hCG level should be obtained prior to biopsy.

Treatment of vulvovaginal melanoma may include surgical excision, systemic therapy, radiation therapy, or a combination of treatments. There is growing use of immunotherapy that mirrors cutaneous melanoma therapy.

Vulvar and vaginal melanoma represent a rare yet serious health issue for women and their impact on public health should not be underestimated. Vulvovaginal melanoma often goes unrecognized until it has reached an advanced stage. Increased awareness about these rare forms of melanoma among both patients and healthcare professionals is vital to improve early detection and treatment outcomes. With greater attention to this disease, we can strive for better diagnostic methods, more effective treatments, and ultimately, a reduction in mortality rates associated with vulvar and vaginal melanoma.

Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no conflicts of interest.

References

1. National Cancer Institute. Cancer Stat Facts: Melanoma of the skin. 2024 Dec 2. Available from: https://seer.cancer.gov/statfacts/html/melan.html.

2. Piura B. Lancet Oncol. 2008 Oct;9(10):973-81. .

3. Mert I et al. Int J Gynecol Cancer. 2013;23(6):1118-25.

4. Wang D et al. Am J Cancer Res. 2020 Dec 1;10(12):4017-37.

5. Albert A et al. J Gynecol Oncol. 2020 Sep;31(5):e66.

Cutaneous melanoma is a type of skin cancer typically associated with significant ultraviolet radiation exposure. Melanoma arises from melanocytes, cells found within the lower portion of the epidermis that make the pigment melanin.

While much less common than squamous cell carcinoma or basal cell carcinoma, melanoma is responsible for most deaths from skin cancer. In 2024, there will be more than 100,000 new cases of melanoma and over 8,000 melanoma-related deaths.¹ If localized at the time of diagnosis, survival rates are excellent. Cutaneous melanomas are more common in those with fair complexions or who have had long periods of exposure to natural or artificial sunlight.

Melanoma can also occur in mucous membranes. Mucosal melanoma is much less common than cutaneous melanoma and accounts for only a very small percentage of all new melanoma diagnoses. Unlike their cutaneous counterparts, risk factors for mucosal melanomas have yet to be identified. Although there is some disagreement on whether vulvar melanomas represent cutaneous or mucous melanomas, vulvovaginal melanomas have historically been considered to be mucosal melanomas.

Vulvovaginal melanomas are characterized by a high mortality rate, diagnostic challenges, and lack of awareness, making early detection and intervention crucial to improving patient outcomes. The 5-year overall survival rate for vulvar melanoma is 36% and for vaginal melanoma ranges between 5% and 25%.² Survival rates for vulvovaginal melanomas are lower than for other types of vulvar cancers (72%) or for cutaneous melanomas (72%-81%).²

Racial disparities in survival rates for mucosal and cutaneous melanomas were highlighted in a retrospective study using the Surveillance Epidemiology and End Results (SEER) database. Although the number of Black patients included was small, the median overall survival in that population was less than that in non-Black patients with vulvovaginal melanoma (16 vs. 39 months). Similar findings were noted in Black patients with cutaneous melanoma, compared with non-Black patients (median overall survival, 124 vs 319 months).³

One of the most significant obstacles in the diagnosis of vulvar and vaginal melanoma is its rarity. Both patients and clinicians alike may fail to recognize early warning signs. In a world where skin cancer is heavily publicized, melanoma in the genital area is not as frequently discussed or understood. Postmenopausal patients may have less regular gynecologic care, and unless they present with specific symptoms prompting an exam, melanomas can grow undetected, progressing to more advanced stages before they are discovered.

The median age of patients diagnosed with vulvar and vaginal melanomas is 67-68.^4,5 Symptoms can be subtle and nonspecific. Women with vulvar melanoma may experience symptoms that are similar to other vulvar cancers including pruritus, irritation, pain, bleeding, or a new or growing mass. While vaginal melanoma can be asymptomatic, patients frequently present with vaginal bleeding, discharge, and/or pain (including dyspareunia).

Vulvovaginal melanomas may present differently than cutaneous melanomas. Vulvar melanomas are often pigmented and frequently present as ulcerated lesions. In some cases, though, they appear amelanotic (lacking pigment), making them even harder to identify. The ABCDEs of skin cancer (asymmetry, border, color, diameter, evolving) should be applied to these lesions. Change in the size, shape, or pigment of preexisting melanosis (areas of hyperpigmentation caused by increased melanin), should raise concern for possible malignant transformation. 

Most vaginal melanomas occur within the distal third of the vagina, frequently along the anterior vaginal wall.⁶ They can be polypoid or nodular in appearance and may be ulcerated. While biopsy of any suspicious, enlarging/changing, or symptomatic lesion should be performed, it may be prudent to pause prior to biopsy of a vaginal lesion depending on its appearance. Although rare, gestational trophoblastic neoplasia (GTN) can present with vaginal metastases, and these lesions are frequently very vascular and pose a high bleeding risk if biopsied. They may look dark blue or black. If there is any concern for metastatic GTN on vaginal exam, a beta-hCG level should be obtained prior to biopsy.

Treatment of vulvovaginal melanoma may include surgical excision, systemic therapy, radiation therapy, or a combination of treatments. There is growing use of immunotherapy that mirrors cutaneous melanoma therapy.

Vulvar and vaginal melanoma represent a rare yet serious health issue for women and their impact on public health should not be underestimated. Vulvovaginal melanoma often goes unrecognized until it has reached an advanced stage. Increased awareness about these rare forms of melanoma among both patients and healthcare professionals is vital to improve early detection and treatment outcomes. With greater attention to this disease, we can strive for better diagnostic methods, more effective treatments, and ultimately, a reduction in mortality rates associated with vulvar and vaginal melanoma.

Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no conflicts of interest.

References

1. National Cancer Institute. Cancer Stat Facts: Melanoma of the skin. 2024 Dec 2. Available from: https://seer.cancer.gov/statfacts/html/melan.html.

2. Piura B. Lancet Oncol. 2008 Oct;9(10):973-81. .

3. Mert I et al. Int J Gynecol Cancer. 2013;23(6):1118-25.

4. Wang D et al. Am J Cancer Res. 2020 Dec 1;10(12):4017-37.

5. Albert A et al. J Gynecol Oncol. 2020 Sep;31(5):e66.

Cutaneous melanoma is a type of skin cancer typically associated with significant ultraviolet radiation exposure. Melanoma arises from melanocytes, cells found within the lower portion of the epidermis that make the pigment melanin.

While much less common than squamous cell carcinoma or basal cell carcinoma, melanoma is responsible for most deaths from skin cancer. In 2024, there will be more than 100,000 new cases of melanoma and over 8,000 melanoma-related deaths.¹ If localized at the time of diagnosis, survival rates are excellent. Cutaneous melanomas are more common in those with fair complexions or who have had long periods of exposure to natural or artificial sunlight.

Melanoma can also occur in mucous membranes. Mucosal melanoma is much less common than cutaneous melanoma and accounts for only a very small percentage of all new melanoma diagnoses. Unlike their cutaneous counterparts, risk factors for mucosal melanomas have yet to be identified. Although there is some disagreement on whether vulvar melanomas represent cutaneous or mucous melanomas, vulvovaginal melanomas have historically been considered to be mucosal melanomas.

Vulvovaginal melanomas are characterized by a high mortality rate, diagnostic challenges, and lack of awareness, making early detection and intervention crucial to improving patient outcomes. The 5-year overall survival rate for vulvar melanoma is 36% and for vaginal melanoma ranges between 5% and 25%.² Survival rates for vulvovaginal melanomas are lower than for other types of vulvar cancers (72%) or for cutaneous melanomas (72%-81%).²

Racial disparities in survival rates for mucosal and cutaneous melanomas were highlighted in a retrospective study using the Surveillance Epidemiology and End Results (SEER) database. Although the number of Black patients included was small, the median overall survival in that population was less than that in non-Black patients with vulvovaginal melanoma (16 vs. 39 months). Similar findings were noted in Black patients with cutaneous melanoma, compared with non-Black patients (median overall survival, 124 vs 319 months).³

One of the most significant obstacles in the diagnosis of vulvar and vaginal melanoma is its rarity. Both patients and clinicians alike may fail to recognize early warning signs. In a world where skin cancer is heavily publicized, melanoma in the genital area is not as frequently discussed or understood. Postmenopausal patients may have less regular gynecologic care, and unless they present with specific symptoms prompting an exam, melanomas can grow undetected, progressing to more advanced stages before they are discovered.

The median age of patients diagnosed with vulvar and vaginal melanomas is 67-68.^4,5 Symptoms can be subtle and nonspecific. Women with vulvar melanoma may experience symptoms that are similar to other vulvar cancers including pruritus, irritation, pain, bleeding, or a new or growing mass. While vaginal melanoma can be asymptomatic, patients frequently present with vaginal bleeding, discharge, and/or pain (including dyspareunia).

Vulvovaginal melanomas may present differently than cutaneous melanomas. Vulvar melanomas are often pigmented and frequently present as ulcerated lesions. In some cases, though, they appear amelanotic (lacking pigment), making them even harder to identify. The ABCDEs of skin cancer (asymmetry, border, color, diameter, evolving) should be applied to these lesions. Change in the size, shape, or pigment of preexisting melanosis (areas of hyperpigmentation caused by increased melanin), should raise concern for possible malignant transformation. 

Most vaginal melanomas occur within the distal third of the vagina, frequently along the anterior vaginal wall.⁶ They can be polypoid or nodular in appearance and may be ulcerated. While biopsy of any suspicious, enlarging/changing, or symptomatic lesion should be performed, it may be prudent to pause prior to biopsy of a vaginal lesion depending on its appearance. Although rare, gestational trophoblastic neoplasia (GTN) can present with vaginal metastases, and these lesions are frequently very vascular and pose a high bleeding risk if biopsied. They may look dark blue or black. If there is any concern for metastatic GTN on vaginal exam, a beta-hCG level should be obtained prior to biopsy.

Treatment of vulvovaginal melanoma may include surgical excision, systemic therapy, radiation therapy, or a combination of treatments. There is growing use of immunotherapy that mirrors cutaneous melanoma therapy.

Vulvar and vaginal melanoma represent a rare yet serious health issue for women and their impact on public health should not be underestimated. Vulvovaginal melanoma often goes unrecognized until it has reached an advanced stage. Increased awareness about these rare forms of melanoma among both patients and healthcare professionals is vital to improve early detection and treatment outcomes. With greater attention to this disease, we can strive for better diagnostic methods, more effective treatments, and ultimately, a reduction in mortality rates associated with vulvar and vaginal melanoma.

Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no conflicts of interest.

References

1. National Cancer Institute. Cancer Stat Facts: Melanoma of the skin. 2024 Dec 2. Available from: https://seer.cancer.gov/statfacts/html/melan.html.

2. Piura B. Lancet Oncol. 2008 Oct;9(10):973-81. .

3. Mert I et al. Int J Gynecol Cancer. 2013;23(6):1118-25.

4. Wang D et al. Am J Cancer Res. 2020 Dec 1;10(12):4017-37.

5. Albert A et al. J Gynecol Oncol. 2020 Sep;31(5):e66.

The World Health Organization Regional Office for Europe (WHO/Europe) and the European Association for the Study of the Liver held a symposium on December 11 to establish the European Alcohol Health Alliance to reduce alcohol-related harms across Europe. 

Europe has the highest levels of alcohol consumption in the world. Alcohol is the continent’s leading cause of death, accounting for almost 800,000 deaths per year, or 1 in 11 deaths in the region. 

This news organization spoke with Frank Murray, MBBCh, a consultant gastroenterologist and hepatologist at Bon Secours Hospital and Beaumont Private Clinic in Dublin, Ireland, who attended the symposium. The intention is to launch the European Alcohol Health Alliance in 2025. 

“We’d like to see evidence-based policies to reduce alcohol harm, which we think would be good for individual citizens and the economy,” said Murray. 

The symposium brought together multiple professional societies to discuss problems related to alcohol use, possible solutions, and their willingness to collaborate. Murray noted that attendees were enthusiastic about forming an alliance. 

Among the alliance’s first priorities, he noted, are changing the pricing and availability of alcohol, implementing restrictions in marketing and advertising, protecting children from alcohol harm, and labeling products with health warnings. 

“It’s interesting that the most dangerous product in the supermarket is sold without any nutrition or content information and without any warnings,” he said. 

 

‘David and Goliath’ 

This news organization also spoke with Barbara Broers, MD, professor of addiction medicine at the University of Geneva in Switzerland, who did not attend the meeting. 

She noted that although methods for reducing alcohol intake are well known, little action is taken to implement them. The alcohol industry is a major reason for this, she said, because it will “do everything to keep its business going.” 

One tactic, according to Broers and Murray, is heavy governmental lobbying. The industry’s resources for lobbying and advocating greatly outweigh any counterforce in what Murray described as a “bit of a David and Goliath” situation. 

“The alcohol industry should not have any role in policy making for alcohol, because it has a conflict of interest that clearly gets in the way of giving public health advice. It wants to maximize profits, while public health requires policies to reduce alcohol consumption,” he noted. 

Among the aims of the European Alcohol Health Alliance is “to rebalance the battle between those advocating for and against alcohol,” he continued.

 

Public Misperceptions

Although alcohol’s harmful effects on the liver are well known, Broers and Murray noted that its other effects are less known. 

A 2024 study found that whereas 90% of Europeans are aware of alcohol’s causal role in liver disease, just 68% are aware of a causal role for heart diseases and 53% for cancer. And only 15% were aware of a causal link with female breast cancer, even though drinking alcohol causes up to 1 in 10 cases of breast cancer.

Adding to a general lack of public awareness, methodologically flawed research may have generated a false impression that moderate drinking is beneficial for health, according to a s ystematic review and meta-analysis of 107 longitudinal studies. 

Broers noted that more work must be done to increase public knowledge about the harmful effects of alcohol, and especially its link to cancer. “We now know that a person’s risk of cancer increases right from the first drink, but I think the people don’t know this,” she said. 

“Local context and culture have a significant impact on the prevalence of alcohol consumption within a population, as well as the pattern of alcohol consumption,” Andrew Smyth, MBBCh, PhD, professor of clinical epidemiology at the University of Galway in Ireland, told this news organization. 

