Cisplatin is a preferred treatment for a wide range of cancers, including breast, head and neck, lung, ovary, and more. However, its side effects — particularly nephrotoxicity — can be severe. Kidney injury on cisplatin is associated with higher mortality and can jeopardize a patient’s eligibility for other therapies.

Now, in a large study using data from six US cancer centers, researchers have developed a risk algorithm to predict acute kidney injury (AKI) after cisplatin administration.

A risk prediction calculator based on the algorithm is available online for patients and providers to determine an individual patient›s risk for kidney injury from cisplatin using readily available clinical data.

Other risk scores and risk prediction models have been developed to help clinicians assess in advance whether a patient might develop AKI after receiving cisplatin, so that more careful monitoring, dose adjustments, or an alternative treatment, if available, might be considered.

However, previous models were limited by factors such as small sample sizes, lack of external validation, older data, and liberal definitions of AKI, said Shruti Gupta, MD, MPH, director of onco-nephrology at Brigham and Women’s Hospital (BWH) and Dana-Farber Cancer Institute, and David E. Leaf, MD, MMSc, director of clinical and translational research in AKI, Division of Renal Medicine, BWH, Boston.

Dr. Gupta and Dr. Leaf believe their risk score for predicting severe AKI after intravenous (IV) cisplatin, published online in The BMJ, is “more accurate and generalizable than prior models for several reasons,” they told this news organization in a joint email.

“First, we externally validated our findings across cancer centers other than the one where it was developed,” they said. “Second, we focused on moderate to severe kidney injury, the most clinically relevant form of kidney damage, whereas prior models examined more mild forms of kidney injury. Third, we collected data on nearly 25,000 patients receiving their first dose of IV cisplatin, which is larger than all previous studies combined.”
 

‘Herculean Effort’

“We conceived of this study back in 2018, contacted collaborators at each participating cancer center, and had numerous meetings to try to gather granular data on patients treated with their first dose of intravenous (IV) cisplatin,” Dr. Gupta and Dr. Leaf explained. They also incorporated patient feedback from focus groups and surveys.

“This was truly a Herculean effort that involved physicians, programmers, research coordinators, and patients,” they said.

The multicenter study included 24,717 patients — 11,766 in the derivation cohort and 12,951 in the validation cohort. Overall, the median age was about 60 years, about 58% were men, and about 78% were White.

The primary outcome was cisplatin-induced AKI (CP-AKI), defined as a twofold or greater increase in serum creatinine or kidney replacement therapy within 14 days of a first dose of IV cisplatin.

The researchers found that the incidence of CP-AKI was 5.2% in the derivation cohort and 3.3% in the validation cohort. Their simple risk score consisting of nine covariates — age, hypertension, type 2 diabetes, hemoglobin level, white blood cell count, platelet count, serum albumin level, serum magnesium level, and cisplatin dose — predicted a higher risk for CP-AKI in both cohorts.

Notably, adding serum creatinine to the model did not change the area under the curve, and therefore, serum creatinine, though also an independent risk factor for CP-AKI, was not included in the score.

Patients in the highest risk category had 24-fold higher odds of CP-AKI in the derivation cohort and close to 18-fold higher odds in the validation cohort than those in the lowest risk category.

The primary model had a C statistic of 0.75 (95% CI, 0.73-0.76) and showed better discrimination for CP-AKI than previously published models, for which the C statistics ranged from 0.60 to 0.68. The first author of a paper on an earlier model, Shveta Motwani, MD, MMSc, of BWH and Dana-Farber Cancer Institute in Boston, is also a coauthor of the new study.

Greater severity of CP-AKI was associated with shorter 90-day survival (adjusted hazard ratio, 4.63; 95% CI, 3.56-6.02) for stage III CP-AKI vs no CP-AKI.
 

‘Definitive Work’

Joel M. Topf, MD, a nephrologist with expertise in chronic kidney disease in Detroit, who wasn’t involved in the development of the risk score, called the study “a definitive work on an important concept in oncology and nephrology.”

“While this is not the first attempt to devise a risk score, it is by far the biggest,” he told this news organization. Furthermore, the authors “used a diverse population, recruiting patients with a variety of cancers (previous attempts had often used a homogenous diagnosis, putting into question how generalizable the results were) from six different cancer centers.”

In addition, he said, “The authors did not restrict patients with chronic kidney disease or other significant comorbidities and used the geographic diversity to produce a cohort that has an age, gender, racial, and ethnic distribution, which is more representative of the US than previous, single-center attempts to risk score patients.”

An earlier model used the Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI of an increase in serum creatinine of 0.3 mg/dL, he noted. “While a sensitive definition of AKI, it captures mild, hemodynamic increases in creatinine of questionable significance,” he said.

By contrast, the new score uses KDIGO stage II and above to define AKI. “This is a better choice, as we do not want to dissuade patients and doctors from choosing chemotherapy due to a fear of insignificant kidney damage,” he said.

All that said, Dr. Topf noted that neither the current score nor the earlier model included serum creatinine. “This is curious to me and may represent the small number of patients with representative elevated creatinine in the derivation cohort (only 1.3% with an estimated glomerular filtration rate [eGFR] < 45).”

“Since the cohort is made up of people who received cis-platinum, the low prevalence of eGFRs < 45 may be due to physicians steering away from cis-platinum in this group,” he suggested. “It would be unfortunate if this risk score gave an unintentional ‘green light’ to these patients, exposing them to predictable harm.”
 

‘Certainly Useful’

Anushree Shirali, MD, an associate professor in the Section of Nephrology and consulting physician, Yale Onco-Nephrology, Yale School of Medicine, in New Haven, Connecticut, said that having a prediction score for which patients are more likely to develop AKI after a single dose of cisplatin would be helpful for oncologists, as well as nephrologists.

As a nephrologist, Dr. Shirali mostly sees patients who already have AKI, she told this news organization. But there are circumstances in which the tool could still be helpful.

“Let’s say someone has abnormal kidney function at baseline — ie, creatinine is higher than the normal range — and they were on dialysis 5 years ago for something else, and now, they have cancer and may be given cisplatin. They worry about their chances of getting AKI and needing dialysis again,” she said. “That’s just one scenario in which I might be asked to answer that question and the tool would certainly be useful.”

Other scenarios could include someone who has just one kidney because they donated a kidney for transplant years ago, and now, they have a malignancy and wonder what their actual risk is of getting kidney issues on cisplatin.

Oncologists could use the tool to determine whether a patient should be treated with cisplatin, or if they’re at high risk, whether an alternative that’s not nephrotoxic might be used. By contrast, “if somebody’s low risk and an oncologist thinks cisplatin is the best agent they have, then they might want to go ahead and use it,” Dr. Shirali said.

Future research could take into consideration that CP-AKI is dose dependent, she suggested, because a prediction score that included the number of cisplatin doses could be even more helpful to determine risk. And, even though the derivation and validation cohorts for the new tool are representative of the US population, additional research should also include more racial/ethnic diversity, she said.

Dr. Gupta and Dr. Leaf hope their tool “will be utilized immediately by patients and providers to help predict an individual’s risk of cisplatin-associated kidney damage. It is easy to use, available for free online, and incorporates readily available clinical variables.”

If a patient is at high risk, the clinical team can consider preventive measures such as administering more IV fluids before receiving cisplatin or monitoring kidney function more closely afterward, they suggested.

Dr. Gupta reported research support from the National Institutes of Health (NIH) and the National Institute of Diabetes and Digestive and Kidney Diseases. She also reported research funding from BTG International, GE HealthCare, and AstraZeneca outside the submitted work. She is a member of GlaxoSmithKline’s Global Anemia Council, a consultant for Secretome and Proletariat Therapeutics, and founder and president emeritus of the American Society of Onconephrology (unpaid). Dr. Leaf is supported by NIH grants, reported research support from BioPorto, BTG International, and Metro International Biotech, and has served as a consultant. Dr. Topf reported an ownership stake in a few DaVita-run dialysis clinics. He also runs a vascular access center and has participated in advisory boards with Cara Therapeutics, Vifor, Astra Zeneca, Bayer, Renibus Therapeutics, Travere Therapeutics, and GlaxoSmithKline. He is president of NephJC, a nonprofit educational organization with no industry support. Dr. Shirali declared no competing interests.

A version of this article appeared on Medscape.com.

Cisplatin is a preferred treatment for a wide range of cancers, including breast, head and neck, lung, ovary, and more. However, its side effects — particularly nephrotoxicity — can be severe. Kidney injury on cisplatin is associated with higher mortality and can jeopardize a patient’s eligibility for other therapies.

Now, in a large study using data from six US cancer centers, researchers have developed a risk algorithm to predict acute kidney injury (AKI) after cisplatin administration.

A risk prediction calculator based on the algorithm is available online for patients and providers to determine an individual patient›s risk for kidney injury from cisplatin using readily available clinical data.

Other risk scores and risk prediction models have been developed to help clinicians assess in advance whether a patient might develop AKI after receiving cisplatin, so that more careful monitoring, dose adjustments, or an alternative treatment, if available, might be considered.

However, previous models were limited by factors such as small sample sizes, lack of external validation, older data, and liberal definitions of AKI, said Shruti Gupta, MD, MPH, director of onco-nephrology at Brigham and Women’s Hospital (BWH) and Dana-Farber Cancer Institute, and David E. Leaf, MD, MMSc, director of clinical and translational research in AKI, Division of Renal Medicine, BWH, Boston.

Dr. Gupta and Dr. Leaf believe their risk score for predicting severe AKI after intravenous (IV) cisplatin, published online in The BMJ, is “more accurate and generalizable than prior models for several reasons,” they told this news organization in a joint email.

“First, we externally validated our findings across cancer centers other than the one where it was developed,” they said. “Second, we focused on moderate to severe kidney injury, the most clinically relevant form of kidney damage, whereas prior models examined more mild forms of kidney injury. Third, we collected data on nearly 25,000 patients receiving their first dose of IV cisplatin, which is larger than all previous studies combined.”
 

‘Herculean Effort’

“We conceived of this study back in 2018, contacted collaborators at each participating cancer center, and had numerous meetings to try to gather granular data on patients treated with their first dose of intravenous (IV) cisplatin,” Dr. Gupta and Dr. Leaf explained. They also incorporated patient feedback from focus groups and surveys.

“This was truly a Herculean effort that involved physicians, programmers, research coordinators, and patients,” they said.

The multicenter study included 24,717 patients — 11,766 in the derivation cohort and 12,951 in the validation cohort. Overall, the median age was about 60 years, about 58% were men, and about 78% were White.

The primary outcome was cisplatin-induced AKI (CP-AKI), defined as a twofold or greater increase in serum creatinine or kidney replacement therapy within 14 days of a first dose of IV cisplatin.

The researchers found that the incidence of CP-AKI was 5.2% in the derivation cohort and 3.3% in the validation cohort. Their simple risk score consisting of nine covariates — age, hypertension, type 2 diabetes, hemoglobin level, white blood cell count, platelet count, serum albumin level, serum magnesium level, and cisplatin dose — predicted a higher risk for CP-AKI in both cohorts.

Notably, adding serum creatinine to the model did not change the area under the curve, and therefore, serum creatinine, though also an independent risk factor for CP-AKI, was not included in the score.

Patients in the highest risk category had 24-fold higher odds of CP-AKI in the derivation cohort and close to 18-fold higher odds in the validation cohort than those in the lowest risk category.

The primary model had a C statistic of 0.75 (95% CI, 0.73-0.76) and showed better discrimination for CP-AKI than previously published models, for which the C statistics ranged from 0.60 to 0.68. The first author of a paper on an earlier model, Shveta Motwani, MD, MMSc, of BWH and Dana-Farber Cancer Institute in Boston, is also a coauthor of the new study.

Greater severity of CP-AKI was associated with shorter 90-day survival (adjusted hazard ratio, 4.63; 95% CI, 3.56-6.02) for stage III CP-AKI vs no CP-AKI.
 

‘Definitive Work’

Joel M. Topf, MD, a nephrologist with expertise in chronic kidney disease in Detroit, who wasn’t involved in the development of the risk score, called the study “a definitive work on an important concept in oncology and nephrology.”

“While this is not the first attempt to devise a risk score, it is by far the biggest,” he told this news organization. Furthermore, the authors “used a diverse population, recruiting patients with a variety of cancers (previous attempts had often used a homogenous diagnosis, putting into question how generalizable the results were) from six different cancer centers.”

In addition, he said, “The authors did not restrict patients with chronic kidney disease or other significant comorbidities and used the geographic diversity to produce a cohort that has an age, gender, racial, and ethnic distribution, which is more representative of the US than previous, single-center attempts to risk score patients.”

An earlier model used the Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI of an increase in serum creatinine of 0.3 mg/dL, he noted. “While a sensitive definition of AKI, it captures mild, hemodynamic increases in creatinine of questionable significance,” he said.

By contrast, the new score uses KDIGO stage II and above to define AKI. “This is a better choice, as we do not want to dissuade patients and doctors from choosing chemotherapy due to a fear of insignificant kidney damage,” he said.

All that said, Dr. Topf noted that neither the current score nor the earlier model included serum creatinine. “This is curious to me and may represent the small number of patients with representative elevated creatinine in the derivation cohort (only 1.3% with an estimated glomerular filtration rate [eGFR] < 45).”

“Since the cohort is made up of people who received cis-platinum, the low prevalence of eGFRs < 45 may be due to physicians steering away from cis-platinum in this group,” he suggested. “It would be unfortunate if this risk score gave an unintentional ‘green light’ to these patients, exposing them to predictable harm.”
 

‘Certainly Useful’

Anushree Shirali, MD, an associate professor in the Section of Nephrology and consulting physician, Yale Onco-Nephrology, Yale School of Medicine, in New Haven, Connecticut, said that having a prediction score for which patients are more likely to develop AKI after a single dose of cisplatin would be helpful for oncologists, as well as nephrologists.

As a nephrologist, Dr. Shirali mostly sees patients who already have AKI, she told this news organization. But there are circumstances in which the tool could still be helpful.

“Let’s say someone has abnormal kidney function at baseline — ie, creatinine is higher than the normal range — and they were on dialysis 5 years ago for something else, and now, they have cancer and may be given cisplatin. They worry about their chances of getting AKI and needing dialysis again,” she said. “That’s just one scenario in which I might be asked to answer that question and the tool would certainly be useful.”

Other scenarios could include someone who has just one kidney because they donated a kidney for transplant years ago, and now, they have a malignancy and wonder what their actual risk is of getting kidney issues on cisplatin.

Oncologists could use the tool to determine whether a patient should be treated with cisplatin, or if they’re at high risk, whether an alternative that’s not nephrotoxic might be used. By contrast, “if somebody’s low risk and an oncologist thinks cisplatin is the best agent they have, then they might want to go ahead and use it,” Dr. Shirali said.

Future research could take into consideration that CP-AKI is dose dependent, she suggested, because a prediction score that included the number of cisplatin doses could be even more helpful to determine risk. And, even though the derivation and validation cohorts for the new tool are representative of the US population, additional research should also include more racial/ethnic diversity, she said.

Dr. Gupta and Dr. Leaf hope their tool “will be utilized immediately by patients and providers to help predict an individual’s risk of cisplatin-associated kidney damage. It is easy to use, available for free online, and incorporates readily available clinical variables.”

If a patient is at high risk, the clinical team can consider preventive measures such as administering more IV fluids before receiving cisplatin or monitoring kidney function more closely afterward, they suggested.

Dr. Gupta reported research support from the National Institutes of Health (NIH) and the National Institute of Diabetes and Digestive and Kidney Diseases. She also reported research funding from BTG International, GE HealthCare, and AstraZeneca outside the submitted work. She is a member of GlaxoSmithKline’s Global Anemia Council, a consultant for Secretome and Proletariat Therapeutics, and founder and president emeritus of the American Society of Onconephrology (unpaid). Dr. Leaf is supported by NIH grants, reported research support from BioPorto, BTG International, and Metro International Biotech, and has served as a consultant. Dr. Topf reported an ownership stake in a few DaVita-run dialysis clinics. He also runs a vascular access center and has participated in advisory boards with Cara Therapeutics, Vifor, Astra Zeneca, Bayer, Renibus Therapeutics, Travere Therapeutics, and GlaxoSmithKline. He is president of NephJC, a nonprofit educational organization with no industry support. Dr. Shirali declared no competing interests.

A version of this article appeared on Medscape.com.