“Each country, region, and area are likely to need culturally appropriate and socially acceptable solutions to overcome their own hurdles,” he added.

 

Normalizing Abstinence

“Alcohol is involved in our social lives in so many ways. Reducing it would be Sisyphus’s work,” said Bernhard Maisch, MD, professor at Philipps University of Marburg, Germany. 

Jelena Šarić Posavec, a former PhD student at the University of Ljubljana in Slovenia, said that, while numerous obstacles make addressing alcohol-related harms difficult in Europe, solutions exist, too. 

Broers noted, for example, that Germany is working to change social perceptions around not drinking. “No alcohol should be the norm and should be considered positive. People should know that they might feel much better if they don’t drink at all.” 

Short-term improvements from abstaining from alcohol may be felt in sleep and energy levels, with long-term health effects ranging from weight to liver health and cancer risk, she noted. The problem, she said, however, lies in how to communicate this message. 

Murray, Broers, Smyth, Maisch, and Posavec reported having no relevant financial relationships.

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

The World Health Organization Regional Office for Europe (WHO/Europe) and the European Association for the Study of the Liver held a symposium on December 11 to establish the European Alcohol Health Alliance to reduce alcohol-related harms across Europe. 

Europe has the highest levels of alcohol consumption in the world. Alcohol is the continent’s leading cause of death, accounting for almost 800,000 deaths per year, or 1 in 11 deaths in the region. 

This news organization spoke with Frank Murray, MBBCh, a consultant gastroenterologist and hepatologist at Bon Secours Hospital and Beaumont Private Clinic in Dublin, Ireland, who attended the symposium. The intention is to launch the European Alcohol Health Alliance in 2025. 

“We’d like to see evidence-based policies to reduce alcohol harm, which we think would be good for individual citizens and the economy,” said Murray. 

The symposium brought together multiple professional societies to discuss problems related to alcohol use, possible solutions, and their willingness to collaborate. Murray noted that attendees were enthusiastic about forming an alliance. 

Among the alliance’s first priorities, he noted, are changing the pricing and availability of alcohol, implementing restrictions in marketing and advertising, protecting children from alcohol harm, and labeling products with health warnings. 

“It’s interesting that the most dangerous product in the supermarket is sold without any nutrition or content information and without any warnings,” he said. 

 

‘David and Goliath’ 

This news organization also spoke with Barbara Broers, MD, professor of addiction medicine at the University of Geneva in Switzerland, who did not attend the meeting. 

She noted that although methods for reducing alcohol intake are well known, little action is taken to implement them. The alcohol industry is a major reason for this, she said, because it will “do everything to keep its business going.” 

One tactic, according to Broers and Murray, is heavy governmental lobbying. The industry’s resources for lobbying and advocating greatly outweigh any counterforce in what Murray described as a “bit of a David and Goliath” situation. 

“The alcohol industry should not have any role in policy making for alcohol, because it has a conflict of interest that clearly gets in the way of giving public health advice. It wants to maximize profits, while public health requires policies to reduce alcohol consumption,” he noted. 

Among the aims of the European Alcohol Health Alliance is “to rebalance the battle between those advocating for and against alcohol,” he continued.

 

Public Misperceptions

Although alcohol’s harmful effects on the liver are well known, Broers and Murray noted that its other effects are less known. 

A 2024 study found that whereas 90% of Europeans are aware of alcohol’s causal role in liver disease, just 68% are aware of a causal role for heart diseases and 53% for cancer. And only 15% were aware of a causal link with female breast cancer, even though drinking alcohol causes up to 1 in 10 cases of breast cancer.

Adding to a general lack of public awareness, methodologically flawed research may have generated a false impression that moderate drinking is beneficial for health, according to a s ystematic review and meta-analysis of 107 longitudinal studies. 

Broers noted that more work must be done to increase public knowledge about the harmful effects of alcohol, and especially its link to cancer. “We now know that a person’s risk of cancer increases right from the first drink, but I think the people don’t know this,” she said. 

“Local context and culture have a significant impact on the prevalence of alcohol consumption within a population, as well as the pattern of alcohol consumption,” Andrew Smyth, MBBCh, PhD, professor of clinical epidemiology at the University of Galway in Ireland, told this news organization. 

“Each country, region, and area are likely to need culturally appropriate and socially acceptable solutions to overcome their own hurdles,” he added.

 

Normalizing Abstinence

“Alcohol is involved in our social lives in so many ways. Reducing it would be Sisyphus’s work,” said Bernhard Maisch, MD, professor at Philipps University of Marburg, Germany. 

Jelena Šarić Posavec, a former PhD student at the University of Ljubljana in Slovenia, said that, while numerous obstacles make addressing alcohol-related harms difficult in Europe, solutions exist, too. 

Broers noted, for example, that Germany is working to change social perceptions around not drinking. “No alcohol should be the norm and should be considered positive. People should know that they might feel much better if they don’t drink at all.” 

Short-term improvements from abstaining from alcohol may be felt in sleep and energy levels, with long-term health effects ranging from weight to liver health and cancer risk, she noted. The problem, she said, however, lies in how to communicate this message. 

Murray, Broers, Smyth, Maisch, and Posavec reported having no relevant financial relationships.

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

The World Health Organization Regional Office for Europe (WHO/Europe) and the European Association for the Study of the Liver held a symposium on December 11 to establish the European Alcohol Health Alliance to reduce alcohol-related harms across Europe. 

Europe has the highest levels of alcohol consumption in the world. Alcohol is the continent’s leading cause of death, accounting for almost 800,000 deaths per year, or 1 in 11 deaths in the region. 

This news organization spoke with Frank Murray, MBBCh, a consultant gastroenterologist and hepatologist at Bon Secours Hospital and Beaumont Private Clinic in Dublin, Ireland, who attended the symposium. The intention is to launch the European Alcohol Health Alliance in 2025. 

“We’d like to see evidence-based policies to reduce alcohol harm, which we think would be good for individual citizens and the economy,” said Murray. 

The symposium brought together multiple professional societies to discuss problems related to alcohol use, possible solutions, and their willingness to collaborate. Murray noted that attendees were enthusiastic about forming an alliance. 

Among the alliance’s first priorities, he noted, are changing the pricing and availability of alcohol, implementing restrictions in marketing and advertising, protecting children from alcohol harm, and labeling products with health warnings. 

“It’s interesting that the most dangerous product in the supermarket is sold without any nutrition or content information and without any warnings,” he said. 

 

‘David and Goliath’ 

This news organization also spoke with Barbara Broers, MD, professor of addiction medicine at the University of Geneva in Switzerland, who did not attend the meeting. 

She noted that although methods for reducing alcohol intake are well known, little action is taken to implement them. The alcohol industry is a major reason for this, she said, because it will “do everything to keep its business going.” 

One tactic, according to Broers and Murray, is heavy governmental lobbying. The industry’s resources for lobbying and advocating greatly outweigh any counterforce in what Murray described as a “bit of a David and Goliath” situation. 

“The alcohol industry should not have any role in policy making for alcohol, because it has a conflict of interest that clearly gets in the way of giving public health advice. It wants to maximize profits, while public health requires policies to reduce alcohol consumption,” he noted. 

Among the aims of the European Alcohol Health Alliance is “to rebalance the battle between those advocating for and against alcohol,” he continued.

 

Public Misperceptions

Although alcohol’s harmful effects on the liver are well known, Broers and Murray noted that its other effects are less known. 

A 2024 study found that whereas 90% of Europeans are aware of alcohol’s causal role in liver disease, just 68% are aware of a causal role for heart diseases and 53% for cancer. And only 15% were aware of a causal link with female breast cancer, even though drinking alcohol causes up to 1 in 10 cases of breast cancer.

Adding to a general lack of public awareness, methodologically flawed research may have generated a false impression that moderate drinking is beneficial for health, according to a s ystematic review and meta-analysis of 107 longitudinal studies. 

Broers noted that more work must be done to increase public knowledge about the harmful effects of alcohol, and especially its link to cancer. “We now know that a person’s risk of cancer increases right from the first drink, but I think the people don’t know this,” she said. 

“Local context and culture have a significant impact on the prevalence of alcohol consumption within a population, as well as the pattern of alcohol consumption,” Andrew Smyth, MBBCh, PhD, professor of clinical epidemiology at the University of Galway in Ireland, told this news organization. 

“Each country, region, and area are likely to need culturally appropriate and socially acceptable solutions to overcome their own hurdles,” he added.

 

Normalizing Abstinence

“Alcohol is involved in our social lives in so many ways. Reducing it would be Sisyphus’s work,” said Bernhard Maisch, MD, professor at Philipps University of Marburg, Germany. 

Jelena Šarić Posavec, a former PhD student at the University of Ljubljana in Slovenia, said that, while numerous obstacles make addressing alcohol-related harms difficult in Europe, solutions exist, too. 

Broers noted, for example, that Germany is working to change social perceptions around not drinking. “No alcohol should be the norm and should be considered positive. People should know that they might feel much better if they don’t drink at all.” 

Short-term improvements from abstaining from alcohol may be felt in sleep and energy levels, with long-term health effects ranging from weight to liver health and cancer risk, she noted. The problem, she said, however, lies in how to communicate this message. 

Murray, Broers, Smyth, Maisch, and Posavec reported having no relevant financial relationships.

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

While fewer than 10% of US physicians are unionized, the number of official union drives among private-sector doctors have skyrocketed in the last 2 years, compared with 2 decades prior, according to a new study. 

Researchers counted 21 union drives in 2023 and 12 in the first 5 months of 2024, compared with 0-6 drives each year between 2000 and 2022. 

If the 2023 and 2024 drives succeed, unions will represent 3523 new physicians — nearly equal to the 3541 doctors who sought unionization between 2000 and 2022.

“We were able to document a significant uptick in union petitions and success in certification drives,” said corresponding author Hayden Rooke-Ley, JD, of the Center for Advancing Health Policy Through Research, Brown University School of Public Health, Providence, Rhode Island. “We were surprised to see such a marked shift in 2023.”

About 72,000 physicians, an estimated 8% of all US doctors, are covered by unions, including some in the public sector. Physicians who are self-employed, now comprising less than a fifth of all doctors, are not eligible to join labor unions.

The study authors launched their research to better understand trends in physician unionization in light of high-profile union drives, especially among residents. Rooke-Ley said: “We suspected that declining morale and increased corporate employment for physicians were leading them to consider unionization.”

The researchers gathered data from the National Labor Relations Board about union drives by potential bargaining units that included physicians. From 2000 to 2022, 44 union petitions were filed. The number jumped to 33 from 2023-2024. 

 

“Tip of the Iceberg”

“This is the tip of the iceberg,” said ethicist Joseph F. Kras, MD, DDS, MA, an associate professor of anesthesiology at Washington University in St. Louis, Missouri, and corresponding author of a recent Anesthesia & Analgesia report about physician unionization.

“We are independent by nature,” Kras said. “But when you put us in an employed environment and start treating us as widgets, then we will act like employees of Amazon, Starbucks, and other companies and join together to push back against the increasing emphasis on profit over all at the expense of our independent judgment on what’s best for the patient.”

Of the 66 unionization efforts between 2000 and 2024 that were decided, 62% were certified, according to the JAMA study. The drives targeted hospitals (49%), community health centers (38%), and nonhospital corporate owners (13%).

The researchers only analyzed private-sector unionization and did not include physicians who are unionized at public institutions. 

 

What’s Behind Union Drives?

Alyssa Burgart, MD, MA, an ethicist and clinical associate professor of anesthesiology and pediatrics at Stanford University in California, told this news organization that physician unionization “is a big topic with a lot of really strong opinions.” 

Many doctors wrongly assume they can’t unionize because they’re physicians, said Burgart, a coauthor of the Anesthesia & Analgesia report.

Supporters of unionization believe it’s a strategy to be “recognized not as simply as a single physician with a concern,” she said. “When you’re among clinicians who can speak as a more unified group, organizations are more likely to take that seriously.”

A union may also be able to hold employers to account in areas such as the gender wage gap, sexual harassment, and bias in hiring and firing, Burgart said. And union supporters believe they’ll make more money if they collectively bargain. 

Other factors driving interest in unions include “increasing physician burnout, increasing physician exhaustion, and immense frustration with the ways that private equity is influencing how physicians need to work in order to practice,” she said. 

Earlier in 2024, physicians in Delaware’s ChristianaCare health system voted 288-130 to be represented by Doctors Council/Service Employees International, according to the union. 

“We have still not been able to staff up enough to where us physicians can get back to just focusing on taking care of patients,” a unionization leader told WHYY. 

The JAMA study examined news reports regarding most of the 2023-2024 union drives and found that supporters claimed they were motivated by working conditions (85%), lack of voice in management (81%), patient care concerns (54%), and pay (4%).

 

Critics Worry They’ll Lose Pay Because of Unions

Skeptics of unionization worry about whether “I’m going to be required to stand by some union stance that is actually out of alignment with my values as a physician,” Burgart said. And, she said, critics such as highly paid surgeons fear that adjustments to salaries because of union contracts could cause them to lose income.

In regard to compensation, a 2024 study surveyed unionized residents — along with faculty and staff — at general surgery programs and found evidence that unionization didn’t improve resident well-being or benefits, although it “provided a mechanism for resident voice and agency.”

“It is critical to study the outcomes of those who unionized to ensure that the reasons for unionizing were realized over time,” said that study’s coauthor Karl Bilimoria, MD, MS, chair of surgery at Indiana University School of Medicine, Indianapolis. “The unintended consequences of unionization must be examined along with the potential improvements.”

Rooke-Ley discloses consulting fees from the American Economic Liberties Project, National Academy of State Health Policy, and 32BJ Funds. Kras and Burgart disclose previous union membership. Bilimoria has no disclosures.

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

While fewer than 10% of US physicians are unionized, the number of official union drives among private-sector doctors have skyrocketed in the last 2 years, compared with 2 decades prior, according to a new study. 

Researchers counted 21 union drives in 2023 and 12 in the first 5 months of 2024, compared with 0-6 drives each year between 2000 and 2022. 

If the 2023 and 2024 drives succeed, unions will represent 3523 new physicians — nearly equal to the 3541 doctors who sought unionization between 2000 and 2022.