Cisplatin is a preferred treatment for a wide range of cancers, including breast, head and neck, lung, ovary, and more. However, its side effects — particularly nephrotoxicity — can be severe. Kidney injury on cisplatin is associated with higher mortality and can jeopardize a patient’s eligibility for other therapies.

Now, in a large study using data from six US cancer centers, researchers have developed a risk algorithm to predict acute kidney injury (AKI) after cisplatin administration.

A risk prediction calculator based on the algorithm is available online for patients and providers to determine an individual patient›s risk for kidney injury from cisplatin using readily available clinical data.

Other risk scores and risk prediction models have been developed to help clinicians assess in advance whether a patient might develop AKI after receiving cisplatin, so that more careful monitoring, dose adjustments, or an alternative treatment, if available, might be considered.

However, previous models were limited by factors such as small sample sizes, lack of external validation, older data, and liberal definitions of AKI, said Shruti Gupta, MD, MPH, director of onco-nephrology at Brigham and Women’s Hospital (BWH) and Dana-Farber Cancer Institute, and David E. Leaf, MD, MMSc, director of clinical and translational research in AKI, Division of Renal Medicine, BWH, Boston.

Dr. Gupta and Dr. Leaf believe their risk score for predicting severe AKI after intravenous (IV) cisplatin, published online in The BMJ, is “more accurate and generalizable than prior models for several reasons,” they told this news organization in a joint email.

“First, we externally validated our findings across cancer centers other than the one where it was developed,” they said. “Second, we focused on moderate to severe kidney injury, the most clinically relevant form of kidney damage, whereas prior models examined more mild forms of kidney injury. Third, we collected data on nearly 25,000 patients receiving their first dose of IV cisplatin, which is larger than all previous studies combined.”
 

‘Herculean Effort’

“We conceived of this study back in 2018, contacted collaborators at each participating cancer center, and had numerous meetings to try to gather granular data on patients treated with their first dose of intravenous (IV) cisplatin,” Dr. Gupta and Dr. Leaf explained. They also incorporated patient feedback from focus groups and surveys.

“This was truly a Herculean effort that involved physicians, programmers, research coordinators, and patients,” they said.

The multicenter study included 24,717 patients — 11,766 in the derivation cohort and 12,951 in the validation cohort. Overall, the median age was about 60 years, about 58% were men, and about 78% were White.

The primary outcome was cisplatin-induced AKI (CP-AKI), defined as a twofold or greater increase in serum creatinine or kidney replacement therapy within 14 days of a first dose of IV cisplatin.

The researchers found that the incidence of CP-AKI was 5.2% in the derivation cohort and 3.3% in the validation cohort. Their simple risk score consisting of nine covariates — age, hypertension, type 2 diabetes, hemoglobin level, white blood cell count, platelet count, serum albumin level, serum magnesium level, and cisplatin dose — predicted a higher risk for CP-AKI in both cohorts.

Notably, adding serum creatinine to the model did not change the area under the curve, and therefore, serum creatinine, though also an independent risk factor for CP-AKI, was not included in the score.

Patients in the highest risk category had 24-fold higher odds of CP-AKI in the derivation cohort and close to 18-fold higher odds in the validation cohort than those in the lowest risk category.

The primary model had a C statistic of 0.75 (95% CI, 0.73-0.76) and showed better discrimination for CP-AKI than previously published models, for which the C statistics ranged from 0.60 to 0.68. The first author of a paper on an earlier model, Shveta Motwani, MD, MMSc, of BWH and Dana-Farber Cancer Institute in Boston, is also a coauthor of the new study.

Greater severity of CP-AKI was associated with shorter 90-day survival (adjusted hazard ratio, 4.63; 95% CI, 3.56-6.02) for stage III CP-AKI vs no CP-AKI.
 

‘Definitive Work’

Joel M. Topf, MD, a nephrologist with expertise in chronic kidney disease in Detroit, who wasn’t involved in the development of the risk score, called the study “a definitive work on an important concept in oncology and nephrology.”

“While this is not the first attempt to devise a risk score, it is by far the biggest,” he told this news organization. Furthermore, the authors “used a diverse population, recruiting patients with a variety of cancers (previous attempts had often used a homogenous diagnosis, putting into question how generalizable the results were) from six different cancer centers.”

In addition, he said, “The authors did not restrict patients with chronic kidney disease or other significant comorbidities and used the geographic diversity to produce a cohort that has an age, gender, racial, and ethnic distribution, which is more representative of the US than previous, single-center attempts to risk score patients.”

An earlier model used the Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI of an increase in serum creatinine of 0.3 mg/dL, he noted. “While a sensitive definition of AKI, it captures mild, hemodynamic increases in creatinine of questionable significance,” he said.

By contrast, the new score uses KDIGO stage II and above to define AKI. “This is a better choice, as we do not want to dissuade patients and doctors from choosing chemotherapy due to a fear of insignificant kidney damage,” he said.

All that said, Dr. Topf noted that neither the current score nor the earlier model included serum creatinine. “This is curious to me and may represent the small number of patients with representative elevated creatinine in the derivation cohort (only 1.3% with an estimated glomerular filtration rate [eGFR] < 45).”

“Since the cohort is made up of people who received cis-platinum, the low prevalence of eGFRs < 45 may be due to physicians steering away from cis-platinum in this group,” he suggested. “It would be unfortunate if this risk score gave an unintentional ‘green light’ to these patients, exposing them to predictable harm.”
 

‘Certainly Useful’

Anushree Shirali, MD, an associate professor in the Section of Nephrology and consulting physician, Yale Onco-Nephrology, Yale School of Medicine, in New Haven, Connecticut, said that having a prediction score for which patients are more likely to develop AKI after a single dose of cisplatin would be helpful for oncologists, as well as nephrologists.

As a nephrologist, Dr. Shirali mostly sees patients who already have AKI, she told this news organization. But there are circumstances in which the tool could still be helpful.

“Let’s say someone has abnormal kidney function at baseline — ie, creatinine is higher than the normal range — and they were on dialysis 5 years ago for something else, and now, they have cancer and may be given cisplatin. They worry about their chances of getting AKI and needing dialysis again,” she said. “That’s just one scenario in which I might be asked to answer that question and the tool would certainly be useful.”

Other scenarios could include someone who has just one kidney because they donated a kidney for transplant years ago, and now, they have a malignancy and wonder what their actual risk is of getting kidney issues on cisplatin.

Oncologists could use the tool to determine whether a patient should be treated with cisplatin, or if they’re at high risk, whether an alternative that’s not nephrotoxic might be used. By contrast, “if somebody’s low risk and an oncologist thinks cisplatin is the best agent they have, then they might want to go ahead and use it,” Dr. Shirali said.

Future research could take into consideration that CP-AKI is dose dependent, she suggested, because a prediction score that included the number of cisplatin doses could be even more helpful to determine risk. And, even though the derivation and validation cohorts for the new tool are representative of the US population, additional research should also include more racial/ethnic diversity, she said.

Dr. Gupta and Dr. Leaf hope their tool “will be utilized immediately by patients and providers to help predict an individual’s risk of cisplatin-associated kidney damage. It is easy to use, available for free online, and incorporates readily available clinical variables.”

If a patient is at high risk, the clinical team can consider preventive measures such as administering more IV fluids before receiving cisplatin or monitoring kidney function more closely afterward, they suggested.

Dr. Gupta reported research support from the National Institutes of Health (NIH) and the National Institute of Diabetes and Digestive and Kidney Diseases. She also reported research funding from BTG International, GE HealthCare, and AstraZeneca outside the submitted work. She is a member of GlaxoSmithKline’s Global Anemia Council, a consultant for Secretome and Proletariat Therapeutics, and founder and president emeritus of the American Society of Onconephrology (unpaid). Dr. Leaf is supported by NIH grants, reported research support from BioPorto, BTG International, and Metro International Biotech, and has served as a consultant. Dr. Topf reported an ownership stake in a few DaVita-run dialysis clinics. He also runs a vascular access center and has participated in advisory boards with Cara Therapeutics, Vifor, Astra Zeneca, Bayer, Renibus Therapeutics, Travere Therapeutics, and GlaxoSmithKline. He is president of NephJC, a nonprofit educational organization with no industry support. Dr. Shirali declared no competing interests.

A version of this article appeared on Medscape.com.

By age 12 years, more than 14% of children have tried alcohol or tobacco, and religion, race, and income are the top predictors beginning to use these and other substances, new research suggests.

Aside from sociodemographic parameters, risk factors for substance use initiation include prenatal exposure to substances, peer use of alcohol and nicotine, and problematic school behavior, among other things, the study showed.

The results show certain modifiable risk factors may play a role in preventing youth from starting to use substances, said study author ReJoyce Green, PhD, research assistant professor, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston.

“If we’re designing, say, a prevention program or an early intervention program, these are things that could make a difference, so let’s make sure we’re bringing them into the conversation.”

The findings were presented at the annual meeting of the American Psychiatric Association American Psychiatric Association (APA) and published online in The American Journal of Psychiatry.
 

Critical Risk Factors

Use of alcohol, tobacco, and cannabis often begins during adolescence. One recent survey showed that 23% of 13-year-olds reported using alcohol, 17% reported vaping nicotine, and 8% reported vaping cannabis. Other research links younger age at substance use initiation to a more rapid transition to substance use disorders and higher rates of psychiatric disorders.

Previous studies examining predictors of substance use initiation in the Adolescent Brain Cognitive Development (ABCD) Study dataset focused primarily on self-reported measures, but the current study also looked at models that include hormones and neurocognitive factors as well as neuroimaging.

This study included 6829, 9- and 10-year-olds from the ABCD Study who had never tried substances and were followed for 3 years.

A sophisticated statistical approach was used to examine 420 variables as predictors of substance use initiation. Initiation was defined as trying any nonprescribed substance by age 12 years. “That’s including a single sip of alcohol or puff of a cigarette,” said Dr. Green.

In addition to alcohol, nicotine, and cannabis, researchers looked at initiation of synthetic cannabinoids, cocaine, methamphetamine, and ketamine, among other substances.

Self-reported measures included demographic characteristics, self and peer involvement with substance use, parenting behaviors, mental and physical health, and culture and environmental factors.

The analytical approach used machine-learning algorithms to compare the ability of domains to identify the most critical risk factors. Magnitudes of coefficients were used to assess variable importance, with positive coefficients indicating greater likelihood of substance initiation and negative coefficients indicating lower likelihood of initiation.

By age 12 years, 14.4% of the children studied reported substance initiation. Alcohol was the substance most commonly initiated (365 individuals), followed by nicotine (94 individuals) and cannabis (40 individuals), with few or no children initiating other substances.

Both those who did and did not initiate substances were similarly aged, and most participants identified as White and non-Hispanic. But the substance-use group had a lower percentage of girls and higher percentage of White participants compared with the no-substance-use group.

The model with only self-reported data had similar accuracy in predicting substance use initiation (area under the curve [AUC], 0.67) as models that added resource-intensive measures such as neurocognitive tests and hormones (AUC, 0.67) and neuroimaging (AUC, 0.66).
 

Religious Predictors

The strongest predictors of substance use initiation were related to religion: Youths whose parents reported a religious preference for Mormonism were less likely to initiate substance use (coefficient, -0.87), whereas youths whose parents reported a religious preference for Judaism were more likely to initiate substance use (coefficient, 0.32).

The third top predictor was race: Black youths were less likely to initiate substance use (coefficient, -0.32). This was followed by youths whose parents reported a religious preference for Islam who were also less likely to initiate substance use (coefficient, -0.25).

The research examined over 15 different religious categories, “so we really tried to be expansive,” noted Dr. Green.

It’s unclear why some religions appeared to have a protective impact when it comes to substance use initiation whereas others have the opposite effect. Future research could perhaps identify which components of religiosity affect substance use initiation. If so, these aspects could be developed and incorporated into prevention and intervention programs, said Dr. Green.

Next on the list of most important predictors was being a part of a household with an income of $12,000-$15,999; these youths were less likely to initiate substance use (coefficient, 0.22).

Within the culture and environment domain, a history of detention or suspension was a top predictor of substance use initiation (coefficient, 0.20). Prenatal exposure to substance use was also a robust predictor in the physical health category (coefficient, 0.15).

Other predictors included: parents with less than a high school degree or GED (coefficient, -0.14), substance use availability (coefficient, 0.12), and age at baseline (coefficient, 0.12).

The study also showed that better cognitive functioning in selected domains (eg, cognitive control, attention, and language ability) is associated with a greater likelihood of substance use initiation.
 

Shaping Future Prevention

Applying these findings in clinical settings could help tailor prevention and early intervention efforts, said the authors. It might be prudent to allocate resources to collecting data related to self-, peer-, and familial-related factors, “which were more informative in predicting substance use initiation during late childhood and early adolescence in the present study,” they wrote.

Researchers will continue to track these children through to a 10-year follow-up, said Dr. Green. “I’m really curious to see if the factors we found when they were 12 and 13, such as those related to peers and family, still hold when they’re ages 17 and 18, because there’s going to be a huge amount of brain development that’s happening throughout this phase.”

The group that initiated substance use and the group that didn’t initiate substance use were not totally balanced, and sample sizes for some religious categories were small. Another study limitation was that the analytic approach didn’t account for multilevel data within the context of site and families.

Commenting on the findings, Kathleen Brady, MD, PhD, distinguished university professor and director, South Carolina Clinical and Translational Research Institute, Medical University of South Carolina, said that the study is “critical and complex.” This, she said, is especially true as cannabis has become more accessible and potent, and as the federal government reportedly considers reclassifying it from a Schedule I drug (which includes highly dangerous, addictive substances with no medical use) to a Schedule III drug (which can be prescribed as a medication).

“The part that is the most frightening to me is the long-lasting effects that can happen when young people start using high-potency marijuana at an early age,” said Dr. Brady. “So, any information that we can give to parents, to teachers, to the public, and to doctors is important.”

She’s looking forward to getting more “incredibly important” information on substance use initiation as the study progresses and the teens get older. 

The study received support from the National Institute on Alcohol Abuse and Alcoholism and the National Institute on Drug Abuse.

A version of this article appeared on Medscape.com.

By age 12 years, more than 14% of children have tried alcohol or tobacco, and religion, race, and income are the top predictors beginning to use these and other substances, new research suggests.

Aside from sociodemographic parameters, risk factors for substance use initiation include prenatal exposure to substances, peer use of alcohol and nicotine, and problematic school behavior, among other things, the study showed.

The results show certain modifiable risk factors may play a role in preventing youth from starting to use substances, said study author ReJoyce Green, PhD, research assistant professor, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston.

“If we’re designing, say, a prevention program or an early intervention program, these are things that could make a difference, so let’s make sure we’re bringing them into the conversation.”

The findings were presented at the annual meeting of the American Psychiatric Association American Psychiatric Association (APA) and published online in The American Journal of Psychiatry.
 

Critical Risk Factors

Use of alcohol, tobacco, and cannabis often begins during adolescence. One recent survey showed that 23% of 13-year-olds reported using alcohol, 17% reported vaping nicotine, and 8% reported vaping cannabis. Other research links younger age at substance use initiation to a more rapid transition to substance use disorders and higher rates of psychiatric disorders.

Previous studies examining predictors of substance use initiation in the Adolescent Brain Cognitive Development (ABCD) Study dataset focused primarily on self-reported measures, but the current study also looked at models that include hormones and neurocognitive factors as well as neuroimaging.

This study included 6829, 9- and 10-year-olds from the ABCD Study who had never tried substances and were followed for 3 years.

A sophisticated statistical approach was used to examine 420 variables as predictors of substance use initiation. Initiation was defined as trying any nonprescribed substance by age 12 years. “That’s including a single sip of alcohol or puff of a cigarette,” said Dr. Green.

In addition to alcohol, nicotine, and cannabis, researchers looked at initiation of synthetic cannabinoids, cocaine, methamphetamine, and ketamine, among other substances.

Self-reported measures included demographic characteristics, self and peer involvement with substance use, parenting behaviors, mental and physical health, and culture and environmental factors.

The analytical approach used machine-learning algorithms to compare the ability of domains to identify the most critical risk factors. Magnitudes of coefficients were used to assess variable importance, with positive coefficients indicating greater likelihood of substance initiation and negative coefficients indicating lower likelihood of initiation.

By age 12 years, 14.4% of the children studied reported substance initiation. Alcohol was the substance most commonly initiated (365 individuals), followed by nicotine (94 individuals) and cannabis (40 individuals), with few or no children initiating other substances.