“We were able to document a significant uptick in union petitions and success in certification drives,” said corresponding author Hayden Rooke-Ley, JD, of the Center for Advancing Health Policy Through Research, Brown University School of Public Health, Providence, Rhode Island. “We were surprised to see such a marked shift in 2023.”

About 72,000 physicians, an estimated 8% of all US doctors, are covered by unions, including some in the public sector. Physicians who are self-employed, now comprising less than a fifth of all doctors, are not eligible to join labor unions.

The study authors launched their research to better understand trends in physician unionization in light of high-profile union drives, especially among residents. Rooke-Ley said: “We suspected that declining morale and increased corporate employment for physicians were leading them to consider unionization.”

The researchers gathered data from the National Labor Relations Board about union drives by potential bargaining units that included physicians. From 2000 to 2022, 44 union petitions were filed. The number jumped to 33 from 2023-2024. 

 

“Tip of the Iceberg”

“This is the tip of the iceberg,” said ethicist Joseph F. Kras, MD, DDS, MA, an associate professor of anesthesiology at Washington University in St. Louis, Missouri, and corresponding author of a recent Anesthesia & Analgesia report about physician unionization.

“We are independent by nature,” Kras said. “But when you put us in an employed environment and start treating us as widgets, then we will act like employees of Amazon, Starbucks, and other companies and join together to push back against the increasing emphasis on profit over all at the expense of our independent judgment on what’s best for the patient.”

Of the 66 unionization efforts between 2000 and 2024 that were decided, 62% were certified, according to the JAMA study. The drives targeted hospitals (49%), community health centers (38%), and nonhospital corporate owners (13%).

The researchers only analyzed private-sector unionization and did not include physicians who are unionized at public institutions. 

 

What’s Behind Union Drives?

Alyssa Burgart, MD, MA, an ethicist and clinical associate professor of anesthesiology and pediatrics at Stanford University in California, told this news organization that physician unionization “is a big topic with a lot of really strong opinions.” 

Many doctors wrongly assume they can’t unionize because they’re physicians, said Burgart, a coauthor of the Anesthesia & Analgesia report.

Supporters of unionization believe it’s a strategy to be “recognized not as simply as a single physician with a concern,” she said. “When you’re among clinicians who can speak as a more unified group, organizations are more likely to take that seriously.”

A union may also be able to hold employers to account in areas such as the gender wage gap, sexual harassment, and bias in hiring and firing, Burgart said. And union supporters believe they’ll make more money if they collectively bargain. 

Other factors driving interest in unions include “increasing physician burnout, increasing physician exhaustion, and immense frustration with the ways that private equity is influencing how physicians need to work in order to practice,” she said. 

Earlier in 2024, physicians in Delaware’s ChristianaCare health system voted 288-130 to be represented by Doctors Council/Service Employees International, according to the union. 

“We have still not been able to staff up enough to where us physicians can get back to just focusing on taking care of patients,” a unionization leader told WHYY. 

The JAMA study examined news reports regarding most of the 2023-2024 union drives and found that supporters claimed they were motivated by working conditions (85%), lack of voice in management (81%), patient care concerns (54%), and pay (4%).

 

Critics Worry They’ll Lose Pay Because of Unions

Skeptics of unionization worry about whether “I’m going to be required to stand by some union stance that is actually out of alignment with my values as a physician,” Burgart said. And, she said, critics such as highly paid surgeons fear that adjustments to salaries because of union contracts could cause them to lose income.

In regard to compensation, a 2024 study surveyed unionized residents — along with faculty and staff — at general surgery programs and found evidence that unionization didn’t improve resident well-being or benefits, although it “provided a mechanism for resident voice and agency.”

“It is critical to study the outcomes of those who unionized to ensure that the reasons for unionizing were realized over time,” said that study’s coauthor Karl Bilimoria, MD, MS, chair of surgery at Indiana University School of Medicine, Indianapolis. “The unintended consequences of unionization must be examined along with the potential improvements.”

Rooke-Ley discloses consulting fees from the American Economic Liberties Project, National Academy of State Health Policy, and 32BJ Funds. Kras and Burgart disclose previous union membership. Bilimoria has no disclosures.

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

While fewer than 10% of US physicians are unionized, the number of official union drives among private-sector doctors have skyrocketed in the last 2 years, compared with 2 decades prior, according to a new study. 

Researchers counted 21 union drives in 2023 and 12 in the first 5 months of 2024, compared with 0-6 drives each year between 2000 and 2022. 

If the 2023 and 2024 drives succeed, unions will represent 3523 new physicians — nearly equal to the 3541 doctors who sought unionization between 2000 and 2022.

“We were able to document a significant uptick in union petitions and success in certification drives,” said corresponding author Hayden Rooke-Ley, JD, of the Center for Advancing Health Policy Through Research, Brown University School of Public Health, Providence, Rhode Island. “We were surprised to see such a marked shift in 2023.”

About 72,000 physicians, an estimated 8% of all US doctors, are covered by unions, including some in the public sector. Physicians who are self-employed, now comprising less than a fifth of all doctors, are not eligible to join labor unions.

The study authors launched their research to better understand trends in physician unionization in light of high-profile union drives, especially among residents. Rooke-Ley said: “We suspected that declining morale and increased corporate employment for physicians were leading them to consider unionization.”

The researchers gathered data from the National Labor Relations Board about union drives by potential bargaining units that included physicians. From 2000 to 2022, 44 union petitions were filed. The number jumped to 33 from 2023-2024. 

 

“Tip of the Iceberg”

“This is the tip of the iceberg,” said ethicist Joseph F. Kras, MD, DDS, MA, an associate professor of anesthesiology at Washington University in St. Louis, Missouri, and corresponding author of a recent Anesthesia & Analgesia report about physician unionization.

“We are independent by nature,” Kras said. “But when you put us in an employed environment and start treating us as widgets, then we will act like employees of Amazon, Starbucks, and other companies and join together to push back against the increasing emphasis on profit over all at the expense of our independent judgment on what’s best for the patient.”

Of the 66 unionization efforts between 2000 and 2024 that were decided, 62% were certified, according to the JAMA study. The drives targeted hospitals (49%), community health centers (38%), and nonhospital corporate owners (13%).

The researchers only analyzed private-sector unionization and did not include physicians who are unionized at public institutions. 

 

What’s Behind Union Drives?

Alyssa Burgart, MD, MA, an ethicist and clinical associate professor of anesthesiology and pediatrics at Stanford University in California, told this news organization that physician unionization “is a big topic with a lot of really strong opinions.” 

Many doctors wrongly assume they can’t unionize because they’re physicians, said Burgart, a coauthor of the Anesthesia & Analgesia report.

Supporters of unionization believe it’s a strategy to be “recognized not as simply as a single physician with a concern,” she said. “When you’re among clinicians who can speak as a more unified group, organizations are more likely to take that seriously.”

A union may also be able to hold employers to account in areas such as the gender wage gap, sexual harassment, and bias in hiring and firing, Burgart said. And union supporters believe they’ll make more money if they collectively bargain. 

Other factors driving interest in unions include “increasing physician burnout, increasing physician exhaustion, and immense frustration with the ways that private equity is influencing how physicians need to work in order to practice,” she said. 

Earlier in 2024, physicians in Delaware’s ChristianaCare health system voted 288-130 to be represented by Doctors Council/Service Employees International, according to the union. 

“We have still not been able to staff up enough to where us physicians can get back to just focusing on taking care of patients,” a unionization leader told WHYY. 

The JAMA study examined news reports regarding most of the 2023-2024 union drives and found that supporters claimed they were motivated by working conditions (85%), lack of voice in management (81%), patient care concerns (54%), and pay (4%).

 

Critics Worry They’ll Lose Pay Because of Unions

Skeptics of unionization worry about whether “I’m going to be required to stand by some union stance that is actually out of alignment with my values as a physician,” Burgart said. And, she said, critics such as highly paid surgeons fear that adjustments to salaries because of union contracts could cause them to lose income.

In regard to compensation, a 2024 study surveyed unionized residents — along with faculty and staff — at general surgery programs and found evidence that unionization didn’t improve resident well-being or benefits, although it “provided a mechanism for resident voice and agency.”

“It is critical to study the outcomes of those who unionized to ensure that the reasons for unionizing were realized over time,” said that study’s coauthor Karl Bilimoria, MD, MS, chair of surgery at Indiana University School of Medicine, Indianapolis. “The unintended consequences of unionization must be examined along with the potential improvements.”

Rooke-Ley discloses consulting fees from the American Economic Liberties Project, National Academy of State Health Policy, and 32BJ Funds. Kras and Burgart disclose previous union membership. Bilimoria has no disclosures.

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

Interleukin-6 receptor (IL-6r) inhibition is a promising approach for the treatment of calcium pyrophosphate deposition disease (CPPD), although no prospective studies have been conducted to date. Nevertheless, a retrospective analysis of patients treated with the IL-6r inhibitor tocilizumab, presented at American College of Rheumatology (ACR) 2024 Annual Meeting, showed improved CPPD control in more than two thirds of patients who had failed or could not tolerate usual therapies.

Both the monosodium urate (MSU) crystals associated with gout and CPP crystals induce inflammation dependent on IL-1 beta, but IL-1 beta inhibitors have been investigated more as treatments for gout than for CPPD, and they are recommended by both ACR and European Alliance of Associations for Rheumatology (EULAR) guidelines for patients with gout who have flares despite efforts to treat with colchicine, nonsteroidal anti-inflammatory drugs, and corticosteroids. However, IL-1 beta inhibitors are sometimes used off label in CPPD.

There are similarities among the various crystal types that induce arthritis, typically producing similar clinical features of acute arthritis and severe pain and local inflammation and tending to self-resolve within days to weeks. Those shared clinical features suggest common inflammatory mechanisms, likely stemming from the innate immune system, said Augustin Latourte, MD, PhD, of Lariboisière Hospital, Paris, France, during a talk on the topic at the annual research symposium of the Gout Hyperuricemia and Crystal-Associated Disease Network (G-CAN).

CPPD management is generally derived from strategies developed for gout, but there is little evidence supporting IL-1 beta inhibitors outside of case reports, he said. One clinical trial published in 2020 showed efficacy of the IL-1 inhibitor anakinra, but the study was halted due to low patient recruitment, resulting in a small study population. In that study, “anakinra seems to have a faster onset of action than prednisone and could be useful in specific situations regarding acute CPPD arthritis. But it’s not relevant for chronic CPPD arthritis when you have persistent polyarthritis requiring chronic treatment. Anakinra requires daily injections and may not be appropriate in this situation,” he said.

IL-6r inhibition has been studied since IL-6 was first discovered in 1989 as a mediator of inflammatory responses in gout and CPPD, when it was shown that both CPP and MSU crystals can stimulate its production. In monocytes, IL-6 is expressed at higher levels than IL-1 beta in response to both CPP and MSU crystals. IL-6 production in monocytes in response to crystals is dependent on IL-1, and IL-1 inhibition reduces IL-6 production. “So the hypothesis is that IL-1 beta is the first event, and the production of IL-6 and the amplification of crystal inflammation occurs downstream before the self-limitation of the crystal-induced arthritis. IL-6 may be a very important event in the onset of crystal-induced inflammation,” Latourte said.

 

Building on Mechanistic Insights to Test Off-Label Use of Tocilizumab

Inspired by this insight, Latourte’s group tested tocilizumab in a 28-year-old man with a familial ANKH mutation who had not responded to anakinra and other conventional treatments. The patient experienced a reduction in flare intensity in the first month after the initial treatment and no flares after the second tocilizumab infusion. The group went on to test tocilizumab in 10 additional patients with CPPD (median age, 62.5 years), including 6 with idiopathic CPPD, 3 with Gitelman syndrome, and 1 with ANKH mutation. The clinical presentation included four with recurrent acute arthritis and six with chronic polyarthritis, and all had x-ray–proven disease, with a median visual analog scale (VAS) of 60 mm out of 100 mm. Tocilizumab was administered intravenously or subcutaneously. At 3 months, there was a median improvement of 30 mm in the VAS. Treatment efficacy continued for a median follow-up of 5.5 months at the time of publication, and the researchers have noted ongoing efficacy out to 50 months for some patients.

Tocilizumab has gone on to more frequent use in Europe as a second- or third-line therapy for CPPD, which led Latourte and his colleagues to perform the retrospective analysis that they presented at the ACR meeting. It included 55 patients who received tocilizumab for chronic inflammatory CPPD at two university hospitals. Participants had a median age of 72 years, and 67.3% were women. The patient group included 39 with chronic CPPD, 14 with recurrent acute CPPD (who experienced 0-4 attacks per month), and two patients with mixed CPPD. All participants had been treated with colchicine, and 20 had been treated also with prednisone and 24 with anakinra. Patients had stopped anakinra because it was either ineffective (n = 13) or poorly tolerated (n = 11).

Tocilizumab was administered intravenously in 46 patients and subcutaneously in nine patients for a median duration of 16.5 months (range, 0.8-76.4 months). The median VAS for pain (0- to 100-mm scale) dropped from 60 mm at baseline to 40 mm at 3 months and 30 mm at 6 months. There were 21 adverse events, including 8 cytopenias, 6 transaminase elevations, 4 infections (two severe), and 3 injection-site reactions. After a median of 7.8 months, 26 patients discontinued tocilizumab because of lack of efficacy in 15 patients and intolerance in 11. Among those who continued on tocilizumab, the median length of treatment was 26.0 months (range, 3-76.5 months).

 

Comments on the Study

The study population had some unusual characteristics, according to G-CAN President Robert Terkeltaub, MD, who was asked to comment on the study. “Almost half the patients had received anakinra and then, basically, they failed. In about half of the people who got anakinra, it didn’t work, and in the other half, it wasn’t well tolerated. It’s just rather odd. I find anakinra reasonably well tolerated by people, but we’re dealing with an older population of patients, and the subcutaneous administration of anakinra sometimes can give you injection site reactions, but people started off with a pain level that was close to what we register as severe pain, and the pain level decreased,” he said.