Both those who did and did not initiate substances were similarly aged, and most participants identified as White and non-Hispanic. But the substance-use group had a lower percentage of girls and higher percentage of White participants compared with the no-substance-use group.

The model with only self-reported data had similar accuracy in predicting substance use initiation (area under the curve [AUC], 0.67) as models that added resource-intensive measures such as neurocognitive tests and hormones (AUC, 0.67) and neuroimaging (AUC, 0.66).
 

Religious Predictors

The strongest predictors of substance use initiation were related to religion: Youths whose parents reported a religious preference for Mormonism were less likely to initiate substance use (coefficient, -0.87), whereas youths whose parents reported a religious preference for Judaism were more likely to initiate substance use (coefficient, 0.32).

The third top predictor was race: Black youths were less likely to initiate substance use (coefficient, -0.32). This was followed by youths whose parents reported a religious preference for Islam who were also less likely to initiate substance use (coefficient, -0.25).

The research examined over 15 different religious categories, “so we really tried to be expansive,” noted Dr. Green.

It’s unclear why some religions appeared to have a protective impact when it comes to substance use initiation whereas others have the opposite effect. Future research could perhaps identify which components of religiosity affect substance use initiation. If so, these aspects could be developed and incorporated into prevention and intervention programs, said Dr. Green.

Next on the list of most important predictors was being a part of a household with an income of $12,000-$15,999; these youths were less likely to initiate substance use (coefficient, 0.22).

Within the culture and environment domain, a history of detention or suspension was a top predictor of substance use initiation (coefficient, 0.20). Prenatal exposure to substance use was also a robust predictor in the physical health category (coefficient, 0.15).

Other predictors included: parents with less than a high school degree or GED (coefficient, -0.14), substance use availability (coefficient, 0.12), and age at baseline (coefficient, 0.12).

The study also showed that better cognitive functioning in selected domains (eg, cognitive control, attention, and language ability) is associated with a greater likelihood of substance use initiation.
 

Shaping Future Prevention

Applying these findings in clinical settings could help tailor prevention and early intervention efforts, said the authors. It might be prudent to allocate resources to collecting data related to self-, peer-, and familial-related factors, “which were more informative in predicting substance use initiation during late childhood and early adolescence in the present study,” they wrote.

Researchers will continue to track these children through to a 10-year follow-up, said Dr. Green. “I’m really curious to see if the factors we found when they were 12 and 13, such as those related to peers and family, still hold when they’re ages 17 and 18, because there’s going to be a huge amount of brain development that’s happening throughout this phase.”

The group that initiated substance use and the group that didn’t initiate substance use were not totally balanced, and sample sizes for some religious categories were small. Another study limitation was that the analytic approach didn’t account for multilevel data within the context of site and families.

Commenting on the findings, Kathleen Brady, MD, PhD, distinguished university professor and director, South Carolina Clinical and Translational Research Institute, Medical University of South Carolina, said that the study is “critical and complex.” This, she said, is especially true as cannabis has become more accessible and potent, and as the federal government reportedly considers reclassifying it from a Schedule I drug (which includes highly dangerous, addictive substances with no medical use) to a Schedule III drug (which can be prescribed as a medication).

“The part that is the most frightening to me is the long-lasting effects that can happen when young people start using high-potency marijuana at an early age,” said Dr. Brady. “So, any information that we can give to parents, to teachers, to the public, and to doctors is important.”

She’s looking forward to getting more “incredibly important” information on substance use initiation as the study progresses and the teens get older. 

The study received support from the National Institute on Alcohol Abuse and Alcoholism and the National Institute on Drug Abuse.

A version of this article appeared on Medscape.com.

By age 12 years, more than 14% of children have tried alcohol or tobacco, and religion, race, and income are the top predictors beginning to use these and other substances, new research suggests.

Aside from sociodemographic parameters, risk factors for substance use initiation include prenatal exposure to substances, peer use of alcohol and nicotine, and problematic school behavior, among other things, the study showed.

The results show certain modifiable risk factors may play a role in preventing youth from starting to use substances, said study author ReJoyce Green, PhD, research assistant professor, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston.

“If we’re designing, say, a prevention program or an early intervention program, these are things that could make a difference, so let’s make sure we’re bringing them into the conversation.”

The findings were presented at the annual meeting of the American Psychiatric Association American Psychiatric Association (APA) and published online in The American Journal of Psychiatry.
 

Critical Risk Factors

Use of alcohol, tobacco, and cannabis often begins during adolescence. One recent survey showed that 23% of 13-year-olds reported using alcohol, 17% reported vaping nicotine, and 8% reported vaping cannabis. Other research links younger age at substance use initiation to a more rapid transition to substance use disorders and higher rates of psychiatric disorders.

Previous studies examining predictors of substance use initiation in the Adolescent Brain Cognitive Development (ABCD) Study dataset focused primarily on self-reported measures, but the current study also looked at models that include hormones and neurocognitive factors as well as neuroimaging.

This study included 6829, 9- and 10-year-olds from the ABCD Study who had never tried substances and were followed for 3 years.

A sophisticated statistical approach was used to examine 420 variables as predictors of substance use initiation. Initiation was defined as trying any nonprescribed substance by age 12 years. “That’s including a single sip of alcohol or puff of a cigarette,” said Dr. Green.

In addition to alcohol, nicotine, and cannabis, researchers looked at initiation of synthetic cannabinoids, cocaine, methamphetamine, and ketamine, among other substances.

Self-reported measures included demographic characteristics, self and peer involvement with substance use, parenting behaviors, mental and physical health, and culture and environmental factors.

The analytical approach used machine-learning algorithms to compare the ability of domains to identify the most critical risk factors. Magnitudes of coefficients were used to assess variable importance, with positive coefficients indicating greater likelihood of substance initiation and negative coefficients indicating lower likelihood of initiation.

By age 12 years, 14.4% of the children studied reported substance initiation. Alcohol was the substance most commonly initiated (365 individuals), followed by nicotine (94 individuals) and cannabis (40 individuals), with few or no children initiating other substances.

Both those who did and did not initiate substances were similarly aged, and most participants identified as White and non-Hispanic. But the substance-use group had a lower percentage of girls and higher percentage of White participants compared with the no-substance-use group.

The model with only self-reported data had similar accuracy in predicting substance use initiation (area under the curve [AUC], 0.67) as models that added resource-intensive measures such as neurocognitive tests and hormones (AUC, 0.67) and neuroimaging (AUC, 0.66).
 

Religious Predictors

The strongest predictors of substance use initiation were related to religion: Youths whose parents reported a religious preference for Mormonism were less likely to initiate substance use (coefficient, -0.87), whereas youths whose parents reported a religious preference for Judaism were more likely to initiate substance use (coefficient, 0.32).

The third top predictor was race: Black youths were less likely to initiate substance use (coefficient, -0.32). This was followed by youths whose parents reported a religious preference for Islam who were also less likely to initiate substance use (coefficient, -0.25).

The research examined over 15 different religious categories, “so we really tried to be expansive,” noted Dr. Green.

It’s unclear why some religions appeared to have a protective impact when it comes to substance use initiation whereas others have the opposite effect. Future research could perhaps identify which components of religiosity affect substance use initiation. If so, these aspects could be developed and incorporated into prevention and intervention programs, said Dr. Green.

Next on the list of most important predictors was being a part of a household with an income of $12,000-$15,999; these youths were less likely to initiate substance use (coefficient, 0.22).

Within the culture and environment domain, a history of detention or suspension was a top predictor of substance use initiation (coefficient, 0.20). Prenatal exposure to substance use was also a robust predictor in the physical health category (coefficient, 0.15).

Other predictors included: parents with less than a high school degree or GED (coefficient, -0.14), substance use availability (coefficient, 0.12), and age at baseline (coefficient, 0.12).

The study also showed that better cognitive functioning in selected domains (eg, cognitive control, attention, and language ability) is associated with a greater likelihood of substance use initiation.
 

Shaping Future Prevention

Applying these findings in clinical settings could help tailor prevention and early intervention efforts, said the authors. It might be prudent to allocate resources to collecting data related to self-, peer-, and familial-related factors, “which were more informative in predicting substance use initiation during late childhood and early adolescence in the present study,” they wrote.

Researchers will continue to track these children through to a 10-year follow-up, said Dr. Green. “I’m really curious to see if the factors we found when they were 12 and 13, such as those related to peers and family, still hold when they’re ages 17 and 18, because there’s going to be a huge amount of brain development that’s happening throughout this phase.”

The group that initiated substance use and the group that didn’t initiate substance use were not totally balanced, and sample sizes for some religious categories were small. Another study limitation was that the analytic approach didn’t account for multilevel data within the context of site and families.

Commenting on the findings, Kathleen Brady, MD, PhD, distinguished university professor and director, South Carolina Clinical and Translational Research Institute, Medical University of South Carolina, said that the study is “critical and complex.” This, she said, is especially true as cannabis has become more accessible and potent, and as the federal government reportedly considers reclassifying it from a Schedule I drug (which includes highly dangerous, addictive substances with no medical use) to a Schedule III drug (which can be prescribed as a medication).

“The part that is the most frightening to me is the long-lasting effects that can happen when young people start using high-potency marijuana at an early age,” said Dr. Brady. “So, any information that we can give to parents, to teachers, to the public, and to doctors is important.”

She’s looking forward to getting more “incredibly important” information on substance use initiation as the study progresses and the teens get older. 

The study received support from the National Institute on Alcohol Abuse and Alcoholism and the National Institute on Drug Abuse.

A version of this article appeared on Medscape.com.

The expression of the protein Nectin-4 can predict how patients with metastatic urothelial cancer (m)UC will respond to the anti-Nectin-4 antibody-drug conjugate (ADC) enfortumab vedotin (EV), a new study finds.

Identifying biomarkers to predict how patients will respond to targeted therapies is crucial to improve treatments for patients with cancer, authors Niklas Klümper, MD, with the Department of Urology and Pediatric Urology at University Hospital Bonn, in Germany, and colleagues, wrote in the Journal of Clinical Oncology (doi: 10.1200/JCO.23.01983).

The researchers used a Nectin-4-specific fluorescence in situ hybridization (FISH) assay in an (m)UC cohort of 108 patients to test Nectin-4’s ability to predict responses, analyzing slides with a fluorescence microscope. The copy number variations (CNVs) were correlated with membranous Nectin-4 protein expression, responses to EV treatment, and outcomes.

They also evaluated the prognostic value of Nectin-4 CNVs with biopsies of 103 (m)UC patients not treated with EV. Additionally, they searched The Cancer Genome Atlas (TCGA) data sets (10,712 patients across 32 cancer types) for Nectin-4 CNVs.
 

Why Was This Study Done?

Urothelial carcinoma accounts for 90% of bladder cancer cases globally. Though EV was approved to treat (m)UC in 2019, lasting benefit has been achieved only in a small subset of patients.

EV is given to all without selecting patients based on biomarkers that may predict how well they will respond to EV. In this study, researchers investigated whether response to EV was better when people had amplification — defined as increased numbers of copies — of Nectin-4.
 

How Common Is It for Patients With (m)UC to Have Nectin-4 Amplifications?

Nectin-4 amplifications happen frequently in (m)UC; they occurred in about 26% of the (m)UC patients the researchers studied, according to the new paper.

The amplifications are frequent in other cancer types as well, and this study suggests that this biomarker is a promising candidate for developing Nectin-4–targeted antibody-drug conjugates for other cancers.

“Nectin-4 amplifications can be found in 5%-10% of breast cancer and non–small cell lung cancer, both tumor types with a high impact on all-cancer mortality, which are currently being evaluated for EV response,” the authors wrote.

Currently, (m)UC is the only cancer for which EV is approved as standard-of-care, the researchers explain, in their paper.
 

What Were the Differences Between the EV and Non-EV Groups?

Almost all (27 of the 28) patients in the cohort (96%) who had Nectin-4 amplifications had objective responses to EV compared with 24 of 74 (32%) in the group without amplifications (P less than .001). Among the 96% with a response, 82% had partial response and 14% had a complete response.

The amplifications for those treated with EV were linked with longer progression-free survival (90% 12-month PFS vs 41% for those with nonamplified tumors) and longer overall survival (OS).

For those patients treated with EV who had the amplifications, OS was not reached. This was because the researchers could not calculate the OS at 12 months for this group due to more than half of the patients still being alive at that time. That finding contrasts with a median OS of 8.8 months in those patients treated with EV who did not have the amplifications.

EV-treated patients who had Nectin-4 amplifications had a 92% lower risk of death compared with EV-treated patients without the amplifications, according to an analysis that adjusted for factors including age and sex.

“Importantly, in the non–EV-treated patients with (m)UC, Nectin-4 amplifications have no impact on OS [overall survival], suggesting that Nectin-4 amplifications are neither indicating aggressive nor favorable tumor biology, strengthening its potential value as a pure predictive biomarker,” the researchers wrote.
 

What Are the Implications of These Findings?

“[O]ur study suggests that Nectin-4 amplification is a simple, valuable, and easy-to-implement predictive biomarker for EV in patients with (m)UC. The frequent occurrence of Nectin-4 amplifications in other cancer types suggests that this biomarker is a promising candidate with broader applicability for clinical development of Nectin-4-targeted ADCs in a tumor-agnostic context.”

Choosing the best therapy sequence for (m)UC is crucial, the authors write. Considering Nectin-4 amplifications could inform EV drug development — even at earlier stages of the disease — by defining which patient subgroup has the highest chance for long-term benefit.

The authors acknowledge that the primary limitation of the study is that it is retrospective, using archived primary and metastatic tumor specimens with varying ranges between the time of tumor sampling and start of EV treatment.

“Therefore, our data are hypothesis-generating and prospective confirmation in larger, biomarker-driven trials is mandatory,” the authors wrote.

They note that EV plus pembrolizumab [Keytruda] (EV/P) was recently approved as the new standard of care in first-line treatment for (m)UC, so the predictive value of Nectin-4 amplification in this new treatment setting warrants further research.

Dr. Klümper reports stock and other ownership interests in Bicycle Therapeutics, Pfizer, Daiichi Sankyo/UCB Japan, and Immatics; and honoraria for Astellas Pharma and MSD Oncology; and consulting or advisory roles with Astellas Pharma, MSD Oncology, and Eisai. He reports travel reimbursements from Ipsen, Photocure, and MSD Oncology. Other author disclosures are available with the full text of the paper.

The expression of the protein Nectin-4 can predict how patients with metastatic urothelial cancer (m)UC will respond to the anti-Nectin-4 antibody-drug conjugate (ADC) enfortumab vedotin (EV), a new study finds.

Identifying biomarkers to predict how patients will respond to targeted therapies is crucial to improve treatments for patients with cancer, authors Niklas Klümper, MD, with the Department of Urology and Pediatric Urology at University Hospital Bonn, in Germany, and colleagues, wrote in the Journal of Clinical Oncology (doi: 10.1200/JCO.23.01983).

The researchers used a Nectin-4-specific fluorescence in situ hybridization (FISH) assay in an (m)UC cohort of 108 patients to test Nectin-4’s ability to predict responses, analyzing slides with a fluorescence microscope. The copy number variations (CNVs) were correlated with membranous Nectin-4 protein expression, responses to EV treatment, and outcomes.

They also evaluated the prognostic value of Nectin-4 CNVs with biopsies of 103 (m)UC patients not treated with EV. Additionally, they searched The Cancer Genome Atlas (TCGA) data sets (10,712 patients across 32 cancer types) for Nectin-4 CNVs.
 

Why Was This Study Done?

Urothelial carcinoma accounts for 90% of bladder cancer cases globally. Though EV was approved to treat (m)UC in 2019, lasting benefit has been achieved only in a small subset of patients.

EV is given to all without selecting patients based on biomarkers that may predict how well they will respond to EV. In this study, researchers investigated whether response to EV was better when people had amplification — defined as increased numbers of copies — of Nectin-4.
 

How Common Is It for Patients With (m)UC to Have Nectin-4 Amplifications?

Nectin-4 amplifications happen frequently in (m)UC; they occurred in about 26% of the (m)UC patients the researchers studied, according to the new paper.

The amplifications are frequent in other cancer types as well, and this study suggests that this biomarker is a promising candidate for developing Nectin-4–targeted antibody-drug conjugates for other cancers.

“Nectin-4 amplifications can be found in 5%-10% of breast cancer and non–small cell lung cancer, both tumor types with a high impact on all-cancer mortality, which are currently being evaluated for EV response,” the authors wrote.

Currently, (m)UC is the only cancer for which EV is approved as standard-of-care, the researchers explain, in their paper.
 

What Were the Differences Between the EV and Non-EV Groups?

Almost all (27 of the 28) patients in the cohort (96%) who had Nectin-4 amplifications had objective responses to EV compared with 24 of 74 (32%) in the group without amplifications (P less than .001). Among the 96% with a response, 82% had partial response and 14% had a complete response.

The amplifications for those treated with EV were linked with longer progression-free survival (90% 12-month PFS vs 41% for those with nonamplified tumors) and longer overall survival (OS).

For those patients treated with EV who had the amplifications, OS was not reached. This was because the researchers could not calculate the OS at 12 months for this group due to more than half of the patients still being alive at that time. That finding contrasts with a median OS of 8.8 months in those patients treated with EV who did not have the amplifications.

EV-treated patients who had Nectin-4 amplifications had a 92% lower risk of death compared with EV-treated patients without the amplifications, according to an analysis that adjusted for factors including age and sex.

“Importantly, in the non–EV-treated patients with (m)UC, Nectin-4 amplifications have no impact on OS [overall survival], suggesting that Nectin-4 amplifications are neither indicating aggressive nor favorable tumor biology, strengthening its potential value as a pure predictive biomarker,” the researchers wrote.
 

What Are the Implications of These Findings?

“[O]ur study suggests that Nectin-4 amplification is a simple, valuable, and easy-to-implement predictive biomarker for EV in patients with (m)UC. The frequent occurrence of Nectin-4 amplifications in other cancer types suggests that this biomarker is a promising candidate with broader applicability for clinical development of Nectin-4-targeted ADCs in a tumor-agnostic context.”

Choosing the best therapy sequence for (m)UC is crucial, the authors write. Considering Nectin-4 amplifications could inform EV drug development — even at earlier stages of the disease — by defining which patient subgroup has the highest chance for long-term benefit.

The authors acknowledge that the primary limitation of the study is that it is retrospective, using archived primary and metastatic tumor specimens with varying ranges between the time of tumor sampling and start of EV treatment.

“Therefore, our data are hypothesis-generating and prospective confirmation in larger, biomarker-driven trials is mandatory,” the authors wrote.

They note that EV plus pembrolizumab [Keytruda] (EV/P) was recently approved as the new standard of care in first-line treatment for (m)UC, so the predictive value of Nectin-4 amplification in this new treatment setting warrants further research.

Dr. Klümper reports stock and other ownership interests in Bicycle Therapeutics, Pfizer, Daiichi Sankyo/UCB Japan, and Immatics; and honoraria for Astellas Pharma and MSD Oncology; and consulting or advisory roles with Astellas Pharma, MSD Oncology, and Eisai. He reports travel reimbursements from Ipsen, Photocure, and MSD Oncology. Other author disclosures are available with the full text of the paper.

The expression of the protein Nectin-4 can predict how patients with metastatic urothelial cancer (m)UC will respond to the anti-Nectin-4 antibody-drug conjugate (ADC) enfortumab vedotin (EV), a new study finds.

Identifying biomarkers to predict how patients will respond to targeted therapies is crucial to improve treatments for patients with cancer, authors Niklas Klümper, MD, with the Department of Urology and Pediatric Urology at University Hospital Bonn, in Germany, and colleagues, wrote in the Journal of Clinical Oncology (doi: 10.1200/JCO.23.01983).

The researchers used a Nectin-4-specific fluorescence in situ hybridization (FISH) assay in an (m)UC cohort of 108 patients to test Nectin-4’s ability to predict responses, analyzing slides with a fluorescence microscope. The copy number variations (CNVs) were correlated with membranous Nectin-4 protein expression, responses to EV treatment, and outcomes.

They also evaluated the prognostic value of Nectin-4 CNVs with biopsies of 103 (m)UC patients not treated with EV. Additionally, they searched The Cancer Genome Atlas (TCGA) data sets (10,712 patients across 32 cancer types) for Nectin-4 CNVs.
 

Why Was This Study Done?

Urothelial carcinoma accounts for 90% of bladder cancer cases globally. Though EV was approved to treat (m)UC in 2019, lasting benefit has been achieved only in a small subset of patients.

EV is given to all without selecting patients based on biomarkers that may predict how well they will respond to EV. In this study, researchers investigated whether response to EV was better when people had amplification — defined as increased numbers of copies — of Nectin-4.
 

How Common Is It for Patients With (m)UC to Have Nectin-4 Amplifications?

Nectin-4 amplifications happen frequently in (m)UC; they occurred in about 26% of the (m)UC patients the researchers studied, according to the new paper.

The amplifications are frequent in other cancer types as well, and this study suggests that this biomarker is a promising candidate for developing Nectin-4–targeted antibody-drug conjugates for other cancers.

“Nectin-4 amplifications can be found in 5%-10% of breast cancer and non–small cell lung cancer, both tumor types with a high impact on all-cancer mortality, which are currently being evaluated for EV response,” the authors wrote.

Currently, (m)UC is the only cancer for which EV is approved as standard-of-care, the researchers explain, in their paper.
 

What Were the Differences Between the EV and Non-EV Groups?

Almost all (27 of the 28) patients in the cohort (96%) who had Nectin-4 amplifications had objective responses to EV compared with 24 of 74 (32%) in the group without amplifications (P less than .001). Among the 96% with a response, 82% had partial response and 14% had a complete response.

The amplifications for those treated with EV were linked with longer progression-free survival (90% 12-month PFS vs 41% for those with nonamplified tumors) and longer overall survival (OS).

For those patients treated with EV who had the amplifications, OS was not reached. This was because the researchers could not calculate the OS at 12 months for this group due to more than half of the patients still being alive at that time. That finding contrasts with a median OS of 8.8 months in those patients treated with EV who did not have the amplifications.

EV-treated patients who had Nectin-4 amplifications had a 92% lower risk of death compared with EV-treated patients without the amplifications, according to an analysis that adjusted for factors including age and sex.

“Importantly, in the non–EV-treated patients with (m)UC, Nectin-4 amplifications have no impact on OS [overall survival], suggesting that Nectin-4 amplifications are neither indicating aggressive nor favorable tumor biology, strengthening its potential value as a pure predictive biomarker,” the researchers wrote.
 

What Are the Implications of These Findings?

“[O]ur study suggests that Nectin-4 amplification is a simple, valuable, and easy-to-implement predictive biomarker for EV in patients with (m)UC. The frequent occurrence of Nectin-4 amplifications in other cancer types suggests that this biomarker is a promising candidate with broader applicability for clinical development of Nectin-4-targeted ADCs in a tumor-agnostic context.”

Choosing the best therapy sequence for (m)UC is crucial, the authors write. Considering Nectin-4 amplifications could inform EV drug development — even at earlier stages of the disease — by defining which patient subgroup has the highest chance for long-term benefit.

The authors acknowledge that the primary limitation of the study is that it is retrospective, using archived primary and metastatic tumor specimens with varying ranges between the time of tumor sampling and start of EV treatment.

“Therefore, our data are hypothesis-generating and prospective confirmation in larger, biomarker-driven trials is mandatory,” the authors wrote.

They note that EV plus pembrolizumab [Keytruda] (EV/P) was recently approved as the new standard of care in first-line treatment for (m)UC, so the predictive value of Nectin-4 amplification in this new treatment setting warrants further research.

Dr. Klümper reports stock and other ownership interests in Bicycle Therapeutics, Pfizer, Daiichi Sankyo/UCB Japan, and Immatics; and honoraria for Astellas Pharma and MSD Oncology; and consulting or advisory roles with Astellas Pharma, MSD Oncology, and Eisai. He reports travel reimbursements from Ipsen, Photocure, and MSD Oncology. Other author disclosures are available with the full text of the paper.

Like it or not, artificial intelligence (AI) is coming to medicine. For many physicians — maybe you — it’s already here.

More than a third of physicians use AI in their practice. And the vast majority of healthcare companies — 94%, according to Morgan Stanley — use some kind of AI machine learning.

“It’s incumbent on physicians, as well as physicians in training, to become familiar with at least the basics [of AI],” said internist Matthew DeCamp, MD, PhD, an associate professor in the Center for Bioethics and Humanities at the University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Understanding AI can help you leverage it safely and effectively — plus “make better-informed decisions about whether or not to use it in [your] practice,” Dr. DeCamp said.

“Frankly, the people who are deciding whether to implement algorithms in our day-to-day lives are oftentimes not physicians,” noted Ravi B. Parikh, MD, an assistant professor at the University of Pennsylvania and director of augmented and artificial intelligence at the Penn Center for Cancer Care Innovation, Philadelphia. Yet, physicians are most qualified to assess an AI tool’s usefulness in clinical practice.

That brings us to the best starting place for your AI education: Your own institution. Find out what AI tools your organization is implementing — and how you can influence them.

“Getting involved with our hospital data governance is the best way not only to learn practically what these AI tools do but also to influence the development process in positive ways,” Dr. Parikh said.

From there, consider the following resources to enhance your AI knowledge.
 

Get a Lay of the Land: Free Primers

Many clinical societies and interest groups have put out AI primers, an easy way to get a broad overview of the technology. The following were recommended or developed by the experts we spoke to, and all are free:

• The American Medical Association’s (AMA’s) framework for advancing healthcare AI lays out actionable guidance. Ask three key questions, the AMA recommends: Does it work? Does it work for my patients? Does it improve health outcomes?
• The Coalition for Health AI’s Blueprint for Trustworthy AI Implementation Guidance and Assurance for Healthcare provides a high-level summary of how to evaluate AI in healthcare, plus steps for implementing it. AI systems should be useful, safe, accountable, explainable, fair, and secure, the report asserted.
• The National Academy of Medicine’s draft code of conduct for AI in healthcare proposes core principles and commitments. These “reflect simple guideposts to guide and gauge behavior in a complex system and provide a starting point for real-time decision-making,” the report said.
• Health AI Partnership — a collaboration of Duke Health and Microsoft — outlines eight key decision points to consider at any stage of AI implementation, whether you’re still planning how to use it or you’ve started but want to improve it. The site also provides a breakdown of standards by regulatory agencies, organizations, and oversight bodies — so you can make sure your practices align with their guidance.

Make the Most of Conferences

Next time you’re at a conference, check the agenda for sessions on AI. “For someone who’s interested in this, I would be looking for content in my next national meeting because, undoubtedly, it’s going to be there,” said Dr. DeCamp. In a fast-moving field like AI, it’s a great way to get fresh, up-to-the-moment insights.

Listen to This Podcast

The New England Journal of Medicine’s free monthly podcast AI Grand Rounds is made for researchers and clinicians. Available on Apple, Spotify, and YouTube, the pod is good for “someone who’s looking to see both where the field is going [and to hear] a retrospective on big-name papers,” said Dr. Parikh . Episodes run for about an hour.

To learn about the challenges of applying AI to biology: Listen to Daphne Koller, PhD, founder of AI-driven drug discovery and development company insitro. For insights on the potential of AI in medicine, tune into the one with Eric Horvitz, MD, PhD, Microsoft’s chief scientific officer.
 

Consider a Class

Look for courses that focus on AI applications in clinical practice rather than a deep dive into theory. (You need to understand how these tools will influence your work, not the intricacies of large language model development.) Be wary of corporate-funded training that centers on one product , which could present conflicts of interest, said Dr. DeCamp. See the chart for courses that meet these criteria.

A version of this article appeared on Medscape.com.

Like it or not, artificial intelligence (AI) is coming to medicine. For many physicians — maybe you — it’s already here.

More than a third of physicians use AI in their practice. And the vast majority of healthcare companies — 94%, according to Morgan Stanley — use some kind of AI machine learning.

“It’s incumbent on physicians, as well as physicians in training, to become familiar with at least the basics [of AI],” said internist Matthew DeCamp, MD, PhD, an associate professor in the Center for Bioethics and Humanities at the University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Understanding AI can help you leverage it safely and effectively — plus “make better-informed decisions about whether or not to use it in [your] practice,” Dr. DeCamp said.

“Frankly, the people who are deciding whether to implement algorithms in our day-to-day lives are oftentimes not physicians,” noted Ravi B. Parikh, MD, an assistant professor at the University of Pennsylvania and director of augmented and artificial intelligence at the Penn Center for Cancer Care Innovation, Philadelphia. Yet, physicians are most qualified to assess an AI tool’s usefulness in clinical practice.

That brings us to the best starting place for your AI education: Your own institution. Find out what AI tools your organization is implementing — and how you can influence them.

“Getting involved with our hospital data governance is the best way not only to learn practically what these AI tools do but also to influence the development process in positive ways,” Dr. Parikh said.

From there, consider the following resources to enhance your AI knowledge.
 

Get a Lay of the Land: Free Primers

Many clinical societies and interest groups have put out AI primers, an easy way to get a broad overview of the technology. The following were recommended or developed by the experts we spoke to, and all are free:

• The American Medical Association’s (AMA’s) framework for advancing healthcare AI lays out actionable guidance. Ask three key questions, the AMA recommends: Does it work? Does it work for my patients? Does it improve health outcomes?
• The Coalition for Health AI’s Blueprint for Trustworthy AI Implementation Guidance and Assurance for Healthcare provides a high-level summary of how to evaluate AI in healthcare, plus steps for implementing it. AI systems should be useful, safe, accountable, explainable, fair, and secure, the report asserted.
• The National Academy of Medicine’s draft code of conduct for AI in healthcare proposes core principles and commitments. These “reflect simple guideposts to guide and gauge behavior in a complex system and provide a starting point for real-time decision-making,” the report said.
• Health AI Partnership — a collaboration of Duke Health and Microsoft — outlines eight key decision points to consider at any stage of AI implementation, whether you’re still planning how to use it or you’ve started but want to improve it. The site also provides a breakdown of standards by regulatory agencies, organizations, and oversight bodies — so you can make sure your practices align with their guidance.

Make the Most of Conferences

Next time you’re at a conference, check the agenda for sessions on AI. “For someone who’s interested in this, I would be looking for content in my next national meeting because, undoubtedly, it’s going to be there,” said Dr. DeCamp. In a fast-moving field like AI, it’s a great way to get fresh, up-to-the-moment insights.

Listen to This Podcast

The New England Journal of Medicine’s free monthly podcast AI Grand Rounds is made for researchers and clinicians. Available on Apple, Spotify, and YouTube, the pod is good for “someone who’s looking to see both where the field is going [and to hear] a retrospective on big-name papers,” said Dr. Parikh . Episodes run for about an hour.

To learn about the challenges of applying AI to biology: Listen to Daphne Koller, PhD, founder of AI-driven drug discovery and development company insitro. For insights on the potential of AI in medicine, tune into the one with Eric Horvitz, MD, PhD, Microsoft’s chief scientific officer.
 

Consider a Class

Look for courses that focus on AI applications in clinical practice rather than a deep dive into theory. (You need to understand how these tools will influence your work, not the intricacies of large language model development.) Be wary of corporate-funded training that centers on one product , which could present conflicts of interest, said Dr. DeCamp. See the chart for courses that meet these criteria.

A version of this article appeared on Medscape.com.

Like it or not, artificial intelligence (AI) is coming to medicine. For many physicians — maybe you — it’s already here.

More than a third of physicians use AI in their practice. And the vast majority of healthcare companies — 94%, according to Morgan Stanley — use some kind of AI machine learning.

“It’s incumbent on physicians, as well as physicians in training, to become familiar with at least the basics [of AI],” said internist Matthew DeCamp, MD, PhD, an associate professor in the Center for Bioethics and Humanities at the University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Understanding AI can help you leverage it safely and effectively — plus “make better-informed decisions about whether or not to use it in [your] practice,” Dr. DeCamp said.

“Frankly, the people who are deciding whether to implement algorithms in our day-to-day lives are oftentimes not physicians,” noted Ravi B. Parikh, MD, an assistant professor at the University of Pennsylvania and director of augmented and artificial intelligence at the Penn Center for Cancer Care Innovation, Philadelphia. Yet, physicians are most qualified to assess an AI tool’s usefulness in clinical practice.

That brings us to the best starting place for your AI education: Your own institution. Find out what AI tools your organization is implementing — and how you can influence them.

“Getting involved with our hospital data governance is the best way not only to learn practically what these AI tools do but also to influence the development process in positive ways,” Dr. Parikh said.