Treatment decisions can be difficult in patients with chronic or acute recurrent CPPD, said Terkeltaub, professor of medicine at the University of California, San Diego. “What’s the lesser evil? Putting people on chronic prednisone is really hard on patients or using a biologic that’s more of an immunologic scalpel here, and more selective, and trying to get people through a long course of therapy. If you have chronic arthritis, it took a while for it to get chronic, and it generally doesn’t go away overnight.”

Terkeltaub also pointed out the gastrointestinal side effects of IL-6r inhibitors, which can include diverticulitis, but there are also concerns over infections and lipid and liver abnormalities. Subcutaneously injected tocilizumab also has a longer half-life than something like anakinra.

Beyond the retrospective nature of the study and the limits it imposes on conclusions that can be drawn, Terkeltaub noted a lack of data on the number of “inflamed joints [in each patient] and what the functioning of the patients was.”

Still, the findings are encouraging. “What I can glean from this study is that the first biologic drug might be an IL-6 inhibitor, but you really need prospective, controlled, blinded clinical trials to know, and it’s hard. It’s just hard to do those trials” because patients tend to be of advanced age, Terkeltaub said.

Latourte said a randomized controlled trial of tocilizumab vs placebo, called TociCCAre, is planned to begin in France in 2025.

Latourte has financial relationships with Fresenius Kabi, Roche Chugai, AbbVie, Arsylab, Celltrion, Janssen, Nordic, Pfizer, UCB, Amgen, Biogen, Galapagos, and Eli Lilly. Terkeltaub had no relevant financial disclosures.

A version of this article appeared on Medscape.com.

Interleukin-6 receptor (IL-6r) inhibition is a promising approach for the treatment of calcium pyrophosphate deposition disease (CPPD), although no prospective studies have been conducted to date. Nevertheless, a retrospective analysis of patients treated with the IL-6r inhibitor tocilizumab, presented at American College of Rheumatology (ACR) 2024 Annual Meeting, showed improved CPPD control in more than two thirds of patients who had failed or could not tolerate usual therapies.

Both the monosodium urate (MSU) crystals associated with gout and CPP crystals induce inflammation dependent on IL-1 beta, but IL-1 beta inhibitors have been investigated more as treatments for gout than for CPPD, and they are recommended by both ACR and European Alliance of Associations for Rheumatology (EULAR) guidelines for patients with gout who have flares despite efforts to treat with colchicine, nonsteroidal anti-inflammatory drugs, and corticosteroids. However, IL-1 beta inhibitors are sometimes used off label in CPPD.

There are similarities among the various crystal types that induce arthritis, typically producing similar clinical features of acute arthritis and severe pain and local inflammation and tending to self-resolve within days to weeks. Those shared clinical features suggest common inflammatory mechanisms, likely stemming from the innate immune system, said Augustin Latourte, MD, PhD, of Lariboisière Hospital, Paris, France, during a talk on the topic at the annual research symposium of the Gout Hyperuricemia and Crystal-Associated Disease Network (G-CAN).

CPPD management is generally derived from strategies developed for gout, but there is little evidence supporting IL-1 beta inhibitors outside of case reports, he said. One clinical trial published in 2020 showed efficacy of the IL-1 inhibitor anakinra, but the study was halted due to low patient recruitment, resulting in a small study population. In that study, “anakinra seems to have a faster onset of action than prednisone and could be useful in specific situations regarding acute CPPD arthritis. But it’s not relevant for chronic CPPD arthritis when you have persistent polyarthritis requiring chronic treatment. Anakinra requires daily injections and may not be appropriate in this situation,” he said.

IL-6r inhibition has been studied since IL-6 was first discovered in 1989 as a mediator of inflammatory responses in gout and CPPD, when it was shown that both CPP and MSU crystals can stimulate its production. In monocytes, IL-6 is expressed at higher levels than IL-1 beta in response to both CPP and MSU crystals. IL-6 production in monocytes in response to crystals is dependent on IL-1, and IL-1 inhibition reduces IL-6 production. “So the hypothesis is that IL-1 beta is the first event, and the production of IL-6 and the amplification of crystal inflammation occurs downstream before the self-limitation of the crystal-induced arthritis. IL-6 may be a very important event in the onset of crystal-induced inflammation,” Latourte said.

 

Building on Mechanistic Insights to Test Off-Label Use of Tocilizumab

Inspired by this insight, Latourte’s group tested tocilizumab in a 28-year-old man with a familial ANKH mutation who had not responded to anakinra and other conventional treatments. The patient experienced a reduction in flare intensity in the first month after the initial treatment and no flares after the second tocilizumab infusion. The group went on to test tocilizumab in 10 additional patients with CPPD (median age, 62.5 years), including 6 with idiopathic CPPD, 3 with Gitelman syndrome, and 1 with ANKH mutation. The clinical presentation included four with recurrent acute arthritis and six with chronic polyarthritis, and all had x-ray–proven disease, with a median visual analog scale (VAS) of 60 mm out of 100 mm. Tocilizumab was administered intravenously or subcutaneously. At 3 months, there was a median improvement of 30 mm in the VAS. Treatment efficacy continued for a median follow-up of 5.5 months at the time of publication, and the researchers have noted ongoing efficacy out to 50 months for some patients.

Tocilizumab has gone on to more frequent use in Europe as a second- or third-line therapy for CPPD, which led Latourte and his colleagues to perform the retrospective analysis that they presented at the ACR meeting. It included 55 patients who received tocilizumab for chronic inflammatory CPPD at two university hospitals. Participants had a median age of 72 years, and 67.3% were women. The patient group included 39 with chronic CPPD, 14 with recurrent acute CPPD (who experienced 0-4 attacks per month), and two patients with mixed CPPD. All participants had been treated with colchicine, and 20 had been treated also with prednisone and 24 with anakinra. Patients had stopped anakinra because it was either ineffective (n = 13) or poorly tolerated (n = 11).

Tocilizumab was administered intravenously in 46 patients and subcutaneously in nine patients for a median duration of 16.5 months (range, 0.8-76.4 months). The median VAS for pain (0- to 100-mm scale) dropped from 60 mm at baseline to 40 mm at 3 months and 30 mm at 6 months. There were 21 adverse events, including 8 cytopenias, 6 transaminase elevations, 4 infections (two severe), and 3 injection-site reactions. After a median of 7.8 months, 26 patients discontinued tocilizumab because of lack of efficacy in 15 patients and intolerance in 11. Among those who continued on tocilizumab, the median length of treatment was 26.0 months (range, 3-76.5 months).

 

Comments on the Study

The study population had some unusual characteristics, according to G-CAN President Robert Terkeltaub, MD, who was asked to comment on the study. “Almost half the patients had received anakinra and then, basically, they failed. In about half of the people who got anakinra, it didn’t work, and in the other half, it wasn’t well tolerated. It’s just rather odd. I find anakinra reasonably well tolerated by people, but we’re dealing with an older population of patients, and the subcutaneous administration of anakinra sometimes can give you injection site reactions, but people started off with a pain level that was close to what we register as severe pain, and the pain level decreased,” he said.

Treatment decisions can be difficult in patients with chronic or acute recurrent CPPD, said Terkeltaub, professor of medicine at the University of California, San Diego. “What’s the lesser evil? Putting people on chronic prednisone is really hard on patients or using a biologic that’s more of an immunologic scalpel here, and more selective, and trying to get people through a long course of therapy. If you have chronic arthritis, it took a while for it to get chronic, and it generally doesn’t go away overnight.”

Terkeltaub also pointed out the gastrointestinal side effects of IL-6r inhibitors, which can include diverticulitis, but there are also concerns over infections and lipid and liver abnormalities. Subcutaneously injected tocilizumab also has a longer half-life than something like anakinra.

Beyond the retrospective nature of the study and the limits it imposes on conclusions that can be drawn, Terkeltaub noted a lack of data on the number of “inflamed joints [in each patient] and what the functioning of the patients was.”

Still, the findings are encouraging. “What I can glean from this study is that the first biologic drug might be an IL-6 inhibitor, but you really need prospective, controlled, blinded clinical trials to know, and it’s hard. It’s just hard to do those trials” because patients tend to be of advanced age, Terkeltaub said.

Latourte said a randomized controlled trial of tocilizumab vs placebo, called TociCCAre, is planned to begin in France in 2025.

Latourte has financial relationships with Fresenius Kabi, Roche Chugai, AbbVie, Arsylab, Celltrion, Janssen, Nordic, Pfizer, UCB, Amgen, Biogen, Galapagos, and Eli Lilly. Terkeltaub had no relevant financial disclosures.

A version of this article appeared on Medscape.com.

Interleukin-6 receptor (IL-6r) inhibition is a promising approach for the treatment of calcium pyrophosphate deposition disease (CPPD), although no prospective studies have been conducted to date. Nevertheless, a retrospective analysis of patients treated with the IL-6r inhibitor tocilizumab, presented at American College of Rheumatology (ACR) 2024 Annual Meeting, showed improved CPPD control in more than two thirds of patients who had failed or could not tolerate usual therapies.

Both the monosodium urate (MSU) crystals associated with gout and CPP crystals induce inflammation dependent on IL-1 beta, but IL-1 beta inhibitors have been investigated more as treatments for gout than for CPPD, and they are recommended by both ACR and European Alliance of Associations for Rheumatology (EULAR) guidelines for patients with gout who have flares despite efforts to treat with colchicine, nonsteroidal anti-inflammatory drugs, and corticosteroids. However, IL-1 beta inhibitors are sometimes used off label in CPPD.

There are similarities among the various crystal types that induce arthritis, typically producing similar clinical features of acute arthritis and severe pain and local inflammation and tending to self-resolve within days to weeks. Those shared clinical features suggest common inflammatory mechanisms, likely stemming from the innate immune system, said Augustin Latourte, MD, PhD, of Lariboisière Hospital, Paris, France, during a talk on the topic at the annual research symposium of the Gout Hyperuricemia and Crystal-Associated Disease Network (G-CAN).

CPPD management is generally derived from strategies developed for gout, but there is little evidence supporting IL-1 beta inhibitors outside of case reports, he said. One clinical trial published in 2020 showed efficacy of the IL-1 inhibitor anakinra, but the study was halted due to low patient recruitment, resulting in a small study population. In that study, “anakinra seems to have a faster onset of action than prednisone and could be useful in specific situations regarding acute CPPD arthritis. But it’s not relevant for chronic CPPD arthritis when you have persistent polyarthritis requiring chronic treatment. Anakinra requires daily injections and may not be appropriate in this situation,” he said.

IL-6r inhibition has been studied since IL-6 was first discovered in 1989 as a mediator of inflammatory responses in gout and CPPD, when it was shown that both CPP and MSU crystals can stimulate its production. In monocytes, IL-6 is expressed at higher levels than IL-1 beta in response to both CPP and MSU crystals. IL-6 production in monocytes in response to crystals is dependent on IL-1, and IL-1 inhibition reduces IL-6 production. “So the hypothesis is that IL-1 beta is the first event, and the production of IL-6 and the amplification of crystal inflammation occurs downstream before the self-limitation of the crystal-induced arthritis. IL-6 may be a very important event in the onset of crystal-induced inflammation,” Latourte said.

 

Building on Mechanistic Insights to Test Off-Label Use of Tocilizumab

Inspired by this insight, Latourte’s group tested tocilizumab in a 28-year-old man with a familial ANKH mutation who had not responded to anakinra and other conventional treatments. The patient experienced a reduction in flare intensity in the first month after the initial treatment and no flares after the second tocilizumab infusion. The group went on to test tocilizumab in 10 additional patients with CPPD (median age, 62.5 years), including 6 with idiopathic CPPD, 3 with Gitelman syndrome, and 1 with ANKH mutation. The clinical presentation included four with recurrent acute arthritis and six with chronic polyarthritis, and all had x-ray–proven disease, with a median visual analog scale (VAS) of 60 mm out of 100 mm. Tocilizumab was administered intravenously or subcutaneously. At 3 months, there was a median improvement of 30 mm in the VAS. Treatment efficacy continued for a median follow-up of 5.5 months at the time of publication, and the researchers have noted ongoing efficacy out to 50 months for some patients.

Tocilizumab has gone on to more frequent use in Europe as a second- or third-line therapy for CPPD, which led Latourte and his colleagues to perform the retrospective analysis that they presented at the ACR meeting. It included 55 patients who received tocilizumab for chronic inflammatory CPPD at two university hospitals. Participants had a median age of 72 years, and 67.3% were women. The patient group included 39 with chronic CPPD, 14 with recurrent acute CPPD (who experienced 0-4 attacks per month), and two patients with mixed CPPD. All participants had been treated with colchicine, and 20 had been treated also with prednisone and 24 with anakinra. Patients had stopped anakinra because it was either ineffective (n = 13) or poorly tolerated (n = 11).

Tocilizumab was administered intravenously in 46 patients and subcutaneously in nine patients for a median duration of 16.5 months (range, 0.8-76.4 months). The median VAS for pain (0- to 100-mm scale) dropped from 60 mm at baseline to 40 mm at 3 months and 30 mm at 6 months. There were 21 adverse events, including 8 cytopenias, 6 transaminase elevations, 4 infections (two severe), and 3 injection-site reactions. After a median of 7.8 months, 26 patients discontinued tocilizumab because of lack of efficacy in 15 patients and intolerance in 11. Among those who continued on tocilizumab, the median length of treatment was 26.0 months (range, 3-76.5 months).

 

Comments on the Study

The study population had some unusual characteristics, according to G-CAN President Robert Terkeltaub, MD, who was asked to comment on the study. “Almost half the patients had received anakinra and then, basically, they failed. In about half of the people who got anakinra, it didn’t work, and in the other half, it wasn’t well tolerated. It’s just rather odd. I find anakinra reasonably well tolerated by people, but we’re dealing with an older population of patients, and the subcutaneous administration of anakinra sometimes can give you injection site reactions, but people started off with a pain level that was close to what we register as severe pain, and the pain level decreased,” he said.

Treatment decisions can be difficult in patients with chronic or acute recurrent CPPD, said Terkeltaub, professor of medicine at the University of California, San Diego. “What’s the lesser evil? Putting people on chronic prednisone is really hard on patients or using a biologic that’s more of an immunologic scalpel here, and more selective, and trying to get people through a long course of therapy. If you have chronic arthritis, it took a while for it to get chronic, and it generally doesn’t go away overnight.”