From there, consider the following resources to enhance your AI knowledge.
 

Get a Lay of the Land: Free Primers

Many clinical societies and interest groups have put out AI primers, an easy way to get a broad overview of the technology. The following were recommended or developed by the experts we spoke to, and all are free:

• The American Medical Association’s (AMA’s) framework for advancing healthcare AI lays out actionable guidance. Ask three key questions, the AMA recommends: Does it work? Does it work for my patients? Does it improve health outcomes?
• The Coalition for Health AI’s Blueprint for Trustworthy AI Implementation Guidance and Assurance for Healthcare provides a high-level summary of how to evaluate AI in healthcare, plus steps for implementing it. AI systems should be useful, safe, accountable, explainable, fair, and secure, the report asserted.
• The National Academy of Medicine’s draft code of conduct for AI in healthcare proposes core principles and commitments. These “reflect simple guideposts to guide and gauge behavior in a complex system and provide a starting point for real-time decision-making,” the report said.
• Health AI Partnership — a collaboration of Duke Health and Microsoft — outlines eight key decision points to consider at any stage of AI implementation, whether you’re still planning how to use it or you’ve started but want to improve it. The site also provides a breakdown of standards by regulatory agencies, organizations, and oversight bodies — so you can make sure your practices align with their guidance.

Make the Most of Conferences

Next time you’re at a conference, check the agenda for sessions on AI. “For someone who’s interested in this, I would be looking for content in my next national meeting because, undoubtedly, it’s going to be there,” said Dr. DeCamp. In a fast-moving field like AI, it’s a great way to get fresh, up-to-the-moment insights.

Listen to This Podcast

The New England Journal of Medicine’s free monthly podcast AI Grand Rounds is made for researchers and clinicians. Available on Apple, Spotify, and YouTube, the pod is good for “someone who’s looking to see both where the field is going [and to hear] a retrospective on big-name papers,” said Dr. Parikh . Episodes run for about an hour.

To learn about the challenges of applying AI to biology: Listen to Daphne Koller, PhD, founder of AI-driven drug discovery and development company insitro. For insights on the potential of AI in medicine, tune into the one with Eric Horvitz, MD, PhD, Microsoft’s chief scientific officer.
 

Consider a Class

Look for courses that focus on AI applications in clinical practice rather than a deep dive into theory. (You need to understand how these tools will influence your work, not the intricacies of large language model development.) Be wary of corporate-funded training that centers on one product , which could present conflicts of interest, said Dr. DeCamp. See the chart for courses that meet these criteria.

A version of this article appeared on Medscape.com.

One in nine patients with steatotic liver disease reported concurrent alcohol use, and more than 11% reported high-risk consumption, a national study of more than a million US veterans found.

Moreover, the combination of steatotic liver disease and high-risk alcohol intake carried a more than 43% higher long-term risk of liver cirrhosis compared with no alcohol use, according to researchers led by Robert J. Wong, MD, MS, of the Division of Gastroenterology and Hepatology, Veterans Affairs Healthcare System Palo Alto, at Stanford University School of Medicine in Palo Alto, California.

However, the study found that “reducing alcohol use lowers risk of cirrhosis, emphasizing the importance of timely alcohol use assessment and early interventions to address high-risk alcohol use in steatotic liver disease,” Dr. Wong and associates wrote in Gastroenterology.

Although concurrent moderate to heavy alcohol intake would be expected to lead more rapidly to liver disease progression, the existing literature has been conflicting, the authors noted. Several studies have even found moderate alcohol associated with a lower risk of advanced liver disease among MASLD patients, including that by Dunn et al. .
 

The Study

MASLD patients were identified through the US Veterans Affairs Corporate Data Warehouse from January 1, 2010, through December 31, 2017, with follow-up through December 31, 2022.

Alcohol use was assessed by Alcohol Use Disorders Identification Test–Concise (AUDIT-C) scores and was categorized as follows: no alcohol (AUDIT-C = 0), low-risk alcohol use (AUDIT-C 1-2 for women and 1–3 for men), and high-risk alcohol (AUDIT-C ≥ 3 for women and ≥ 4 for men).

Among the 1,156,189 veterans with MASLD, 54.2% reported no alcohol, 34.6% low-risk alcohol, and 11.2% high-risk alcohol use. In median follow-up of nine to 10 years, incidence rates of cirrhosis were .53 per 100 person-years for no use, .42 for low-risk use, and .76 for high-risk use.

In contrast to patients with baseline high-risk alcohol intake who reported no change in use, those who decreased their alcohol intake during follow-up experienced a 39% reduction in the long-term risk of cirrhosis, for a hazard ratio of .61 (95% CI, .45-.83, P < .01).

Dr. Wong

One in nine patients with steatotic liver disease reported concurrent alcohol use, and more than 11% reported high-risk consumption, a national study of more than a million US veterans found.

Moreover, the combination of steatotic liver disease and high-risk alcohol intake carried a more than 43% higher long-term risk of liver cirrhosis compared with no alcohol use, according to researchers led by Robert J. Wong, MD, MS, of the Division of Gastroenterology and Hepatology, Veterans Affairs Healthcare System Palo Alto, at Stanford University School of Medicine in Palo Alto, California.

However, the study found that “reducing alcohol use lowers risk of cirrhosis, emphasizing the importance of timely alcohol use assessment and early interventions to address high-risk alcohol use in steatotic liver disease,” Dr. Wong and associates wrote in Gastroenterology.

Although concurrent moderate to heavy alcohol intake would be expected to lead more rapidly to liver disease progression, the existing literature has been conflicting, the authors noted. Several studies have even found moderate alcohol associated with a lower risk of advanced liver disease among MASLD patients, including that by Dunn et al. .
 

The Study

MASLD patients were identified through the US Veterans Affairs Corporate Data Warehouse from January 1, 2010, through December 31, 2017, with follow-up through December 31, 2022.

Alcohol use was assessed by Alcohol Use Disorders Identification Test–Concise (AUDIT-C) scores and was categorized as follows: no alcohol (AUDIT-C = 0), low-risk alcohol use (AUDIT-C 1-2 for women and 1–3 for men), and high-risk alcohol (AUDIT-C ≥ 3 for women and ≥ 4 for men).

Among the 1,156,189 veterans with MASLD, 54.2% reported no alcohol, 34.6% low-risk alcohol, and 11.2% high-risk alcohol use. In median follow-up of nine to 10 years, incidence rates of cirrhosis were .53 per 100 person-years for no use, .42 for low-risk use, and .76 for high-risk use.

In contrast to patients with baseline high-risk alcohol intake who reported no change in use, those who decreased their alcohol intake during follow-up experienced a 39% reduction in the long-term risk of cirrhosis, for a hazard ratio of .61 (95% CI, .45-.83, P < .01).

Dr. Wong

One in nine patients with steatotic liver disease reported concurrent alcohol use, and more than 11% reported high-risk consumption, a national study of more than a million US veterans found.

Moreover, the combination of steatotic liver disease and high-risk alcohol intake carried a more than 43% higher long-term risk of liver cirrhosis compared with no alcohol use, according to researchers led by Robert J. Wong, MD, MS, of the Division of Gastroenterology and Hepatology, Veterans Affairs Healthcare System Palo Alto, at Stanford University School of Medicine in Palo Alto, California.

However, the study found that “reducing alcohol use lowers risk of cirrhosis, emphasizing the importance of timely alcohol use assessment and early interventions to address high-risk alcohol use in steatotic liver disease,” Dr. Wong and associates wrote in Gastroenterology.

Although concurrent moderate to heavy alcohol intake would be expected to lead more rapidly to liver disease progression, the existing literature has been conflicting, the authors noted. Several studies have even found moderate alcohol associated with a lower risk of advanced liver disease among MASLD patients, including that by Dunn et al. .
 

The Study

MASLD patients were identified through the US Veterans Affairs Corporate Data Warehouse from January 1, 2010, through December 31, 2017, with follow-up through December 31, 2022.

Alcohol use was assessed by Alcohol Use Disorders Identification Test–Concise (AUDIT-C) scores and was categorized as follows: no alcohol (AUDIT-C = 0), low-risk alcohol use (AUDIT-C 1-2 for women and 1–3 for men), and high-risk alcohol (AUDIT-C ≥ 3 for women and ≥ 4 for men).

Among the 1,156,189 veterans with MASLD, 54.2% reported no alcohol, 34.6% low-risk alcohol, and 11.2% high-risk alcohol use. In median follow-up of nine to 10 years, incidence rates of cirrhosis were .53 per 100 person-years for no use, .42 for low-risk use, and .76 for high-risk use.

In contrast to patients with baseline high-risk alcohol intake who reported no change in use, those who decreased their alcohol intake during follow-up experienced a 39% reduction in the long-term risk of cirrhosis, for a hazard ratio of .61 (95% CI, .45-.83, P < .01).

Dr. Wong

Replacing meat with plant-based proteins for just one meal reduced ammonia levels in patients with cirrhosis, a proof-of-concept study showed.

High levels of serum ammonia after protein loads may predict poor outcomes, including hepatic encephalopathy (HE), in patients with cirrhosis, whereas vegetable protein diets are associated with decreased serum ammonia, according to Jasmohan Bajaj, MD, a gastroenterologist at Virginia Commonwealth University School of Medicine and the Richmond VA Medical Center, Richmond, Virginia, and colleagues.

However, changing from meat-based to non–meat-based meals is difficult to do over a long period.

“Previous studies have changed people’s diets completely, expecting them to be on a meatless or vegetarian diet with a similar amount of protein when they’ve been eating meat their entire life,” Dr. Bajaj told this news organization. “That’s not really sustainable in the long run.”

“Our hope is that occasional meal substitutions would be beneficial,” he said. “This study is a first step toward seeing if that works.”

The study was published online on May 2 in Clinical and Translational Gastroenterology.

Meal Type Affects Ammonia Levels Differently

The researchers randomized 30 men with cirrhosis and on a traditional Western meat-based diet into three groups, where they received a pork/beef burger, a vegetarian bean burger, or a burger made of vegan meat substitute. The burgers provided 20 g of protein each, and all meals contained low-fat potato chips, a whole-grain bun, water, and no condiments.

The participants’ median age was 66 years in the meat and vegetarian arms and 71 years in the vegan arm. About half had diabetes, and half had prior HE and were evenly distributed across the treatment arms. Cirrhosis etiologies included hepatitis C virus infection, alcohol, and metabolic-associated steatohepatitis.

Stool microbiome characteristics, changes in ammonia, and metabolomics were compared between and within groups.

In the 3 days prior to the intervention, participants had similar intakes of red meat, poultry, fish, eggs, bread, cheese, rice, fruits, vegetables, yogurt, coffee, tea, and carbonated caffeinated and decaffeinated beverages.

Blood for metabolomics and ammonia was drawn at baseline and hourly for 3 hours post-meal while patients were under observation. All participants completed the entire meal, as shown subsequently by markers of food consumption, and none developed HE symptoms during the observation period.

The composition of the stool microbiome was similar at baseline across groups and remained unchanged. However, serum ammonia increased from baseline in the meat group but not in the vegetarian or vegan groups. The serum microbiome was not analyzed because of the low yield.

Serum metabolomics showed beneficial changes over time associated with branched-chain amino acid metabolism and urea cycle, phospholipid, and acylcarnitine levels in the vegetarian and vegan meal groups compared with the meat-based group.

In contrast, alterations in lipid profiles (higher sphingomyelins and lower lysophospholipids) were seen in the meat group.

The study was limited by its relatively small sample size, focus on the impact of only one meal, and lack of clinical outcomes, sarcopenia assessment, cognitive testing, or urine collection.

“Intermittent meat substitution with vegan or vegetarian alternatives could be helpful in reducing ammonia generation in cirrhosis,” the authors concluded.

The next step “is to substitute one meal two or three times a week, so we can move forward with this analysis and eventually be able to show that the liver is in better shape,” Dr. Bajaj said.

Meanwhile, clinicians should encourage patients with liver disease who eat meat regularly to try to substitute it with protein from plant or dairy sources, at least occasionally, he said. When doing so, “clinicians should ask their patients’ preferences before assuming that they will do everything that you ask them to do because nutrition in cirrhosis is really critical — not only what they eat but also when they eat. Working with a dietitian, like we did in our study, is critical, or at least having access to one if you don’t have one in your practice.”

Positive Results From a Simple Change

Commenting on the study, Nancy S. Reau, MD, section chief, hepatology and associate director of organ transplantation at Rush Medical College in Chicago, said, “My biggest concern is making sure patients are ingesting enough quality protein and calories because anorexia is a common complication in cirrhosis, and sarcopenia is associated with poor outcomes.

“You don’t want to suggest a change that will result in eating less or skipping a meal,” she said. So, “it is encouraging to see that suggesting a small change, just one meal a day, that may not impact calorie intake could have positive results.”

Dr. Reau added that “it is great to see evidence that this small change also could be a way of decreasing the risk of HE while not compromising on patient nutrition.”

Larger studies with outcome data showing that this approach could prevent readmission in patients hospitalized for HE would be helpful, she said.

The study was partly supported by the ACG Clinical Research Award, VA Merit Review 2I01CX001076, I01CX002472, and NIAAA RO1AA29398. Dr. Bajaj and Dr. Reau reported no conflicts of interest.
 

A version of this article appeared on Medscape.com.

Replacing meat with plant-based proteins for just one meal reduced ammonia levels in patients with cirrhosis, a proof-of-concept study showed.

High levels of serum ammonia after protein loads may predict poor outcomes, including hepatic encephalopathy (HE), in patients with cirrhosis, whereas vegetable protein diets are associated with decreased serum ammonia, according to Jasmohan Bajaj, MD, a gastroenterologist at Virginia Commonwealth University School of Medicine and the Richmond VA Medical Center, Richmond, Virginia, and colleagues.

However, changing from meat-based to non–meat-based meals is difficult to do over a long period.

“Previous studies have changed people’s diets completely, expecting them to be on a meatless or vegetarian diet with a similar amount of protein when they’ve been eating meat their entire life,” Dr. Bajaj told this news organization. “That’s not really sustainable in the long run.”

“Our hope is that occasional meal substitutions would be beneficial,” he said. “This study is a first step toward seeing if that works.”

The study was published online on May 2 in Clinical and Translational Gastroenterology.

Meal Type Affects Ammonia Levels Differently

The researchers randomized 30 men with cirrhosis and on a traditional Western meat-based diet into three groups, where they received a pork/beef burger, a vegetarian bean burger, or a burger made of vegan meat substitute. The burgers provided 20 g of protein each, and all meals contained low-fat potato chips, a whole-grain bun, water, and no condiments.

The participants’ median age was 66 years in the meat and vegetarian arms and 71 years in the vegan arm. About half had diabetes, and half had prior HE and were evenly distributed across the treatment arms. Cirrhosis etiologies included hepatitis C virus infection, alcohol, and metabolic-associated steatohepatitis.

Stool microbiome characteristics, changes in ammonia, and metabolomics were compared between and within groups.

In the 3 days prior to the intervention, participants had similar intakes of red meat, poultry, fish, eggs, bread, cheese, rice, fruits, vegetables, yogurt, coffee, tea, and carbonated caffeinated and decaffeinated beverages.

Blood for metabolomics and ammonia was drawn at baseline and hourly for 3 hours post-meal while patients were under observation. All participants completed the entire meal, as shown subsequently by markers of food consumption, and none developed HE symptoms during the observation period.

The composition of the stool microbiome was similar at baseline across groups and remained unchanged. However, serum ammonia increased from baseline in the meat group but not in the vegetarian or vegan groups. The serum microbiome was not analyzed because of the low yield.

Serum metabolomics showed beneficial changes over time associated with branched-chain amino acid metabolism and urea cycle, phospholipid, and acylcarnitine levels in the vegetarian and vegan meal groups compared with the meat-based group.

In contrast, alterations in lipid profiles (higher sphingomyelins and lower lysophospholipids) were seen in the meat group.

The study was limited by its relatively small sample size, focus on the impact of only one meal, and lack of clinical outcomes, sarcopenia assessment, cognitive testing, or urine collection.

“Intermittent meat substitution with vegan or vegetarian alternatives could be helpful in reducing ammonia generation in cirrhosis,” the authors concluded.

The next step “is to substitute one meal two or three times a week, so we can move forward with this analysis and eventually be able to show that the liver is in better shape,” Dr. Bajaj said.

Meanwhile, clinicians should encourage patients with liver disease who eat meat regularly to try to substitute it with protein from plant or dairy sources, at least occasionally, he said. When doing so, “clinicians should ask their patients’ preferences before assuming that they will do everything that you ask them to do because nutrition in cirrhosis is really critical — not only what they eat but also when they eat. Working with a dietitian, like we did in our study, is critical, or at least having access to one if you don’t have one in your practice.”

Positive Results From a Simple Change

Commenting on the study, Nancy S. Reau, MD, section chief, hepatology and associate director of organ transplantation at Rush Medical College in Chicago, said, “My biggest concern is making sure patients are ingesting enough quality protein and calories because anorexia is a common complication in cirrhosis, and sarcopenia is associated with poor outcomes.

“You don’t want to suggest a change that will result in eating less or skipping a meal,” she said. So, “it is encouraging to see that suggesting a small change, just one meal a day, that may not impact calorie intake could have positive results.”

Dr. Reau added that “it is great to see evidence that this small change also could be a way of decreasing the risk of HE while not compromising on patient nutrition.”

Larger studies with outcome data showing that this approach could prevent readmission in patients hospitalized for HE would be helpful, she said.

The study was partly supported by the ACG Clinical Research Award, VA Merit Review 2I01CX001076, I01CX002472, and NIAAA RO1AA29398. Dr. Bajaj and Dr. Reau reported no conflicts of interest.
 

A version of this article appeared on Medscape.com.

Replacing meat with plant-based proteins for just one meal reduced ammonia levels in patients with cirrhosis, a proof-of-concept study showed.

High levels of serum ammonia after protein loads may predict poor outcomes, including hepatic encephalopathy (HE), in patients with cirrhosis, whereas vegetable protein diets are associated with decreased serum ammonia, according to Jasmohan Bajaj, MD, a gastroenterologist at Virginia Commonwealth University School of Medicine and the Richmond VA Medical Center, Richmond, Virginia, and colleagues.

However, changing from meat-based to non–meat-based meals is difficult to do over a long period.

“Previous studies have changed people’s diets completely, expecting them to be on a meatless or vegetarian diet with a similar amount of protein when they’ve been eating meat their entire life,” Dr. Bajaj told this news organization. “That’s not really sustainable in the long run.”

“Our hope is that occasional meal substitutions would be beneficial,” he said. “This study is a first step toward seeing if that works.”

The study was published online on May 2 in Clinical and Translational Gastroenterology.

Meal Type Affects Ammonia Levels Differently

The researchers randomized 30 men with cirrhosis and on a traditional Western meat-based diet into three groups, where they received a pork/beef burger, a vegetarian bean burger, or a burger made of vegan meat substitute. The burgers provided 20 g of protein each, and all meals contained low-fat potato chips, a whole-grain bun, water, and no condiments.

The participants’ median age was 66 years in the meat and vegetarian arms and 71 years in the vegan arm. About half had diabetes, and half had prior HE and were evenly distributed across the treatment arms. Cirrhosis etiologies included hepatitis C virus infection, alcohol, and metabolic-associated steatohepatitis.

Stool microbiome characteristics, changes in ammonia, and metabolomics were compared between and within groups.

In the 3 days prior to the intervention, participants had similar intakes of red meat, poultry, fish, eggs, bread, cheese, rice, fruits, vegetables, yogurt, coffee, tea, and carbonated caffeinated and decaffeinated beverages.

Blood for metabolomics and ammonia was drawn at baseline and hourly for 3 hours post-meal while patients were under observation. All participants completed the entire meal, as shown subsequently by markers of food consumption, and none developed HE symptoms during the observation period.

The composition of the stool microbiome was similar at baseline across groups and remained unchanged. However, serum ammonia increased from baseline in the meat group but not in the vegetarian or vegan groups. The serum microbiome was not analyzed because of the low yield.

Serum metabolomics showed beneficial changes over time associated with branched-chain amino acid metabolism and urea cycle, phospholipid, and acylcarnitine levels in the vegetarian and vegan meal groups compared with the meat-based group.

In contrast, alterations in lipid profiles (higher sphingomyelins and lower lysophospholipids) were seen in the meat group.

The study was limited by its relatively small sample size, focus on the impact of only one meal, and lack of clinical outcomes, sarcopenia assessment, cognitive testing, or urine collection.

“Intermittent meat substitution with vegan or vegetarian alternatives could be helpful in reducing ammonia generation in cirrhosis,” the authors concluded.

The next step “is to substitute one meal two or three times a week, so we can move forward with this analysis and eventually be able to show that the liver is in better shape,” Dr. Bajaj said.

Meanwhile, clinicians should encourage patients with liver disease who eat meat regularly to try to substitute it with protein from plant or dairy sources, at least occasionally, he said. When doing so, “clinicians should ask their patients’ preferences before assuming that they will do everything that you ask them to do because nutrition in cirrhosis is really critical — not only what they eat but also when they eat. Working with a dietitian, like we did in our study, is critical, or at least having access to one if you don’t have one in your practice.”

Positive Results From a Simple Change

Commenting on the study, Nancy S. Reau, MD, section chief, hepatology and associate director of organ transplantation at Rush Medical College in Chicago, said, “My biggest concern is making sure patients are ingesting enough quality protein and calories because anorexia is a common complication in cirrhosis, and sarcopenia is associated with poor outcomes.

“You don’t want to suggest a change that will result in eating less or skipping a meal,” she said. So, “it is encouraging to see that suggesting a small change, just one meal a day, that may not impact calorie intake could have positive results.”

Dr. Reau added that “it is great to see evidence that this small change also could be a way of decreasing the risk of HE while not compromising on patient nutrition.”

Larger studies with outcome data showing that this approach could prevent readmission in patients hospitalized for HE would be helpful, she said.

The study was partly supported by the ACG Clinical Research Award, VA Merit Review 2I01CX001076, I01CX002472, and NIAAA RO1AA29398. Dr. Bajaj and Dr. Reau reported no conflicts of interest.
 

A version of this article appeared on Medscape.com.

Outcomes of Acute and Preventive Migraine Therapy Based on Patient Sex

I previously have addressed myths about migraine as they pertain to men and women. When I found an interesting study recently published in Cephalalgia investigating the effectiveness of calcitonin gene-related peptide receptor (CGRP-R) antagonists (gepants) for acute care and prevention of episodic migraine and CGRP monoclonal antibodies for preventive treatment of episodic and chronic migraine in men and women, I thought I would discuss it here.

The study’s aim was to discern if patient sex contributed to outcomes in each specific treatment arm. Female sex hormones have been recognized as factors in promoting migraine, and women show increased severity, persistence, and comorbidity in migraine profiles, and increased prevalence of migraine relative to men.

Gepants used for acute therapy (ubrogepant, rimegepant, zavegepant) and preventive therapy (atogepant, rimegepant) were studied in this trial. Erenumab, fremanezumab, galcanezumab, and eptinezumab are monoclonal antibodies that either sit on the CGRP receptor (erenumab) or inactivate the CGRP ligand (fremanezumab, galcanezumab, and eptinezumab) and are used for migraine prevention. CGRP-based therapies are not effective in all patients and understanding which patient groups respond preferentially could reduce trial and error in treatment selection. The effectiveness of treatments targeting CGRP or the CGRP receptor may not be uniform in men and women, highlighting the need for further research and understanding of CGRP neurobiology in both sexes.

Key findings:

• In the trial by Porreca et al: In women, the 3 gepants approved by the FDA for the acute care of migraine (ubrogepant, rimegepant, zavegepant) produced a statistically significant drug effect for the 2-hour pain freedom (2h-PF) endpoint, with an average drug effect of 9.5% (CI: 7.4 to 11.6) and an average number needed to treat (NNT) of 11.
• Men did not show statistically significant effects with the acute use of gepants. The average drug effect was 2.8%, and the average NNT was 36.
• For both men and women, CGRP-targeting therapies for prevention of migraine (the 4 monoclonal antibodies) were equally effective; however, possible sex differences remain uncertain and need further study.
• In patients with chronic migraine, CGRP/CGRP-R antibodies were similarly effective in both men and women.
• For the 2-hour freedom from most bothersome symptom (2h-MBS) endpoint when gepants were given acutely, the effects were much better in women than men, with an average drug effect of 10.2% and an average NNT of 10.
• In men, these medications produced observed treatment effects on 2h-MBS with an average drug effect of 3.2% and an average NNT of 32.
• In men, 5 out of 12 estimates favored placebo over the active treatment, suggesting a treatment with little to no effect.
• The pooled treatment effects for women were 3 times as large, at 9.2% and 10.2%, respectively.
• The placebo response rates for 2 of the 3 ubrogepant studies and one of 2 zavegepant studies were higher in men than in women.

The study concludes that, while small molecule CGRP-R antagonists are dramatically effective for acute therapy of migraine in women, available data do not demonstrate effectiveness in men. The treatment effect was found to always favor active treatment numerically for both men and women for prevention of episodic and chronic migraine. The data highlight possible differential effects of CGRP-targeted therapies in different patient populations and the need for increased understanding of CGRP neurobiology in men and women. The study also emphasizes the need to understand which patient groups preferentially respond to CGRP-based therapies to reduce trial and error in treatment. Note that rimegepant data on prevention were not available for analysis at the time of the writing.

It would be interesting to perform a meta-analysis of multiple well-done, large, real-world studies to see if the same differences and similarities are found in men versus women for acute care of migraine and prevention of episodic and chronic migraine. I suspect that we would find that acute care results favor women but that some men do well.

The Effectiveness of Prednisolone for Treating Medication Overuse Headache

I often discuss medication overuse headache (MOH), as it is difficult to diagnose and treat, so I wanted to comment on another pertinent study. It is a post hoc analysis of the Registry for Load and Management of Medication Overuse Headache (RELEASE). The RELEASE trial is an ongoing, multicenter, observational, cohort study of MOH that has been conducted in Korea since April 2020. Findings were recently published in Headache by Lee et al.

MOH is a secondary headache disorder that develops in patients with a preexisting primary headache when they overuse acute care headache medications of any type except gepants. This includes prescription medications such as triptans, ergots, butalbital-containing medications; opioids; aspirin; acetaminophen; any type of combination medication often containing caffeine; or a combination of medications. This condition significantly impacts patients’ quality of life and productivity, usually increasing the frequency of headaches per month and leading to higher healthcare-related costs.

Treating MOH is challenging due to the lack of high-quality drug trials specifically designed for MOH and doctor inexperience. Current evidence is based largely on subgroup analyses of drug trials for the treatment of chronic migraine that contain these patient types.

Withdrawal of acute care headache medications that are being overused has traditionally been considered an important aspect of MOH treatment, although this may be changing. Withdrawal symptoms, such as increased intensity of headache pain, frequency of headaches, and other symptoms like agitation and sleep disturbance, can prevent patients from discontinuing overused medications. Systemic corticosteroids are widely used to reduce these withdrawal headaches, but clinical trials are sparse and have failed to meet proper endpoints. Despite this, corticosteroids have shown potential benefits, such as decreasing withdrawal headaches, reducing the use of rescue medications, and lowering headache intensity at certain time points after treatment.

Given these findings, this published study hypothesized that prednisolone may play a role in converting MOH to non-MOH at 3 months after treatment. The objective was to evaluate the outcome of prednisolone therapy in reversing medication overuse at 3 months posttreatment in patients with MOH using prospective multicenter registry data. Prednisolone was prescribed to 59 out of 309 patients (19.1%) enrolled during this observational study period, with doses ranging from 10 to 40 mg/day for 5-14 days. Of these patients, 228 (73.8%) completed the 3-month follow-up period.

Key findings:

• The MOH reversal rates at 3 months postbaseline were 76% (31/41) in the prednisolone group and 57.8% (108/187) in the no prednisolone group (p = 0.034).
• The steroid effect remained significant (adjusted odds ratio, 2.78; 95% confidence interval 1.27-6.1, p = 0.010) after adjusting for the number of monthly headache days at baseline, mode of discontinuation of overused medication, use of early preventive medications, and the number of combined preventive medications.

The study had several strengths, including the multicenter collection of data, prospective follow-ups, and comprehensiveness of data acquisition. However, it also had significant limitations, such as the noninterventional, observational nature of the study, potential bias in steroid prescription (every doctor prescribed what they wanted), and heterogeneity in the patient population. Also, there were a variety of treatments, and they were not standardized. Further external validation may be necessary before generalizing the study results.

Despite these limitations, the results do suggest that prednisolone may be one part of a valid treatment option for patients with MOH. I suspect, if the proper studies are done, we will see that using a good preventive medication, with few adverse events, and with careful education of the patient, formal detoxification will not be necessary when treating many patients with MOH. This has been my experience with MOH treatment utilizing the newer anti-CGRP preventive medications, including the older monoclonal antibodies and the newer gepants.

Outcomes of Acute and Preventive Migraine Therapy Based on Patient Sex

I previously have addressed myths about migraine as they pertain to men and women. When I found an interesting study recently published in Cephalalgia investigating the effectiveness of calcitonin gene-related peptide receptor (CGRP-R) antagonists (gepants) for acute care and prevention of episodic migraine and CGRP monoclonal antibodies for preventive treatment of episodic and chronic migraine in men and women, I thought I would discuss it here.

The study’s aim was to discern if patient sex contributed to outcomes in each specific treatment arm. Female sex hormones have been recognized as factors in promoting migraine, and women show increased severity, persistence, and comorbidity in migraine profiles, and increased prevalence of migraine relative to men.

Gepants used for acute therapy (ubrogepant, rimegepant, zavegepant) and preventive therapy (atogepant, rimegepant) were studied in this trial. Erenumab, fremanezumab, galcanezumab, and eptinezumab are monoclonal antibodies that either sit on the CGRP receptor (erenumab) or inactivate the CGRP ligand (fremanezumab, galcanezumab, and eptinezumab) and are used for migraine prevention. CGRP-based therapies are not effective in all patients and understanding which patient groups respond preferentially could reduce trial and error in treatment selection. The effectiveness of treatments targeting CGRP or the CGRP receptor may not be uniform in men and women, highlighting the need for further research and understanding of CGRP neurobiology in both sexes.

Key findings:

• In the trial by Porreca et al: In women, the 3 gepants approved by the FDA for the acute care of migraine (ubrogepant, rimegepant, zavegepant) produced a statistically significant drug effect for the 2-hour pain freedom (2h-PF) endpoint, with an average drug effect of 9.5% (CI: 7.4 to 11.6) and an average number needed to treat (NNT) of 11.
• Men did not show statistically significant effects with the acute use of gepants. The average drug effect was 2.8%, and the average NNT was 36.
• For both men and women, CGRP-targeting therapies for prevention of migraine (the 4 monoclonal antibodies) were equally effective; however, possible sex differences remain uncertain and need further study.
• In patients with chronic migraine, CGRP/CGRP-R antibodies were similarly effective in both men and women.
• For the 2-hour freedom from most bothersome symptom (2h-MBS) endpoint when gepants were given acutely, the effects were much better in women than men, with an average drug effect of 10.2% and an average NNT of 10.
• In men, these medications produced observed treatment effects on 2h-MBS with an average drug effect of 3.2% and an average NNT of 32.
• In men, 5 out of 12 estimates favored placebo over the active treatment, suggesting a treatment with little to no effect.
• The pooled treatment effects for women were 3 times as large, at 9.2% and 10.2%, respectively.
• The placebo response rates for 2 of the 3 ubrogepant studies and one of 2 zavegepant studies were higher in men than in women.

The study concludes that, while small molecule CGRP-R antagonists are dramatically effective for acute therapy of migraine in women, available data do not demonstrate effectiveness in men. The treatment effect was found to always favor active treatment numerically for both men and women for prevention of episodic and chronic migraine. The data highlight possible differential effects of CGRP-targeted therapies in different patient populations and the need for increased understanding of CGRP neurobiology in men and women. The study also emphasizes the need to understand which patient groups preferentially respond to CGRP-based therapies to reduce trial and error in treatment. Note that rimegepant data on prevention were not available for analysis at the time of the writing.

It would be interesting to perform a meta-analysis of multiple well-done, large, real-world studies to see if the same differences and similarities are found in men versus women for acute care of migraine and prevention of episodic and chronic migraine. I suspect that we would find that acute care results favor women but that some men do well.