Terkeltaub also pointed out the gastrointestinal side effects of IL-6r inhibitors, which can include diverticulitis, but there are also concerns over infections and lipid and liver abnormalities. Subcutaneously injected tocilizumab also has a longer half-life than something like anakinra.

Beyond the retrospective nature of the study and the limits it imposes on conclusions that can be drawn, Terkeltaub noted a lack of data on the number of “inflamed joints [in each patient] and what the functioning of the patients was.”

Still, the findings are encouraging. “What I can glean from this study is that the first biologic drug might be an IL-6 inhibitor, but you really need prospective, controlled, blinded clinical trials to know, and it’s hard. It’s just hard to do those trials” because patients tend to be of advanced age, Terkeltaub said.

Latourte said a randomized controlled trial of tocilizumab vs placebo, called TociCCAre, is planned to begin in France in 2025.

Latourte has financial relationships with Fresenius Kabi, Roche Chugai, AbbVie, Arsylab, Celltrion, Janssen, Nordic, Pfizer, UCB, Amgen, Biogen, Galapagos, and Eli Lilly. Terkeltaub had no relevant financial disclosures.

A version of this article appeared on Medscape.com.

XEN-D0501, a transient receptor potential vanilloid 1 (TRPV1) antagonist, is gaining attention for its potential as an oral tablet to treat type 2 diabetes, obesity, and cardiovascular diseases. Dorte X. Gram, PhD, founder of Pila Pharma, a Swedish pharmaceutical company investigating XEN-D0501, first noticed the connection more than 20 years ago as a researcher at Novo Nordisk. 

“In my very first experiments, I noticed that mice who would normally become diabetic didn’t get diabetes at all,” she said in an interview.

These surprising observations prompted Gram to investigate further the potential role of the TRPV1 receptor in regulating metabolism, leading her to file a patent and pursue the development of TRPV1 antagonists for obesity and related conditions. 

The company has received enough attention from investors that it witnessed a triple-digit percentage gain on the Nasdaq First North stock exchange in 2024.

While XEN-D0501 shows promise, researchers urge caution, as the drug is still in early development. “There is simply no quality human data to say anything about the possibilities for this pathway,” said John B. Dixon, PhD, professor at Iverson Health Innovation Research Institute, Swinburne University of Technology, Melbourne, Australia.

 

What Is TRPV1 and How Do TRPV1 Modulators Work? 

TRPV1 is a homotetrameric receptor with six transmembrane domains expressed primarily in sensory nerve fibers. It is responsible for detecting noxious signals, including heat and chemical irritants — particularly capsaicin, the active component of chili peppers.

TRPV1 mediates the sensation of burning pain, often associated with inflammation and heat exposure. It also helps detect and regulate body temperature and influences the release of inflammatory mediators. In the central nervous system, it affects synaptic function and plasticity.

Given TRPV1’s broad physiologic role, its modulation has potential for treating several conditions, including pain disorders, inflammation, and cardiovascular diseases. 

Studies have shown that activating TRPV1 can help counter diet-induced obesity by increasing thermogenesis in brown adipose tissue and improving metabolic activity. TRPV1 agonists such as capsaicin have been shown to reduce weight gain in high-fat-diet‒induced obese mice, with clinical trials further supporting its potential for decreasing body weight in people with overweight. 

For instance, a clinical trial showed that participants with obesity taking capsinoid supplementation for 12 weeks experienced a reduction in body weight compared with those who took a placebo. 

While TRPV1 agonists have been more commonly studied for obesity management, most studies involving antagonists have focused on pain relief, inflammation, and conditions like erythromelalgia rather than weight loss. 

However, some evidence suggests that TRPV1 antagonism may influence metabolism. For example, in one study, mice lacking TRPV1 were resistant to obesity, “but that is not sufficient [to come to any conclusion],” said Vincenzo Di Marzo, PhD, director of the Joint International Research Unit for the Chemical and Biomolecular Study of the Microbiome in Metabolic Health and Nutrition between the Consiglio Nazionale delle Ricerche, Italy, and Université Laval, Quebec City, Canada. He was not involved in the study.

Gram admits that the picture around the mechanism of action of TRPV1 modulators is unclear. “There is not a consensus in the literature about the effect of this receptor. Should it be agonized or should it be antagonized?” she said. 

 

What Is XEN-D0501?

XEN-D0501 is a novel selective TRPV1 antagonist, which Pila Pharma is developing for treating erythromelalgia, a rare condition that causes burning pain, redness, and hotness in the skin, especially the feet. It has received orphan-drug status for this indication in the United States. 

Initially, the company explored XEN-D0501 for treating overactive bladder, but the development of the drug for this condition has been discontinued. Now, attention has moved to investigating XEN-D0501 for its potential in treating type 2 diabetes, obesity, and cardiovascular disease.

Although phase 2a clinical trials showed that XEN-D0501 is generally well tolerated in healthy participants, it has been associated with several side effects, including hyperthermia and oral discomfort, thought to be due to TRPV1 antagonism at sensory nerve endings in the mouth, in addition to transient urinary retention and postvoiding residual volumes, indicating potential issues with bladder function.

Another phase 2a trial (PP-CT03) is planned to assess the maximum tolerable dose of XEN-D0501 in people with obesity and type 2 diabetes, focusing on safety and potential effects on body weight. Gram said that early data show these populations experience less hyperthermia than healthy participants. However, the mechanism behind it is still not understood. These studies also showed some positive effects on insulin sensitivity and a biomarker for heart failure.

“The company data provided so far for XEN-D0501 are promising but still too preliminary,” said Di Marzo.

The company is now planning a further 3-month-long dose-escalation study in people with obesity and diabetes. “If these studies show that the molecule is as efficacious and safe as we think it is, then it would make life a lot better for a lot of people because it is a tablet, not an injectable,” Gram said.

Also being explored by the company is the potential of the molecule for treating cardiovascular diseases, particularly abdominal aortic aneurysms, and as a potential nonopioid painkiller. 

Dixon and Di Marzo disclosed no relevant financial relationships. Gram is founder and CSO at Pila Pharma.

A version of this article appeared on Medscape.com.

XEN-D0501, a transient receptor potential vanilloid 1 (TRPV1) antagonist, is gaining attention for its potential as an oral tablet to treat type 2 diabetes, obesity, and cardiovascular diseases. Dorte X. Gram, PhD, founder of Pila Pharma, a Swedish pharmaceutical company investigating XEN-D0501, first noticed the connection more than 20 years ago as a researcher at Novo Nordisk. 

“In my very first experiments, I noticed that mice who would normally become diabetic didn’t get diabetes at all,” she said in an interview.

These surprising observations prompted Gram to investigate further the potential role of the TRPV1 receptor in regulating metabolism, leading her to file a patent and pursue the development of TRPV1 antagonists for obesity and related conditions. 

The company has received enough attention from investors that it witnessed a triple-digit percentage gain on the Nasdaq First North stock exchange in 2024.

While XEN-D0501 shows promise, researchers urge caution, as the drug is still in early development. “There is simply no quality human data to say anything about the possibilities for this pathway,” said John B. Dixon, PhD, professor at Iverson Health Innovation Research Institute, Swinburne University of Technology, Melbourne, Australia.

 

What Is TRPV1 and How Do TRPV1 Modulators Work? 

TRPV1 is a homotetrameric receptor with six transmembrane domains expressed primarily in sensory nerve fibers. It is responsible for detecting noxious signals, including heat and chemical irritants — particularly capsaicin, the active component of chili peppers.

TRPV1 mediates the sensation of burning pain, often associated with inflammation and heat exposure. It also helps detect and regulate body temperature and influences the release of inflammatory mediators. In the central nervous system, it affects synaptic function and plasticity.

Given TRPV1’s broad physiologic role, its modulation has potential for treating several conditions, including pain disorders, inflammation, and cardiovascular diseases. 

Studies have shown that activating TRPV1 can help counter diet-induced obesity by increasing thermogenesis in brown adipose tissue and improving metabolic activity. TRPV1 agonists such as capsaicin have been shown to reduce weight gain in high-fat-diet‒induced obese mice, with clinical trials further supporting its potential for decreasing body weight in people with overweight. 

For instance, a clinical trial showed that participants with obesity taking capsinoid supplementation for 12 weeks experienced a reduction in body weight compared with those who took a placebo. 

While TRPV1 agonists have been more commonly studied for obesity management, most studies involving antagonists have focused on pain relief, inflammation, and conditions like erythromelalgia rather than weight loss. 

However, some evidence suggests that TRPV1 antagonism may influence metabolism. For example, in one study, mice lacking TRPV1 were resistant to obesity, “but that is not sufficient [to come to any conclusion],” said Vincenzo Di Marzo, PhD, director of the Joint International Research Unit for the Chemical and Biomolecular Study of the Microbiome in Metabolic Health and Nutrition between the Consiglio Nazionale delle Ricerche, Italy, and Université Laval, Quebec City, Canada. He was not involved in the study.

Gram admits that the picture around the mechanism of action of TRPV1 modulators is unclear. “There is not a consensus in the literature about the effect of this receptor. Should it be agonized or should it be antagonized?” she said. 

 

What Is XEN-D0501?

XEN-D0501 is a novel selective TRPV1 antagonist, which Pila Pharma is developing for treating erythromelalgia, a rare condition that causes burning pain, redness, and hotness in the skin, especially the feet. It has received orphan-drug status for this indication in the United States. 

Initially, the company explored XEN-D0501 for treating overactive bladder, but the development of the drug for this condition has been discontinued. Now, attention has moved to investigating XEN-D0501 for its potential in treating type 2 diabetes, obesity, and cardiovascular disease.

Although phase 2a clinical trials showed that XEN-D0501 is generally well tolerated in healthy participants, it has been associated with several side effects, including hyperthermia and oral discomfort, thought to be due to TRPV1 antagonism at sensory nerve endings in the mouth, in addition to transient urinary retention and postvoiding residual volumes, indicating potential issues with bladder function.

Another phase 2a trial (PP-CT03) is planned to assess the maximum tolerable dose of XEN-D0501 in people with obesity and type 2 diabetes, focusing on safety and potential effects on body weight. Gram said that early data show these populations experience less hyperthermia than healthy participants. However, the mechanism behind it is still not understood. These studies also showed some positive effects on insulin sensitivity and a biomarker for heart failure.

“The company data provided so far for XEN-D0501 are promising but still too preliminary,” said Di Marzo.

The company is now planning a further 3-month-long dose-escalation study in people with obesity and diabetes. “If these studies show that the molecule is as efficacious and safe as we think it is, then it would make life a lot better for a lot of people because it is a tablet, not an injectable,” Gram said.

Also being explored by the company is the potential of the molecule for treating cardiovascular diseases, particularly abdominal aortic aneurysms, and as a potential nonopioid painkiller. 

Dixon and Di Marzo disclosed no relevant financial relationships. Gram is founder and CSO at Pila Pharma.

A version of this article appeared on Medscape.com.

XEN-D0501, a transient receptor potential vanilloid 1 (TRPV1) antagonist, is gaining attention for its potential as an oral tablet to treat type 2 diabetes, obesity, and cardiovascular diseases. Dorte X. Gram, PhD, founder of Pila Pharma, a Swedish pharmaceutical company investigating XEN-D0501, first noticed the connection more than 20 years ago as a researcher at Novo Nordisk. 

“In my very first experiments, I noticed that mice who would normally become diabetic didn’t get diabetes at all,” she said in an interview.

These surprising observations prompted Gram to investigate further the potential role of the TRPV1 receptor in regulating metabolism, leading her to file a patent and pursue the development of TRPV1 antagonists for obesity and related conditions. 

The company has received enough attention from investors that it witnessed a triple-digit percentage gain on the Nasdaq First North stock exchange in 2024.

While XEN-D0501 shows promise, researchers urge caution, as the drug is still in early development. “There is simply no quality human data to say anything about the possibilities for this pathway,” said John B. Dixon, PhD, professor at Iverson Health Innovation Research Institute, Swinburne University of Technology, Melbourne, Australia.

 

What Is TRPV1 and How Do TRPV1 Modulators Work? 

TRPV1 is a homotetrameric receptor with six transmembrane domains expressed primarily in sensory nerve fibers. It is responsible for detecting noxious signals, including heat and chemical irritants — particularly capsaicin, the active component of chili peppers.

TRPV1 mediates the sensation of burning pain, often associated with inflammation and heat exposure. It also helps detect and regulate body temperature and influences the release of inflammatory mediators. In the central nervous system, it affects synaptic function and plasticity.

Given TRPV1’s broad physiologic role, its modulation has potential for treating several conditions, including pain disorders, inflammation, and cardiovascular diseases. 

Studies have shown that activating TRPV1 can help counter diet-induced obesity by increasing thermogenesis in brown adipose tissue and improving metabolic activity. TRPV1 agonists such as capsaicin have been shown to reduce weight gain in high-fat-diet‒induced obese mice, with clinical trials further supporting its potential for decreasing body weight in people with overweight. 

For instance, a clinical trial showed that participants with obesity taking capsinoid supplementation for 12 weeks experienced a reduction in body weight compared with those who took a placebo. 

While TRPV1 agonists have been more commonly studied for obesity management, most studies involving antagonists have focused on pain relief, inflammation, and conditions like erythromelalgia rather than weight loss. 

However, some evidence suggests that TRPV1 antagonism may influence metabolism. For example, in one study, mice lacking TRPV1 were resistant to obesity, “but that is not sufficient [to come to any conclusion],” said Vincenzo Di Marzo, PhD, director of the Joint International Research Unit for the Chemical and Biomolecular Study of the Microbiome in Metabolic Health and Nutrition between the Consiglio Nazionale delle Ricerche, Italy, and Université Laval, Quebec City, Canada. He was not involved in the study.

Gram admits that the picture around the mechanism of action of TRPV1 modulators is unclear. “There is not a consensus in the literature about the effect of this receptor. Should it be agonized or should it be antagonized?” she said. 

 

What Is XEN-D0501?

XEN-D0501 is a novel selective TRPV1 antagonist, which Pila Pharma is developing for treating erythromelalgia, a rare condition that causes burning pain, redness, and hotness in the skin, especially the feet. It has received orphan-drug status for this indication in the United States. 