The Effectiveness of Prednisolone for Treating Medication Overuse Headache

I often discuss medication overuse headache (MOH), as it is difficult to diagnose and treat, so I wanted to comment on another pertinent study. It is a post hoc analysis of the Registry for Load and Management of Medication Overuse Headache (RELEASE). The RELEASE trial is an ongoing, multicenter, observational, cohort study of MOH that has been conducted in Korea since April 2020. Findings were recently published in Headache by Lee et al.

MOH is a secondary headache disorder that develops in patients with a preexisting primary headache when they overuse acute care headache medications of any type except gepants. This includes prescription medications such as triptans, ergots, butalbital-containing medications; opioids; aspirin; acetaminophen; any type of combination medication often containing caffeine; or a combination of medications. This condition significantly impacts patients’ quality of life and productivity, usually increasing the frequency of headaches per month and leading to higher healthcare-related costs.

Treating MOH is challenging due to the lack of high-quality drug trials specifically designed for MOH and doctor inexperience. Current evidence is based largely on subgroup analyses of drug trials for the treatment of chronic migraine that contain these patient types.

Withdrawal of acute care headache medications that are being overused has traditionally been considered an important aspect of MOH treatment, although this may be changing. Withdrawal symptoms, such as increased intensity of headache pain, frequency of headaches, and other symptoms like agitation and sleep disturbance, can prevent patients from discontinuing overused medications. Systemic corticosteroids are widely used to reduce these withdrawal headaches, but clinical trials are sparse and have failed to meet proper endpoints. Despite this, corticosteroids have shown potential benefits, such as decreasing withdrawal headaches, reducing the use of rescue medications, and lowering headache intensity at certain time points after treatment.

Given these findings, this published study hypothesized that prednisolone may play a role in converting MOH to non-MOH at 3 months after treatment. The objective was to evaluate the outcome of prednisolone therapy in reversing medication overuse at 3 months posttreatment in patients with MOH using prospective multicenter registry data. Prednisolone was prescribed to 59 out of 309 patients (19.1%) enrolled during this observational study period, with doses ranging from 10 to 40 mg/day for 5-14 days. Of these patients, 228 (73.8%) completed the 3-month follow-up period.

Key findings:

• The MOH reversal rates at 3 months postbaseline were 76% (31/41) in the prednisolone group and 57.8% (108/187) in the no prednisolone group (p = 0.034).
• The steroid effect remained significant (adjusted odds ratio, 2.78; 95% confidence interval 1.27-6.1, p = 0.010) after adjusting for the number of monthly headache days at baseline, mode of discontinuation of overused medication, use of early preventive medications, and the number of combined preventive medications.

The study had several strengths, including the multicenter collection of data, prospective follow-ups, and comprehensiveness of data acquisition. However, it also had significant limitations, such as the noninterventional, observational nature of the study, potential bias in steroid prescription (every doctor prescribed what they wanted), and heterogeneity in the patient population. Also, there were a variety of treatments, and they were not standardized. Further external validation may be necessary before generalizing the study results.

Despite these limitations, the results do suggest that prednisolone may be one part of a valid treatment option for patients with MOH. I suspect, if the proper studies are done, we will see that using a good preventive medication, with few adverse events, and with careful education of the patient, formal detoxification will not be necessary when treating many patients with MOH. This has been my experience with MOH treatment utilizing the newer anti-CGRP preventive medications, including the older monoclonal antibodies and the newer gepants.

Outcomes of Acute and Preventive Migraine Therapy Based on Patient Sex

I previously have addressed myths about migraine as they pertain to men and women. When I found an interesting study recently published in Cephalalgia investigating the effectiveness of calcitonin gene-related peptide receptor (CGRP-R) antagonists (gepants) for acute care and prevention of episodic migraine and CGRP monoclonal antibodies for preventive treatment of episodic and chronic migraine in men and women, I thought I would discuss it here.

The study’s aim was to discern if patient sex contributed to outcomes in each specific treatment arm. Female sex hormones have been recognized as factors in promoting migraine, and women show increased severity, persistence, and comorbidity in migraine profiles, and increased prevalence of migraine relative to men.

Gepants used for acute therapy (ubrogepant, rimegepant, zavegepant) and preventive therapy (atogepant, rimegepant) were studied in this trial. Erenumab, fremanezumab, galcanezumab, and eptinezumab are monoclonal antibodies that either sit on the CGRP receptor (erenumab) or inactivate the CGRP ligand (fremanezumab, galcanezumab, and eptinezumab) and are used for migraine prevention. CGRP-based therapies are not effective in all patients and understanding which patient groups respond preferentially could reduce trial and error in treatment selection. The effectiveness of treatments targeting CGRP or the CGRP receptor may not be uniform in men and women, highlighting the need for further research and understanding of CGRP neurobiology in both sexes.

Key findings:

• In the trial by Porreca et al: In women, the 3 gepants approved by the FDA for the acute care of migraine (ubrogepant, rimegepant, zavegepant) produced a statistically significant drug effect for the 2-hour pain freedom (2h-PF) endpoint, with an average drug effect of 9.5% (CI: 7.4 to 11.6) and an average number needed to treat (NNT) of 11.
• Men did not show statistically significant effects with the acute use of gepants. The average drug effect was 2.8%, and the average NNT was 36.
• For both men and women, CGRP-targeting therapies for prevention of migraine (the 4 monoclonal antibodies) were equally effective; however, possible sex differences remain uncertain and need further study.
• In patients with chronic migraine, CGRP/CGRP-R antibodies were similarly effective in both men and women.
• For the 2-hour freedom from most bothersome symptom (2h-MBS) endpoint when gepants were given acutely, the effects were much better in women than men, with an average drug effect of 10.2% and an average NNT of 10.
• In men, these medications produced observed treatment effects on 2h-MBS with an average drug effect of 3.2% and an average NNT of 32.
• In men, 5 out of 12 estimates favored placebo over the active treatment, suggesting a treatment with little to no effect.
• The pooled treatment effects for women were 3 times as large, at 9.2% and 10.2%, respectively.
• The placebo response rates for 2 of the 3 ubrogepant studies and one of 2 zavegepant studies were higher in men than in women.

The study concludes that, while small molecule CGRP-R antagonists are dramatically effective for acute therapy of migraine in women, available data do not demonstrate effectiveness in men. The treatment effect was found to always favor active treatment numerically for both men and women for prevention of episodic and chronic migraine. The data highlight possible differential effects of CGRP-targeted therapies in different patient populations and the need for increased understanding of CGRP neurobiology in men and women. The study also emphasizes the need to understand which patient groups preferentially respond to CGRP-based therapies to reduce trial and error in treatment. Note that rimegepant data on prevention were not available for analysis at the time of the writing.

It would be interesting to perform a meta-analysis of multiple well-done, large, real-world studies to see if the same differences and similarities are found in men versus women for acute care of migraine and prevention of episodic and chronic migraine. I suspect that we would find that acute care results favor women but that some men do well.

The Effectiveness of Prednisolone for Treating Medication Overuse Headache

I often discuss medication overuse headache (MOH), as it is difficult to diagnose and treat, so I wanted to comment on another pertinent study. It is a post hoc analysis of the Registry for Load and Management of Medication Overuse Headache (RELEASE). The RELEASE trial is an ongoing, multicenter, observational, cohort study of MOH that has been conducted in Korea since April 2020. Findings were recently published in Headache by Lee et al.

MOH is a secondary headache disorder that develops in patients with a preexisting primary headache when they overuse acute care headache medications of any type except gepants. This includes prescription medications such as triptans, ergots, butalbital-containing medications; opioids; aspirin; acetaminophen; any type of combination medication often containing caffeine; or a combination of medications. This condition significantly impacts patients’ quality of life and productivity, usually increasing the frequency of headaches per month and leading to higher healthcare-related costs.

Treating MOH is challenging due to the lack of high-quality drug trials specifically designed for MOH and doctor inexperience. Current evidence is based largely on subgroup analyses of drug trials for the treatment of chronic migraine that contain these patient types.

Withdrawal of acute care headache medications that are being overused has traditionally been considered an important aspect of MOH treatment, although this may be changing. Withdrawal symptoms, such as increased intensity of headache pain, frequency of headaches, and other symptoms like agitation and sleep disturbance, can prevent patients from discontinuing overused medications. Systemic corticosteroids are widely used to reduce these withdrawal headaches, but clinical trials are sparse and have failed to meet proper endpoints. Despite this, corticosteroids have shown potential benefits, such as decreasing withdrawal headaches, reducing the use of rescue medications, and lowering headache intensity at certain time points after treatment.

Given these findings, this published study hypothesized that prednisolone may play a role in converting MOH to non-MOH at 3 months after treatment. The objective was to evaluate the outcome of prednisolone therapy in reversing medication overuse at 3 months posttreatment in patients with MOH using prospective multicenter registry data. Prednisolone was prescribed to 59 out of 309 patients (19.1%) enrolled during this observational study period, with doses ranging from 10 to 40 mg/day for 5-14 days. Of these patients, 228 (73.8%) completed the 3-month follow-up period.

Key findings:

• The MOH reversal rates at 3 months postbaseline were 76% (31/41) in the prednisolone group and 57.8% (108/187) in the no prednisolone group (p = 0.034).
• The steroid effect remained significant (adjusted odds ratio, 2.78; 95% confidence interval 1.27-6.1, p = 0.010) after adjusting for the number of monthly headache days at baseline, mode of discontinuation of overused medication, use of early preventive medications, and the number of combined preventive medications.

The study had several strengths, including the multicenter collection of data, prospective follow-ups, and comprehensiveness of data acquisition. However, it also had significant limitations, such as the noninterventional, observational nature of the study, potential bias in steroid prescription (every doctor prescribed what they wanted), and heterogeneity in the patient population. Also, there were a variety of treatments, and they were not standardized. Further external validation may be necessary before generalizing the study results.

Despite these limitations, the results do suggest that prednisolone may be one part of a valid treatment option for patients with MOH. I suspect, if the proper studies are done, we will see that using a good preventive medication, with few adverse events, and with careful education of the patient, formal detoxification will not be necessary when treating many patients with MOH. This has been my experience with MOH treatment utilizing the newer anti-CGRP preventive medications, including the older monoclonal antibodies and the newer gepants.

We are proud to announce the 2024 recipients of our annual recognition prizes, given in honor of outstanding contributions and achievements in gastroenterology and hepatology.

Congratulations to Bishr Omary, MD, PhD, for receiving AGA’s highest honor, the Julius Friedenwald Medal.

Dr. Omary

Presented annually since 1941, this award recognizes a physician for lifelong contributions to the field of gastroenterology.

AGA

2024 recognition prize recipients:

• Julius Friedenwald Medal: Bishr Omary, MD, PhD
• William Beaumont Prize: Hashem B. El-Serag, MD, MPH
• Distinguished Achievement Award in Basic Science: Jerrold R. Turner, MD, PhD, AGAF
• Distinguished Service Award in Diversity, Equity, and Inclusion: Sophie Balzora, MD
• Distinguished Clinician Award in Private Practice: Scott Ketover, MD, AGAF, FASGE
• Distinguished Clinician Award in Academic Practice: Shiv Kumar Sarin, MD
• Distinguished Educator Award: David Katzka, MD, AGAF
• Distinguished Mentor Award: John Pandolfino, MD
• Young Investigator Award in Clinical Science: Mingyang Song, ScD

We are proud to announce the 2024 recipients of our annual recognition prizes, given in honor of outstanding contributions and achievements in gastroenterology and hepatology.

Congratulations to Bishr Omary, MD, PhD, for receiving AGA’s highest honor, the Julius Friedenwald Medal.

Dr. Omary

Presented annually since 1941, this award recognizes a physician for lifelong contributions to the field of gastroenterology.

AGA

2024 recognition prize recipients:

• Julius Friedenwald Medal: Bishr Omary, MD, PhD
• William Beaumont Prize: Hashem B. El-Serag, MD, MPH
• Distinguished Achievement Award in Basic Science: Jerrold R. Turner, MD, PhD, AGAF
• Distinguished Service Award in Diversity, Equity, and Inclusion: Sophie Balzora, MD
• Distinguished Clinician Award in Private Practice: Scott Ketover, MD, AGAF, FASGE
• Distinguished Clinician Award in Academic Practice: Shiv Kumar Sarin, MD
• Distinguished Educator Award: David Katzka, MD, AGAF
• Distinguished Mentor Award: John Pandolfino, MD
• Young Investigator Award in Clinical Science: Mingyang Song, ScD

We are proud to announce the 2024 recipients of our annual recognition prizes, given in honor of outstanding contributions and achievements in gastroenterology and hepatology.

Congratulations to Bishr Omary, MD, PhD, for receiving AGA’s highest honor, the Julius Friedenwald Medal.

Dr. Omary

Presented annually since 1941, this award recognizes a physician for lifelong contributions to the field of gastroenterology.

AGA

2024 recognition prize recipients:

• Julius Friedenwald Medal: Bishr Omary, MD, PhD
• William Beaumont Prize: Hashem B. El-Serag, MD, MPH
• Distinguished Achievement Award in Basic Science: Jerrold R. Turner, MD, PhD, AGAF
• Distinguished Service Award in Diversity, Equity, and Inclusion: Sophie Balzora, MD
• Distinguished Clinician Award in Private Practice: Scott Ketover, MD, AGAF, FASGE
• Distinguished Clinician Award in Academic Practice: Shiv Kumar Sarin, MD
• Distinguished Educator Award: David Katzka, MD, AGAF
• Distinguished Mentor Award: John Pandolfino, MD
• Young Investigator Award in Clinical Science: Mingyang Song, ScD

CHICAGO — At the 2024 AGA Tech Summit, held April 11-12 at the Chicago headquarters of MATTER, a global healthcare startup incubator, five companies made their pitch to be the winner of the Shark Tank competition that recognizes an outstanding tech start up in the gastroenterology field.

After the companies’ rapid-fire pitches and Q&A sessions, four judges convened to determine a winner and returned to make an announcement.

The winner was Arithmedics, which uses AI technology to automate billing codes. Founder Venthan Elango, PhD, has worked as a software engineer at Google, Urban Engines, and Georgia Tech, and his wife of 17 years is Renumathy Dhanasekaran, MD, PhD, a gastroenterologist and assistant professor of medicine at Stanford (California) University.

Their marriage has brought a unique perspective, according to Dr. Elango. “There isn’t a single day that goes by when she talks to me about the inefficiencies in healthcare, and then I say, ‘this can be easily solved with a software solution,’ ” he said.

Arithmedics

Stanford University

• Aspero Medical: Balloon overtube that maximizes frictional properties to improve mucosal wall traction and anchoring consistency. (Voted ‘fan favorite’ by AGA Tech Summit attendees)
• Aurora Medical Technologies: Minimally invasive, guided, tissue-anchoring suturing system for complex endoscopic procedures.
• Ergami Endoscopy: Flexible overtube capable of automatic insertion and fixation in the colon, which could potentially eliminate sedation and prevent endoscopic injuries to the physician.
• Lazurite: Wireless surgical camera that eliminates the need for light or video cables, avoiding the associated fire, trip, and contamination hazards.

The judges were swayed by Arithmedics’ practical solution to a widespread problem. “There is for sure a need in terms of inaccurate billing and billing codes that are wrong. There’s lost revenue for physicians around that. So I think we were really focused from a judging standpoint on the fact that their solution was filling truly an unmet need,” said judge Andrea Vossler, a managing director of Varia Ventures, which has partnered with AGA to launch and manage the GI Opportunity Fund, an AGA-member venture fund.

“We were really focused on how to assist physicians in terms of supporting their practices, and really changing what you’re doing. I think AI has the ability to do that, so we liked that about the company,” she added.

The company is an example of how AI is poised to alter healthcare, according to Ms. Vossler. “I think it’s massive. I think we’re at the very beginning of its impact on healthcare,” she said.

Another judge had a similar view. “They won because there is a screaming need to fix billing. So, it’s well known that lots of money is indeed lost in billing practices, which are stressful for office personnel and stressful for physicians. They can fulfill a long-standing need, and we thought that that was the success story,” said Christopher Gostout, MD, emeritus professor of medicine at Mayo Clinic in Rochester, Minnesota.

Dr. Gostout offered advice for gastroenterologists and other physicians interested in starting tech companies. It’s imperative to be a realist, he said. “Is there a real market for it, or [is it just] a niche market? Does your device have legs — can it expand and can evolve into other [spin-off] products? These are things you need to think about because one-offs or single-trick ponies are pretty hard to move along now,” said Dr. Gostout.

He recommended that entrepreneurs apply for Small Business Innovation Research (SBIR) grants. “I think it’s a great opportunity to bring in money and get the ball rolling.”