Initially, the company explored XEN-D0501 for treating overactive bladder, but the development of the drug for this condition has been discontinued. Now, attention has moved to investigating XEN-D0501 for its potential in treating type 2 diabetes, obesity, and cardiovascular disease.

Although phase 2a clinical trials showed that XEN-D0501 is generally well tolerated in healthy participants, it has been associated with several side effects, including hyperthermia and oral discomfort, thought to be due to TRPV1 antagonism at sensory nerve endings in the mouth, in addition to transient urinary retention and postvoiding residual volumes, indicating potential issues with bladder function.

Another phase 2a trial (PP-CT03) is planned to assess the maximum tolerable dose of XEN-D0501 in people with obesity and type 2 diabetes, focusing on safety and potential effects on body weight. Gram said that early data show these populations experience less hyperthermia than healthy participants. However, the mechanism behind it is still not understood. These studies also showed some positive effects on insulin sensitivity and a biomarker for heart failure.

“The company data provided so far for XEN-D0501 are promising but still too preliminary,” said Di Marzo.

The company is now planning a further 3-month-long dose-escalation study in people with obesity and diabetes. “If these studies show that the molecule is as efficacious and safe as we think it is, then it would make life a lot better for a lot of people because it is a tablet, not an injectable,” Gram said.

Also being explored by the company is the potential of the molecule for treating cardiovascular diseases, particularly abdominal aortic aneurysms, and as a potential nonopioid painkiller. 

Dixon and Di Marzo disclosed no relevant financial relationships. Gram is founder and CSO at Pila Pharma.

A version of this article appeared on Medscape.com.

TOPLINE:

Achieving serum urate to below 6 mg/dL with urate-lowering therapy (ULT) in patients with gout and chronic kidney disease (CKD) stage III is not linked to an increased risk for severe or end-stage kidney disease.

METHODOLOGY:

• Researchers emulated analyses of a hypothetical target trial using a cloning, censoring, and weighting approach to evaluate the association between achieving target serum urate level with ULT and the progression of CKD in patients with gout and CKD stage III.
• They included 14,972 patients (mean age, 73.1 years; 37.7% women) from a general practice database who had a mean baseline serum urate level of 8.9 mg/dL and initiated ULTs such as allopurinol or febuxostat.
• Participants were divided into two groups: Those who achieved a target serum urate level < 6 mg/dL and those who did not within 1 year after the initiation of ULT; the mean follow-up duration was a little more than 3 years in both groups.
• The primary outcome was the occurrence of severe or end-stage kidney disease over 5 years of initiating ULT, defined by an estimated glomerular filtration rate below 30 mL/min per 1.73 m² on two occasions more than 90 days apart within 1 year, or at least one Read code for CKD stages IV or V, dialysis, or kidney transplant.
• A prespecified noninferiority margin for the hazard ratio was set at 1.2 to compare the outcomes between those who achieved the target serum urate level < 6 mg/dL and those who did not.

TAKEAWAY:

• Among the patients who initiated ULT, 31.8% achieved a target serum urate level < 6 mg/dL within 1 year.
• The 5-year risk for severe or end-stage kidney disease was lower (10.32%) in participants with gout and stage III CKD who achieved the target serum urate level than in those who did not (12.73%).
• The adjusted 5-year risk difference for severe to end-stage kidney disease was not inferior in patients who achieved the target serum urate level vs those who did not (adjusted hazard ratio [aHR], 0.89; 95% CI, 0.80-0.98; P for noninferiority < .001); results were consistent for end-stage kidney disease alone (aHR, 0.67; P for noninferiority = .001).
• Similarly, in participants with gout and CKD stages II-III, the 5-year risks for severe or end-stage kidney disease (aHR, 0.91) and end-stage kidney disease alone (aHR, 0.73) were noninferior in the group that did vs that did not achieve target serum urate levels, with P for noninferiority being < .001 and .003, respectively.

IN PRACTICE:

“Our findings suggest that lowering serum urate levels to < 6 mg/dL is generally well tolerated and may even slow CKD progression in these individuals. Initiatives to optimize the use and adherence to ULT could benefit clinicians and patients,” the authors wrote.

SOURCE:

This study was led by Yilun Wang, MD, PhD, Xiangya Hospital, Central South University, Changsha, China. It was published online in JAMA Internal Medicine.

LIMITATIONS:

Residual confounding may still have been present despite rigorous methods to control it, as is common in observational studies. Participants who achieved target serum urate levels may have received better healthcare, adhered to other treatments more consistently, and used ULT for a longer duration. The findings may have limited generalizability, as participants who did not achieve target serum urate levels prior to initiation were excluded.

DISCLOSURES:

This study was supported by the China National Key Research and Development Plan, the National Natural Science Foundation of China, the Project Program of the National Clinical Research Center for Geriatric Disorders, and other sources. Two authors reported receiving personal fees and/or grants from multiple pharmaceutical companies.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Achieving serum urate to below 6 mg/dL with urate-lowering therapy (ULT) in patients with gout and chronic kidney disease (CKD) stage III is not linked to an increased risk for severe or end-stage kidney disease.

METHODOLOGY:

• Researchers emulated analyses of a hypothetical target trial using a cloning, censoring, and weighting approach to evaluate the association between achieving target serum urate level with ULT and the progression of CKD in patients with gout and CKD stage III.
• They included 14,972 patients (mean age, 73.1 years; 37.7% women) from a general practice database who had a mean baseline serum urate level of 8.9 mg/dL and initiated ULTs such as allopurinol or febuxostat.
• Participants were divided into two groups: Those who achieved a target serum urate level < 6 mg/dL and those who did not within 1 year after the initiation of ULT; the mean follow-up duration was a little more than 3 years in both groups.
• The primary outcome was the occurrence of severe or end-stage kidney disease over 5 years of initiating ULT, defined by an estimated glomerular filtration rate below 30 mL/min per 1.73 m² on two occasions more than 90 days apart within 1 year, or at least one Read code for CKD stages IV or V, dialysis, or kidney transplant.
• A prespecified noninferiority margin for the hazard ratio was set at 1.2 to compare the outcomes between those who achieved the target serum urate level < 6 mg/dL and those who did not.

TAKEAWAY:

• Among the patients who initiated ULT, 31.8% achieved a target serum urate level < 6 mg/dL within 1 year.
• The 5-year risk for severe or end-stage kidney disease was lower (10.32%) in participants with gout and stage III CKD who achieved the target serum urate level than in those who did not (12.73%).
• The adjusted 5-year risk difference for severe to end-stage kidney disease was not inferior in patients who achieved the target serum urate level vs those who did not (adjusted hazard ratio [aHR], 0.89; 95% CI, 0.80-0.98; P for noninferiority < .001); results were consistent for end-stage kidney disease alone (aHR, 0.67; P for noninferiority = .001).
• Similarly, in participants with gout and CKD stages II-III, the 5-year risks for severe or end-stage kidney disease (aHR, 0.91) and end-stage kidney disease alone (aHR, 0.73) were noninferior in the group that did vs that did not achieve target serum urate levels, with P for noninferiority being < .001 and .003, respectively.

IN PRACTICE:

“Our findings suggest that lowering serum urate levels to < 6 mg/dL is generally well tolerated and may even slow CKD progression in these individuals. Initiatives to optimize the use and adherence to ULT could benefit clinicians and patients,” the authors wrote.

SOURCE:

This study was led by Yilun Wang, MD, PhD, Xiangya Hospital, Central South University, Changsha, China. It was published online in JAMA Internal Medicine.

LIMITATIONS:

Residual confounding may still have been present despite rigorous methods to control it, as is common in observational studies. Participants who achieved target serum urate levels may have received better healthcare, adhered to other treatments more consistently, and used ULT for a longer duration. The findings may have limited generalizability, as participants who did not achieve target serum urate levels prior to initiation were excluded.

DISCLOSURES:

This study was supported by the China National Key Research and Development Plan, the National Natural Science Foundation of China, the Project Program of the National Clinical Research Center for Geriatric Disorders, and other sources. Two authors reported receiving personal fees and/or grants from multiple pharmaceutical companies.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Achieving serum urate to below 6 mg/dL with urate-lowering therapy (ULT) in patients with gout and chronic kidney disease (CKD) stage III is not linked to an increased risk for severe or end-stage kidney disease.

METHODOLOGY:

• Researchers emulated analyses of a hypothetical target trial using a cloning, censoring, and weighting approach to evaluate the association between achieving target serum urate level with ULT and the progression of CKD in patients with gout and CKD stage III.
• They included 14,972 patients (mean age, 73.1 years; 37.7% women) from a general practice database who had a mean baseline serum urate level of 8.9 mg/dL and initiated ULTs such as allopurinol or febuxostat.
• Participants were divided into two groups: Those who achieved a target serum urate level < 6 mg/dL and those who did not within 1 year after the initiation of ULT; the mean follow-up duration was a little more than 3 years in both groups.
• The primary outcome was the occurrence of severe or end-stage kidney disease over 5 years of initiating ULT, defined by an estimated glomerular filtration rate below 30 mL/min per 1.73 m² on two occasions more than 90 days apart within 1 year, or at least one Read code for CKD stages IV or V, dialysis, or kidney transplant.
• A prespecified noninferiority margin for the hazard ratio was set at 1.2 to compare the outcomes between those who achieved the target serum urate level < 6 mg/dL and those who did not.

TAKEAWAY:

• Among the patients who initiated ULT, 31.8% achieved a target serum urate level < 6 mg/dL within 1 year.
• The 5-year risk for severe or end-stage kidney disease was lower (10.32%) in participants with gout and stage III CKD who achieved the target serum urate level than in those who did not (12.73%).
• The adjusted 5-year risk difference for severe to end-stage kidney disease was not inferior in patients who achieved the target serum urate level vs those who did not (adjusted hazard ratio [aHR], 0.89; 95% CI, 0.80-0.98; P for noninferiority < .001); results were consistent for end-stage kidney disease alone (aHR, 0.67; P for noninferiority = .001).
• Similarly, in participants with gout and CKD stages II-III, the 5-year risks for severe or end-stage kidney disease (aHR, 0.91) and end-stage kidney disease alone (aHR, 0.73) were noninferior in the group that did vs that did not achieve target serum urate levels, with P for noninferiority being < .001 and .003, respectively.

IN PRACTICE:

“Our findings suggest that lowering serum urate levels to < 6 mg/dL is generally well tolerated and may even slow CKD progression in these individuals. Initiatives to optimize the use and adherence to ULT could benefit clinicians and patients,” the authors wrote.

SOURCE:

This study was led by Yilun Wang, MD, PhD, Xiangya Hospital, Central South University, Changsha, China. It was published online in JAMA Internal Medicine.

LIMITATIONS:

Residual confounding may still have been present despite rigorous methods to control it, as is common in observational studies. Participants who achieved target serum urate levels may have received better healthcare, adhered to other treatments more consistently, and used ULT for a longer duration. The findings may have limited generalizability, as participants who did not achieve target serum urate levels prior to initiation were excluded.

DISCLOSURES:

This study was supported by the China National Key Research and Development Plan, the National Natural Science Foundation of China, the Project Program of the National Clinical Research Center for Geriatric Disorders, and other sources. Two authors reported receiving personal fees and/or grants from multiple pharmaceutical companies.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

More Americans than ever are hurting with enduring, life-restricting pain. Like obesity, this condition is on the rise, according to figures in a new National Center for Health Statistics (NCHS) Data Brief from the Centers for Disease Control and Prevention (CDC).

In 2023, 24.3% of US adults had chronic pain, and 8.5% had high-impact chronic pain (HICP) that frequently limited daily activities in the past 3 months. Both types increased with age and with decreasing urbanization level. Women were more likely than men to have HICP (23.2% vs 7.3%). 

Like obesity, chronic pain is multifactorial and is best managed with multidisciplinary intervention, said Jianguo Cheng, MD, PhD, a professor of anesthesiology and medical director of the Cleveland Clinic Consortium for Pain in Ohio. “It’s a complex mix of genetic, biological, and psychosocial dimensions that can cause ongoing pain out of proportion to the original limited injury that triggered it.”

While today’s longer lifespans are the primary driver of the increase, noted Martin Cheatle, PhD, an associate professor of psychiatry, anesthesiology, and critical care and director of behavioral medicine at the Penn Pain Medicine Center at the University of Pennsylvania’s Perelman School of Medicine, Philadelphia, another important factor is the more than 100 million Americans who suffer from obesity. “Obesity is a major risk factor for chronic pain conditions including advancing joint disease, low back pain, and diabetic neuropathies,” he said.

Age is an amplifier, agreed Beth Darnall, PhD, a professor of anesthesiology and perioperative and pain medicine and director of the Pain Relief Innovations Lab at Stanford University in Palo Alto, California, but the increases in chronic pain and HICP cut across age strata. 

“Across the board we see striking increases in chronic pain, such as a 5% increase for those 65 and older, and a nearly 2% increase in HICP in that same age group,” Darnall said, referencing the changes from 2019 data in the new NCHS Data Brief. “And an almost 4% increase was observed for the youngest adult age category,18 to 29. Some of our research is now focusing on how to best treat chronic pain in young adults.”

The rise in chronic pain is broadly linked to the overall decline in the health of the US population, as indicated by the CDC 2024’s Chronic Disease Prevalence in the US: Sociodemographic and Geographic Variations by Zip Code Tabulation Area.

 

The Opioid Crisis and COVID

Beginning in 2016, in response to the opioid crisis and CDC guidelines, opioid prescribing for chronic pain rapidly dropped, both in terms of new prescriptions and tapering of doses of long-term users. “Reduced opioid prescribing yielded benefits for some patients but created new problems and harms for other patients,” said Darnall. Cheng added that the CDC’s recommendations on opioid prescribing were widely misinterpreted and were applied to patients with painful conditions such as cancer and sickle cell disease who were not intended to be affected by the guidelines. “In addition, although medical opioid prescribing dropped by 50%, overdose deaths from non-medical opioid sources increased by more 50%.”

Currently, most opioid overdoses are related to heroin, fentanyl, and newer drugs of abuse such as xylazine. “Most pain clinicians would agree that opioids are not first-line therapy for chronic non-cancer pain, but in a select number of well-vetted patients, opioids can be very effective in improving functionality and quality of life as part of a multimodal approach to pain care,” Cheatle said. 

The impact of the opioid crisis is complex, said Cheatle, noting that only 8%-10% of pain patients on long-term opioid therapy develop a use disorder. “However, opioids were overly prescribed due to clinicians’ lack of training in core competencies of pain management and the insurance companies’ refusal to adequately cover non-opioid therapies such as acupuncture, cognitive behavioral therapy, extended physical therapy, and medical massage,” he said. 

He pointed out that in the late 1990s there were more than 1000 multidisciplinary pain centers, whereas currently there are many fewer owing to lack of insurance reimbursement. “This results in more possibly avoidable invasive surgeries, which can further contribute to the increase in chronic pain.” 

The COVID pandemic further exacerbated the pain problem and delayed access to timely medical interventions for many people. Some adopted a more sedentary lifestyle, already entrenched in today’s technology-driven society, leading in turn to weight gain and more chronic pain. “The isolation and lack of normal human connections during the pandemic could exacerbate pain and loss of autonomy,” Cheatle said. And some individuals developed painful neurologic conditions related to long-haul COVID, for which there is no effective treatment. 

 

Best Approach

“Historically, pain has been treated as a purely biomedical issue. Bringing a biopsychosocial perspective to pain care can support pain relief,” said Darnall. Multiple national clinical guidance documents have called for a comprehensive approach that considers the whole person: their circumstances, their needs, their stressors, and their environment. “And we must provide patients meaningful access to the lowest-risk, non-pharmacologic treatments first – and ideally early on,” she said.

Even effective medications rarely make a person pain free, so other approaches are needed in tandem, Darnall said. Support for stronger patient competency in self-management of chronic pain is mounting.

“It’s vitally important that we help people know how to help themselves have less pain – how to steer their mind and body toward relief by using pain relief skills,” she said. “By so doing they can cultivate a critical level of control over their pain and are less at its mercy, which supports good mood and is shown to help people be more active as the impacts of pain diminish.”

Darnall outlined a recent development in the primary care setting that involves offering patients a brief program in pain-relief skills training. Within Veterans Affairs primary care, for example, patients receive several 30-minute sessions in pain reduction techniques. Outside of the VA, primary care clinics are incorporating an evidence-based, one-session 2-hour pain relief skills class called Empowered Relief, as standard care. 

The class teaches participants three pain management skills and creates a personalized plan for each that includes a free app for ongoing daily use.

Since pain causes agitation in the central nervous system, manifested as fast heart rate, rapid breathing, muscle tension, and distress, people learn various ways to calm the central nervous system – with, for example, a sound technology known as binaural audio to deepen the relaxation response. “They also learn to identify and target worry about pain and develop self-soothing actions to interrupt unhelpful patterns,” Darnall said. 

Data from randomized chronic pain studies, including one by her group using a virtual reality training program for lower back pain, show that 3 months after the training program people report clinically meaningful reductions in pain intensity, pain interference with daily activities, and sleep disturbance, as well as pain-related distress, anxiety, and fatigue

While psychological and complementary approaches have been effective in improving function and mood, there are barriers to accessing them, said Cheatle, such as lack of insurance coverage and the stigma associated with nontraditional, especially psychological, care.

 

Prevention

Good lifestyle behaviors promote better health as people age. “Maintaining a healthy weight, staying active, prioritizing good sleep, and avoiding smoking and alcohol use can support better health and buffer against chronic diseases and pain,” Darnall said.

Cheatle noted the importance of maintaining a safe work environment and avoiding injury risks by, for example, wearing a seatbelt or a cycling helmet. 

 

The Future 

“We need to ensure all individuals have access to effective, low-burden pain treatments, including evidence-based treatments they can receive from home so as to minimize treatment disparities.” Darnall said. Also needed is better comprehensive treatment for acute and chronic pain alike. “If we treat acute pain better, we will have fewer people transitioning to the chronic pain state.”

To that end, added Cheng, healthcare professionals in every specialty from doctors and nurses to psychologists and chiropractors need to develop co-competencies in pain management. 

For Cheatle, the near future looks bleak. “There are some pioneering bioengineering approaches to reduce chronic pain and novel pharmacologic agents such as calcitonin gene-related peptide inhibitors for intractable migraines, but just changing insurance reimbursement for a comprehensive approach to chronic pain care and bolstering healthcare provider education on core pain competencies will benefit the over 50 million adults who suffer from chronic pain.” 

Cheng, however, is more sanguine. “I don’t expect miracles in 10 years’ time, but we’re making rapid progress in understanding the genetics of chronic pain and the mechanisms of disease and therapy. We’re developing biomarkers to help in prognosis and monitor disease progress.” In the meantime, he pointed to an expanding array of non-pharmaceutical options, including neuromodulatory approaches such as nerve blocks and spinal cord stimulation.

Cheng, Cheatle, and Darnall disclosed no relevant competing interests.

A version of this article appeared on Medscape.com.

More Americans than ever are hurting with enduring, life-restricting pain. Like obesity, this condition is on the rise, according to figures in a new National Center for Health Statistics (NCHS) Data Brief from the Centers for Disease Control and Prevention (CDC).

In 2023, 24.3% of US adults had chronic pain, and 8.5% had high-impact chronic pain (HICP) that frequently limited daily activities in the past 3 months. Both types increased with age and with decreasing urbanization level. Women were more likely than men to have HICP (23.2% vs 7.3%). 

Like obesity, chronic pain is multifactorial and is best managed with multidisciplinary intervention, said Jianguo Cheng, MD, PhD, a professor of anesthesiology and medical director of the Cleveland Clinic Consortium for Pain in Ohio. “It’s a complex mix of genetic, biological, and psychosocial dimensions that can cause ongoing pain out of proportion to the original limited injury that triggered it.”

While today’s longer lifespans are the primary driver of the increase, noted Martin Cheatle, PhD, an associate professor of psychiatry, anesthesiology, and critical care and director of behavioral medicine at the Penn Pain Medicine Center at the University of Pennsylvania’s Perelman School of Medicine, Philadelphia, another important factor is the more than 100 million Americans who suffer from obesity. “Obesity is a major risk factor for chronic pain conditions including advancing joint disease, low back pain, and diabetic neuropathies,” he said.

Age is an amplifier, agreed Beth Darnall, PhD, a professor of anesthesiology and perioperative and pain medicine and director of the Pain Relief Innovations Lab at Stanford University in Palo Alto, California, but the increases in chronic pain and HICP cut across age strata. 

“Across the board we see striking increases in chronic pain, such as a 5% increase for those 65 and older, and a nearly 2% increase in HICP in that same age group,” Darnall said, referencing the changes from 2019 data in the new NCHS Data Brief. “And an almost 4% increase was observed for the youngest adult age category,18 to 29. Some of our research is now focusing on how to best treat chronic pain in young adults.”

The rise in chronic pain is broadly linked to the overall decline in the health of the US population, as indicated by the CDC 2024’s Chronic Disease Prevalence in the US: Sociodemographic and Geographic Variations by Zip Code Tabulation Area.

 

The Opioid Crisis and COVID

Beginning in 2016, in response to the opioid crisis and CDC guidelines, opioid prescribing for chronic pain rapidly dropped, both in terms of new prescriptions and tapering of doses of long-term users. “Reduced opioid prescribing yielded benefits for some patients but created new problems and harms for other patients,” said Darnall. Cheng added that the CDC’s recommendations on opioid prescribing were widely misinterpreted and were applied to patients with painful conditions such as cancer and sickle cell disease who were not intended to be affected by the guidelines. “In addition, although medical opioid prescribing dropped by 50%, overdose deaths from non-medical opioid sources increased by more 50%.”

Currently, most opioid overdoses are related to heroin, fentanyl, and newer drugs of abuse such as xylazine. “Most pain clinicians would agree that opioids are not first-line therapy for chronic non-cancer pain, but in a select number of well-vetted patients, opioids can be very effective in improving functionality and quality of life as part of a multimodal approach to pain care,” Cheatle said. 

The impact of the opioid crisis is complex, said Cheatle, noting that only 8%-10% of pain patients on long-term opioid therapy develop a use disorder. “However, opioids were overly prescribed due to clinicians’ lack of training in core competencies of pain management and the insurance companies’ refusal to adequately cover non-opioid therapies such as acupuncture, cognitive behavioral therapy, extended physical therapy, and medical massage,” he said. 

He pointed out that in the late 1990s there were more than 1000 multidisciplinary pain centers, whereas currently there are many fewer owing to lack of insurance reimbursement. “This results in more possibly avoidable invasive surgeries, which can further contribute to the increase in chronic pain.” 

The COVID pandemic further exacerbated the pain problem and delayed access to timely medical interventions for many people. Some adopted a more sedentary lifestyle, already entrenched in today’s technology-driven society, leading in turn to weight gain and more chronic pain. “The isolation and lack of normal human connections during the pandemic could exacerbate pain and loss of autonomy,” Cheatle said. And some individuals developed painful neurologic conditions related to long-haul COVID, for which there is no effective treatment. 

 

Best Approach

“Historically, pain has been treated as a purely biomedical issue. Bringing a biopsychosocial perspective to pain care can support pain relief,” said Darnall. Multiple national clinical guidance documents have called for a comprehensive approach that considers the whole person: their circumstances, their needs, their stressors, and their environment. “And we must provide patients meaningful access to the lowest-risk, non-pharmacologic treatments first – and ideally early on,” she said.

Even effective medications rarely make a person pain free, so other approaches are needed in tandem, Darnall said. Support for stronger patient competency in self-management of chronic pain is mounting.

“It’s vitally important that we help people know how to help themselves have less pain – how to steer their mind and body toward relief by using pain relief skills,” she said. “By so doing they can cultivate a critical level of control over their pain and are less at its mercy, which supports good mood and is shown to help people be more active as the impacts of pain diminish.”

Darnall outlined a recent development in the primary care setting that involves offering patients a brief program in pain-relief skills training. Within Veterans Affairs primary care, for example, patients receive several 30-minute sessions in pain reduction techniques. Outside of the VA, primary care clinics are incorporating an evidence-based, one-session 2-hour pain relief skills class called Empowered Relief, as standard care. 

The class teaches participants three pain management skills and creates a personalized plan for each that includes a free app for ongoing daily use.

Since pain causes agitation in the central nervous system, manifested as fast heart rate, rapid breathing, muscle tension, and distress, people learn various ways to calm the central nervous system – with, for example, a sound technology known as binaural audio to deepen the relaxation response. “They also learn to identify and target worry about pain and develop self-soothing actions to interrupt unhelpful patterns,” Darnall said. 

Data from randomized chronic pain studies, including one by her group using a virtual reality training program for lower back pain, show that 3 months after the training program people report clinically meaningful reductions in pain intensity, pain interference with daily activities, and sleep disturbance, as well as pain-related distress, anxiety, and fatigue

While psychological and complementary approaches have been effective in improving function and mood, there are barriers to accessing them, said Cheatle, such as lack of insurance coverage and the stigma associated with nontraditional, especially psychological, care.

 

Prevention

Good lifestyle behaviors promote better health as people age. “Maintaining a healthy weight, staying active, prioritizing good sleep, and avoiding smoking and alcohol use can support better health and buffer against chronic diseases and pain,” Darnall said.

Cheatle noted the importance of maintaining a safe work environment and avoiding injury risks by, for example, wearing a seatbelt or a cycling helmet. 

 

The Future 

“We need to ensure all individuals have access to effective, low-burden pain treatments, including evidence-based treatments they can receive from home so as to minimize treatment disparities.” Darnall said. Also needed is better comprehensive treatment for acute and chronic pain alike. “If we treat acute pain better, we will have fewer people transitioning to the chronic pain state.”

To that end, added Cheng, healthcare professionals in every specialty from doctors and nurses to psychologists and chiropractors need to develop co-competencies in pain management. 

For Cheatle, the near future looks bleak. “There are some pioneering bioengineering approaches to reduce chronic pain and novel pharmacologic agents such as calcitonin gene-related peptide inhibitors for intractable migraines, but just changing insurance reimbursement for a comprehensive approach to chronic pain care and bolstering healthcare provider education on core pain competencies will benefit the over 50 million adults who suffer from chronic pain.” 

Cheng, however, is more sanguine. “I don’t expect miracles in 10 years’ time, but we’re making rapid progress in understanding the genetics of chronic pain and the mechanisms of disease and therapy. We’re developing biomarkers to help in prognosis and monitor disease progress.” In the meantime, he pointed to an expanding array of non-pharmaceutical options, including neuromodulatory approaches such as nerve blocks and spinal cord stimulation.

Cheng, Cheatle, and Darnall disclosed no relevant competing interests.

A version of this article appeared on Medscape.com.

More Americans than ever are hurting with enduring, life-restricting pain. Like obesity, this condition is on the rise, according to figures in a new National Center for Health Statistics (NCHS) Data Brief from the Centers for Disease Control and Prevention (CDC).

In 2023, 24.3% of US adults had chronic pain, and 8.5% had high-impact chronic pain (HICP) that frequently limited daily activities in the past 3 months. Both types increased with age and with decreasing urbanization level. Women were more likely than men to have HICP (23.2% vs 7.3%). 

Like obesity, chronic pain is multifactorial and is best managed with multidisciplinary intervention, said Jianguo Cheng, MD, PhD, a professor of anesthesiology and medical director of the Cleveland Clinic Consortium for Pain in Ohio. “It’s a complex mix of genetic, biological, and psychosocial dimensions that can cause ongoing pain out of proportion to the original limited injury that triggered it.”

While today’s longer lifespans are the primary driver of the increase, noted Martin Cheatle, PhD, an associate professor of psychiatry, anesthesiology, and critical care and director of behavioral medicine at the Penn Pain Medicine Center at the University of Pennsylvania’s Perelman School of Medicine, Philadelphia, another important factor is the more than 100 million Americans who suffer from obesity. “Obesity is a major risk factor for chronic pain conditions including advancing joint disease, low back pain, and diabetic neuropathies,” he said.

Age is an amplifier, agreed Beth Darnall, PhD, a professor of anesthesiology and perioperative and pain medicine and director of the Pain Relief Innovations Lab at Stanford University in Palo Alto, California, but the increases in chronic pain and HICP cut across age strata. 

“Across the board we see striking increases in chronic pain, such as a 5% increase for those 65 and older, and a nearly 2% increase in HICP in that same age group,” Darnall said, referencing the changes from 2019 data in the new NCHS Data Brief. “And an almost 4% increase was observed for the youngest adult age category,18 to 29. Some of our research is now focusing on how to best treat chronic pain in young adults.”

The rise in chronic pain is broadly linked to the overall decline in the health of the US population, as indicated by the CDC 2024’s Chronic Disease Prevalence in the US: Sociodemographic and Geographic Variations by Zip Code Tabulation Area.

 

The Opioid Crisis and COVID

Beginning in 2016, in response to the opioid crisis and CDC guidelines, opioid prescribing for chronic pain rapidly dropped, both in terms of new prescriptions and tapering of doses of long-term users. “Reduced opioid prescribing yielded benefits for some patients but created new problems and harms for other patients,” said Darnall. Cheng added that the CDC’s recommendations on opioid prescribing were widely misinterpreted and were applied to patients with painful conditions such as cancer and sickle cell disease who were not intended to be affected by the guidelines. “In addition, although medical opioid prescribing dropped by 50%, overdose deaths from non-medical opioid sources increased by more 50%.”

Currently, most opioid overdoses are related to heroin, fentanyl, and newer drugs of abuse such as xylazine. “Most pain clinicians would agree that opioids are not first-line therapy for chronic non-cancer pain, but in a select number of well-vetted patients, opioids can be very effective in improving functionality and quality of life as part of a multimodal approach to pain care,” Cheatle said. 

The impact of the opioid crisis is complex, said Cheatle, noting that only 8%-10% of pain patients on long-term opioid therapy develop a use disorder. “However, opioids were overly prescribed due to clinicians’ lack of training in core competencies of pain management and the insurance companies’ refusal to adequately cover non-opioid therapies such as acupuncture, cognitive behavioral therapy, extended physical therapy, and medical massage,” he said. 

He pointed out that in the late 1990s there were more than 1000 multidisciplinary pain centers, whereas currently there are many fewer owing to lack of insurance reimbursement. “This results in more possibly avoidable invasive surgeries, which can further contribute to the increase in chronic pain.” 

The COVID pandemic further exacerbated the pain problem and delayed access to timely medical interventions for many people. Some adopted a more sedentary lifestyle, already entrenched in today’s technology-driven society, leading in turn to weight gain and more chronic pain. “The isolation and lack of normal human connections during the pandemic could exacerbate pain and loss of autonomy,” Cheatle said. And some individuals developed painful neurologic conditions related to long-haul COVID, for which there is no effective treatment. 

 

Best Approach

“Historically, pain has been treated as a purely biomedical issue. Bringing a biopsychosocial perspective to pain care can support pain relief,” said Darnall. Multiple national clinical guidance documents have called for a comprehensive approach that considers the whole person: their circumstances, their needs, their stressors, and their environment. “And we must provide patients meaningful access to the lowest-risk, non-pharmacologic treatments first – and ideally early on,” she said.

Even effective medications rarely make a person pain free, so other approaches are needed in tandem, Darnall said. Support for stronger patient competency in self-management of chronic pain is mounting.

“It’s vitally important that we help people know how to help themselves have less pain – how to steer their mind and body toward relief by using pain relief skills,” she said. “By so doing they can cultivate a critical level of control over their pain and are less at its mercy, which supports good mood and is shown to help people be more active as the impacts of pain diminish.”

Darnall outlined a recent development in the primary care setting that involves offering patients a brief program in pain-relief skills training. Within Veterans Affairs primary care, for example, patients receive several 30-minute sessions in pain reduction techniques. Outside of the VA, primary care clinics are incorporating an evidence-based, one-session 2-hour pain relief skills class called Empowered Relief, as standard care. 

The class teaches participants three pain management skills and creates a personalized plan for each that includes a free app for ongoing daily use.

Since pain causes agitation in the central nervous system, manifested as fast heart rate, rapid breathing, muscle tension, and distress, people learn various ways to calm the central nervous system – with, for example, a sound technology known as binaural audio to deepen the relaxation response. “They also learn to identify and target worry about pain and develop self-soothing actions to interrupt unhelpful patterns,” Darnall said. 

Data from randomized chronic pain studies, including one by her group using a virtual reality training program for lower back pain, show that 3 months after the training program people report clinically meaningful reductions in pain intensity, pain interference with daily activities, and sleep disturbance, as well as pain-related distress, anxiety, and fatigue

While psychological and complementary approaches have been effective in improving function and mood, there are barriers to accessing them, said Cheatle, such as lack of insurance coverage and the stigma associated with nontraditional, especially psychological, care.

 

Prevention

Good lifestyle behaviors promote better health as people age. “Maintaining a healthy weight, staying active, prioritizing good sleep, and avoiding smoking and alcohol use can support better health and buffer against chronic diseases and pain,” Darnall said.

Cheatle noted the importance of maintaining a safe work environment and avoiding injury risks by, for example, wearing a seatbelt or a cycling helmet. 

 

The Future 

“We need to ensure all individuals have access to effective, low-burden pain treatments, including evidence-based treatments they can receive from home so as to minimize treatment disparities.” Darnall said. Also needed is better comprehensive treatment for acute and chronic pain alike. “If we treat acute pain better, we will have fewer people transitioning to the chronic pain state.”

To that end, added Cheng, healthcare professionals in every specialty from doctors and nurses to psychologists and chiropractors need to develop co-competencies in pain management. 

For Cheatle, the near future looks bleak. “There are some pioneering bioengineering approaches to reduce chronic pain and novel pharmacologic agents such as calcitonin gene-related peptide inhibitors for intractable migraines, but just changing insurance reimbursement for a comprehensive approach to chronic pain care and bolstering healthcare provider education on core pain competencies will benefit the over 50 million adults who suffer from chronic pain.” 

Cheng, however, is more sanguine. “I don’t expect miracles in 10 years’ time, but we’re making rapid progress in understanding the genetics of chronic pain and the mechanisms of disease and therapy. We’re developing biomarkers to help in prognosis and monitor disease progress.” In the meantime, he pointed to an expanding array of non-pharmaceutical options, including neuromodulatory approaches such as nerve blocks and spinal cord stimulation.

Cheng, Cheatle, and Darnall disclosed no relevant competing interests.

A version of this article appeared on Medscape.com.

TOPLINE:

Perfluorohexanoic acid (PFHxA) is found in fluoroelastomer watch bands at concentrations of up to 16,662 ng/g, highlighting the need for further research on dermal absorption and exposure risks.

METHODOLOGY:

• Fluoroelastomers are a subclass of polymeric per- and polyfluoroalkyl substances (PFAS), which are used to help wearable device materials maintain their appearance and structure after contact with the skin, sweat, and personal care products (eg, sunscreen).
• Researchers investigated the presence of PFAS in 22 new and used US fitness and smart watch bands from a range of brands and price points, of which 13 were advertised as containing fluoroelastomers.
• Total fluorine concentrations were measured using particle-induced gamma-ray emission spectroscopy with cut pieces of the watch bands.
• Solvent extraction was performed, and targeted analysis for 20 PFAS compounds was conducted using liquid chromatography-tandem mass spectrometry.
• A subset of six watch bands, with the highest and lowest detectable PFAS concentrations (three each), was subjected to a direct total oxidative precursor assay to determine the presence of PFAS precursors.

TAKEAWAY:

• Watch bands advertised as containing fluoroelastomers had total fluorine concentrations ranging from 28.5% to 90.7%; only two of the nine bands not advertised to contain fluoroelastomers had concentrations of this PFAS, which ranged from 28.1% to 49.7%.
• Expensive watch bands showed high fluorine levels, with concentrations ranging from 49.7% to 90.7%, whereas inexpensive bands contained less than 1% fluorine on their surface.
• PFHxA was the most common PFAS, detected in 41% of the watch bands.
• PFXxA had a median concentration of 773 ng/g, much higher than the concentrations found in other consumer products, with one sample showing a concentration of 16,662 ng/g.
• Bands containing high PFHxA concentrations had total PFAS levels between 253 and 2016 ng/g, whereas those with low or no PFHxA concentrations had total PFAS levels between 3 and 24 ng/g.

IN PRACTICE:

“The thousands of ng/g of PFHxA available, paired with watch band users often wearing these items for more than 12 h per day, poses an opportunity for significant transfer to the dermis and subsequent human exposure,” the authors wrote.

“If the consumer wishes to purchase a higher-priced band, we suggest that they read the product descriptions and avoid any that are listed as containing fluoroelastomers,” said the study’s lead author in a press release.
 

SOURCE:

The study was led by Alyssa Wicks, University of Notre Dame in Indiana, and published online in Environmental Science & Technology Letters.

LIMITATIONS: 

No limitations were reported in the study. 

DISCLOSURES:

The study received funding from the University of Notre Dame. The authors declared no competing financial interests.

This article was created 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.

TOPLINE:

Perfluorohexanoic acid (PFHxA) is found in fluoroelastomer watch bands at concentrations of up to 16,662 ng/g, highlighting the need for further research on dermal absorption and exposure risks.

METHODOLOGY:

• Fluoroelastomers are a subclass of polymeric per- and polyfluoroalkyl substances (PFAS), which are used to help wearable device materials maintain their appearance and structure after contact with the skin, sweat, and personal care products (eg, sunscreen).
• Researchers investigated the presence of PFAS in 22 new and used US fitness and smart watch bands from a range of brands and price points, of which 13 were advertised as containing fluoroelastomers.
• Total fluorine concentrations were measured using particle-induced gamma-ray emission spectroscopy with cut pieces of the watch bands.
• Solvent extraction was performed, and targeted analysis for 20 PFAS compounds was conducted using liquid chromatography-tandem mass spectrometry.
• A subset of six watch bands, with the highest and lowest detectable PFAS concentrations (three each), was subjected to a direct total oxidative precursor assay to determine the presence of PFAS precursors.

TAKEAWAY:

• Watch bands advertised as containing fluoroelastomers had total fluorine concentrations ranging from 28.5% to 90.7%; only two of the nine bands not advertised to contain fluoroelastomers had concentrations of this PFAS, which ranged from 28.1% to 49.7%.
• Expensive watch bands showed high fluorine levels, with concentrations ranging from 49.7% to 90.7%, whereas inexpensive bands contained less than 1% fluorine on their surface.
• PFHxA was the most common PFAS, detected in 41% of the watch bands.
• PFXxA had a median concentration of 773 ng/g, much higher than the concentrations found in other consumer products, with one sample showing a concentration of 16,662 ng/g.
• Bands containing high PFHxA concentrations had total PFAS levels between 253 and 2016 ng/g, whereas those with low or no PFHxA concentrations had total PFAS levels between 3 and 24 ng/g.

IN PRACTICE:

“The thousands of ng/g of PFHxA available, paired with watch band users often wearing these items for more than 12 h per day, poses an opportunity for significant transfer to the dermis and subsequent human exposure,” the authors wrote.

“If the consumer wishes to purchase a higher-priced band, we suggest that they read the product descriptions and avoid any that are listed as containing fluoroelastomers,” said the study’s lead author in a press release.
 

SOURCE:

The study was led by Alyssa Wicks, University of Notre Dame in Indiana, and published online in Environmental Science & Technology Letters.

LIMITATIONS: 

No limitations were reported in the study. 

DISCLOSURES:

The study received funding from the University of Notre Dame. The authors declared no competing financial interests.

This article was created 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.

TOPLINE:

Perfluorohexanoic acid (PFHxA) is found in fluoroelastomer watch bands at concentrations of up to 16,662 ng/g, highlighting the need for further research on dermal absorption and exposure risks.

METHODOLOGY:

• Fluoroelastomers are a subclass of polymeric per- and polyfluoroalkyl substances (PFAS), which are used to help wearable device materials maintain their appearance and structure after contact with the skin, sweat, and personal care products (eg, sunscreen).
• Researchers investigated the presence of PFAS in 22 new and used US fitness and smart watch bands from a range of brands and price points, of which 13 were advertised as containing fluoroelastomers.
• Total fluorine concentrations were measured using particle-induced gamma-ray emission spectroscopy with cut pieces of the watch bands.
• Solvent extraction was performed, and targeted analysis for 20 PFAS compounds was conducted using liquid chromatography-tandem mass spectrometry.
• A subset of six watch bands, with the highest and lowest detectable PFAS concentrations (three each), was subjected to a direct total oxidative precursor assay to determine the presence of PFAS precursors.

TAKEAWAY:

• Watch bands advertised as containing fluoroelastomers had total fluorine concentrations ranging from 28.5% to 90.7%; only two of the nine bands not advertised to contain fluoroelastomers had concentrations of this PFAS, which ranged from 28.1% to 49.7%.
• Expensive watch bands showed high fluorine levels, with concentrations ranging from 49.7% to 90.7%, whereas inexpensive bands contained less than 1% fluorine on their surface.
• PFHxA was the most common PFAS, detected in 41% of the watch bands.
• PFXxA had a median concentration of 773 ng/g, much higher than the concentrations found in other consumer products, with one sample showing a concentration of 16,662 ng/g.
• Bands containing high PFHxA concentrations had total PFAS levels between 253 and 2016 ng/g, whereas those with low or no PFHxA concentrations had total PFAS levels between 3 and 24 ng/g.

IN PRACTICE:

“The thousands of ng/g of PFHxA available, paired with watch band users often wearing these items for more than 12 h per day, poses an opportunity for significant transfer to the dermis and subsequent human exposure,” the authors wrote.

“If the consumer wishes to purchase a higher-priced band, we suggest that they read the product descriptions and avoid any that are listed as containing fluoroelastomers,” said the study’s lead author in a press release.
 

SOURCE:

The study was led by Alyssa Wicks, University of Notre Dame in Indiana, and published online in Environmental Science & Technology Letters.

LIMITATIONS: 

No limitations were reported in the study. 

DISCLOSURES:

The study received funding from the University of Notre Dame. The authors declared no competing financial interests.

This article was created 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.