Finally, he advised entrepreneurs to be thoughtful about their advisory groups. Founders may be tempted to find the highest profile names they can to give the business gravitas, but those big names may not have the best knowledge base to understand the problems that the technology is meant to address. “I’ve seen businesses fail because they went for marquee names that really were not helpful, and they didn’t do their due diligence in seeking out really useful value. You don’t need a lot of advisers, just a couple of really good ones,” said Dr. Gostout.

The summit was sponsored by the AGA Center for GI Innovation and Technology.

Dr. Gostout has founded and advises AdaptivEndo and Lean Medical. He is a consultant to Boston Scientific. Dr. Dhanasekaran has no financial disclosures. Ms. Vossler is an employee of Varia Ventures, which is an investment partner to AGA. Dr. Elango is an employee of Arithmedics.

CHICAGO — At the 2024 AGA Tech Summit, held April 11-12 at the Chicago headquarters of MATTER, a global healthcare startup incubator, five companies made their pitch to be the winner of the Shark Tank competition that recognizes an outstanding tech start up in the gastroenterology field.

After the companies’ rapid-fire pitches and Q&A sessions, four judges convened to determine a winner and returned to make an announcement.

The winner was Arithmedics, which uses AI technology to automate billing codes. Founder Venthan Elango, PhD, has worked as a software engineer at Google, Urban Engines, and Georgia Tech, and his wife of 17 years is Renumathy Dhanasekaran, MD, PhD, a gastroenterologist and assistant professor of medicine at Stanford (California) University.

Their marriage has brought a unique perspective, according to Dr. Elango. “There isn’t a single day that goes by when she talks to me about the inefficiencies in healthcare, and then I say, ‘this can be easily solved with a software solution,’ ” he said.

Arithmedics

Stanford University

• Aspero Medical: Balloon overtube that maximizes frictional properties to improve mucosal wall traction and anchoring consistency. (Voted ‘fan favorite’ by AGA Tech Summit attendees)
• Aurora Medical Technologies: Minimally invasive, guided, tissue-anchoring suturing system for complex endoscopic procedures.
• Ergami Endoscopy: Flexible overtube capable of automatic insertion and fixation in the colon, which could potentially eliminate sedation and prevent endoscopic injuries to the physician.
• Lazurite: Wireless surgical camera that eliminates the need for light or video cables, avoiding the associated fire, trip, and contamination hazards.

The judges were swayed by Arithmedics’ practical solution to a widespread problem. “There is for sure a need in terms of inaccurate billing and billing codes that are wrong. There’s lost revenue for physicians around that. So I think we were really focused from a judging standpoint on the fact that their solution was filling truly an unmet need,” said judge Andrea Vossler, a managing director of Varia Ventures, which has partnered with AGA to launch and manage the GI Opportunity Fund, an AGA-member venture fund.

“We were really focused on how to assist physicians in terms of supporting their practices, and really changing what you’re doing. I think AI has the ability to do that, so we liked that about the company,” she added.

The company is an example of how AI is poised to alter healthcare, according to Ms. Vossler. “I think it’s massive. I think we’re at the very beginning of its impact on healthcare,” she said.

Another judge had a similar view. “They won because there is a screaming need to fix billing. So, it’s well known that lots of money is indeed lost in billing practices, which are stressful for office personnel and stressful for physicians. They can fulfill a long-standing need, and we thought that that was the success story,” said Christopher Gostout, MD, emeritus professor of medicine at Mayo Clinic in Rochester, Minnesota.

Dr. Gostout offered advice for gastroenterologists and other physicians interested in starting tech companies. It’s imperative to be a realist, he said. “Is there a real market for it, or [is it just] a niche market? Does your device have legs — can it expand and can evolve into other [spin-off] products? These are things you need to think about because one-offs or single-trick ponies are pretty hard to move along now,” said Dr. Gostout.

He recommended that entrepreneurs apply for Small Business Innovation Research (SBIR) grants. “I think it’s a great opportunity to bring in money and get the ball rolling.”

Finally, he advised entrepreneurs to be thoughtful about their advisory groups. Founders may be tempted to find the highest profile names they can to give the business gravitas, but those big names may not have the best knowledge base to understand the problems that the technology is meant to address. “I’ve seen businesses fail because they went for marquee names that really were not helpful, and they didn’t do their due diligence in seeking out really useful value. You don’t need a lot of advisers, just a couple of really good ones,” said Dr. Gostout.

The summit was sponsored by the AGA Center for GI Innovation and Technology.

Dr. Gostout has founded and advises AdaptivEndo and Lean Medical. He is a consultant to Boston Scientific. Dr. Dhanasekaran has no financial disclosures. Ms. Vossler is an employee of Varia Ventures, which is an investment partner to AGA. Dr. Elango is an employee of Arithmedics.

CHICAGO — At the 2024 AGA Tech Summit, held April 11-12 at the Chicago headquarters of MATTER, a global healthcare startup incubator, five companies made their pitch to be the winner of the Shark Tank competition that recognizes an outstanding tech start up in the gastroenterology field.

After the companies’ rapid-fire pitches and Q&A sessions, four judges convened to determine a winner and returned to make an announcement.

The winner was Arithmedics, which uses AI technology to automate billing codes. Founder Venthan Elango, PhD, has worked as a software engineer at Google, Urban Engines, and Georgia Tech, and his wife of 17 years is Renumathy Dhanasekaran, MD, PhD, a gastroenterologist and assistant professor of medicine at Stanford (California) University.

Their marriage has brought a unique perspective, according to Dr. Elango. “There isn’t a single day that goes by when she talks to me about the inefficiencies in healthcare, and then I say, ‘this can be easily solved with a software solution,’ ” he said.

Arithmedics

Stanford University

• Aspero Medical: Balloon overtube that maximizes frictional properties to improve mucosal wall traction and anchoring consistency. (Voted ‘fan favorite’ by AGA Tech Summit attendees)
• Aurora Medical Technologies: Minimally invasive, guided, tissue-anchoring suturing system for complex endoscopic procedures.
• Ergami Endoscopy: Flexible overtube capable of automatic insertion and fixation in the colon, which could potentially eliminate sedation and prevent endoscopic injuries to the physician.
• Lazurite: Wireless surgical camera that eliminates the need for light or video cables, avoiding the associated fire, trip, and contamination hazards.

The judges were swayed by Arithmedics’ practical solution to a widespread problem. “There is for sure a need in terms of inaccurate billing and billing codes that are wrong. There’s lost revenue for physicians around that. So I think we were really focused from a judging standpoint on the fact that their solution was filling truly an unmet need,” said judge Andrea Vossler, a managing director of Varia Ventures, which has partnered with AGA to launch and manage the GI Opportunity Fund, an AGA-member venture fund.

“We were really focused on how to assist physicians in terms of supporting their practices, and really changing what you’re doing. I think AI has the ability to do that, so we liked that about the company,” she added.

The company is an example of how AI is poised to alter healthcare, according to Ms. Vossler. “I think it’s massive. I think we’re at the very beginning of its impact on healthcare,” she said.

Another judge had a similar view. “They won because there is a screaming need to fix billing. So, it’s well known that lots of money is indeed lost in billing practices, which are stressful for office personnel and stressful for physicians. They can fulfill a long-standing need, and we thought that that was the success story,” said Christopher Gostout, MD, emeritus professor of medicine at Mayo Clinic in Rochester, Minnesota.

Dr. Gostout offered advice for gastroenterologists and other physicians interested in starting tech companies. It’s imperative to be a realist, he said. “Is there a real market for it, or [is it just] a niche market? Does your device have legs — can it expand and can evolve into other [spin-off] products? These are things you need to think about because one-offs or single-trick ponies are pretty hard to move along now,” said Dr. Gostout.

He recommended that entrepreneurs apply for Small Business Innovation Research (SBIR) grants. “I think it’s a great opportunity to bring in money and get the ball rolling.”

Finally, he advised entrepreneurs to be thoughtful about their advisory groups. Founders may be tempted to find the highest profile names they can to give the business gravitas, but those big names may not have the best knowledge base to understand the problems that the technology is meant to address. “I’ve seen businesses fail because they went for marquee names that really were not helpful, and they didn’t do their due diligence in seeking out really useful value. You don’t need a lot of advisers, just a couple of really good ones,” said Dr. Gostout.

The summit was sponsored by the AGA Center for GI Innovation and Technology.

Dr. Gostout has founded and advises AdaptivEndo and Lean Medical. He is a consultant to Boston Scientific. Dr. Dhanasekaran has no financial disclosures. Ms. Vossler is an employee of Varia Ventures, which is an investment partner to AGA. Dr. Elango is an employee of Arithmedics.

This discussion was recorded on March 29, 2024. The transcript has been edited for clarity.

Robert D. Glatter, MD: Joining me today to discuss the use of methoxyflurane (Penthrox), an inhaled nonopioid analgesic for the relief of acute pain, is Dr. William Kenneth (Ken) Milne, an emergency physician at Strathroy Middlesex General Hospital in Ontario, Canada, and the founder of the well-known podcast The Skeptics’ Guide to Emergency Medicine (SGEM).

Also joining me is Dr. Sergey Motov, an emergency physician and research director at Maimonides Medical Center in Brooklyn, New York, and an expert in pain management. I want to welcome both of you and thank you for joining me.
 

RAMPED Trial: Evaluating the Efficacy of Methoxyflurane

Dr. Glatter: Ken, your recent post on Twitter [now X] regarding the utility of Penthrox in the RAMPED trial really caught my attention. While the trial was from 2021, it really is relevant regarding the prehospital management of pain in the practice of emergency medicine, and certainly in-hospital practice. I was hoping you could review the study design but also get into the rationale behind the use of this novel agent.

William Kenneth (Ken) Milne, MD, MSc: Sure. I’d be happy to kick this episode off with talking about a study that was published in 2020 in Academic Emergency Medicine. It was an Australian study by Brichko et al., and they were doing a randomized controlled trial looking at methoxyflurane vs standard care.

They selected out a population of adults, which they defined as 18-75 years of age. They were in the prehospital setting and they had a pain score of greater than 8. They gave the participants methoxyflurane, which is also called the “green whistle.” They had the subjects take that for their prehospital pain, and they compared that with whatever your standard analgesic in the prehospital setting would be.

Their primary outcome was how many patients had at least 50% reduction in their pain score within 30 minutes. They recruited about 120 people, and they found that there was no statistical difference in the primary outcome between methoxyflurane and standard care. Again, that primary outcome was a reduction in pain score by greater than 50% at 30 minutes, and there wasn’t a statistical difference between the two.

There are obviously limits to any study, and it was a convenience sample. This was an unmasked trial, so people knew if they were getting this green whistle, which is popular in Australia. People would be familiar with this device, and they didn’t compare it with a sham or placebo group.

Pharmacology of Penthrox: Its Role and Mechanism of Action

Dr. Glatter: The primary outcome wasn’t met, but certainly secondary outcomes were. There was, again, a relatively small number of patients in this trial. That said, there was significant pain relief. I think there are issues with the trial, as with any trial limitations.

Getting to the pharmacology of Penthrox, can you describe this inhaled anesthetic and how we use it, specifically its role at the subanesthetic doses?

Sergey M. Motov, MD: Methoxyflurane is embedded in the green whistle package, and that whole contraption is called Penthrox. It’s an inhaled volatile fluorinated hydrocarbon anesthetic that was predominantly used, I’d say 40, 50 years ago, for general anesthesia and slowly but surely fell out of favor due to the fact that, when used for prolonged duration or in supratherapeutic doses, there were cases of severe or even fatal nephrotoxicity and hepatotoxicity.

In the late ‘70s and early ‘80s, all the fluranes came on board that are slightly different as general anesthetics, and methoxyflurane started slowly falling out of favor. Because of this paucity and then a subsequent slightly greater number of cases of nephrotoxicity and hepatotoxicity, [the US Food and Drug Administration] FDA made a decision to pull the drug off the market in 2005. FDA successfully accomplished its mission and since then has pretty much banned the use of inhaled methoxyflurane in any shape, form, or color in the United States.

Going back to the green whistle, it has been used in Australia probably for about 50-60 years, and has been used in Europe for probably 10-20 years. Ken can attest that it has been used in Canada for at least a decade and the track record is phenomenal.

We are using subanesthetic, even supratherapeutic doses that, based on available literature, has no incidence of this fatal hepatotoxicity or nephrotoxicity. We’re talking about 10 million doses administered worldwide, except in the United States. There are 40-plus randomized clinical trials with over 30,000 patients enrolled that prove efficacy and safety.

That’s where we are right now, in a conundrum. We have a great deal of data all over the world, except in the United States, that push for the use of this noninvasive, patient-controlled nonopioid inhaled anesthetic. We just don’t have the access in North America, with the exception of Canada.

Regulatory Hurdles: Challenges in FDA Approval

Dr. Glatter: Absolutely. The FDA wants to be cautious, but if you look at the evidence base of data on this, it really indicates otherwise. Do you think that these roadblocks can be somehow overcome?

Dr. Milne: In the 2000s and 2010s, everybody was focused on opioids and all the dangers and potential adverse events. Opioids are great drugs like many other drugs; it depends on dose and duration. If used properly, it’s an excellent drug. Well, here’s another excellent drug if it’s used properly, and the adverse events are dependent on their dose and duration. Penthrox, or methoxyflurane, is a subtherapeutic, small dose and there have been no reported cases of addiction or abuse related to these inhalers.

Dr. Glatter: That argues for the point — and I’ll turn this over to you, Sergey — of how can this not, in my mind, be an issue that the FDA can overcome.

Dr. Motov: I agree with you. It’s very hard for me to speak on behalf of the FDA, to allude to their thinking processes, but we need to be up to speed with the evidence. The first thing is, why don’t you study the drug in the United States? I’m not asking you to lift the ban, which you put in 2005, but why don’t you honor what has been done over two decades and at least open the door a little bit and let us do what we do best? Why don’t you allow us to do the research in a controlled setting with a carefully, properly selected group of patients without underlying renal or hepatic insufficiency and see where we’re at?

Let’s compare it against placebo. If that’s not ethical, let’s compare it against active comparators — God knows we have 15-20 drugs we can use — and let’s see where we’re at. Ken has been nothing short of superb when it comes to evidence. Let us put the evidence together.

Dr. Milne: If there were concerns decades ago, those need to be addressed. As science is iterative and as other information becomes available, the scientific method would say, Let’s reexamine this and let’s reexamine our position, and do that with evidence. To do that, it has to have validity within the US system. Someone like you doing the research, you are a pain research guru; you should be doing this research to say, “Does it work or not? Does this nonapproval still stand today in 2024?”

Dr. Motov: Thank you for the shout-out, and I agree with you. All of us, those who are interested, on the frontiers of emergency care — as present clinicians — we should be doing this. There is nothing that will convince the FDA more than properly and rightly conducted research, time to reassess the evidence, and time to be less rigid. I understand that you placed a ban 20 years ago, but let’s go with the science. We cannot be behind it.

Exploring the Ecological Footprint of Methoxyflurane

Dr. Milne: There was an Austrian study in 2022 and a very interesting study out of the UK looking at life-cycle impact assessment on the environment. If we’re not just concerned about patient care —obviously, we want to provide patients with a safe and effective product, compared with other products that are available that might not have as good a safety profile — this looks at the impact on the environment.

Dr. Glatter: Ken, can you tell me about some of your recent research regarding the environmental effects related to use of Penthrox, but also its utility pharmacologically and its mechanism of action?

Dr. Milne: There was a really interesting study published this year by Martindale in the Emergency Medicine Journal. It took a different approach to this question about could we be using this drug, and why should we be using this drug? Sergey and I have already talked about the potential benefits and the potential harms. I mentioned opioids and some of the concerns about that. For this drug, if we’re using it in the prehospital setting in this little green whistle, the potential benefits look really good, and we haven’t seen any of the potential harms come through in the literature.

This was another line of evidence of why this might be a good drug, because of the environmental impact of this low-dose methoxyflurane. They compared it with nitrous oxide and said, “Well, what about the life-cycle impact on the environment of using this and the overall cradle-to-grave environmental impacts?”

Obviously, Sergey and I are interested in patient care, and we treat patients one at a time. But we have a larger responsibility to social determinants of health, like our environment. If you look at the overall cradle-to-grave environmental impact of this drug, it was better than for nitrous oxide when looking specifically at climate-change impact. That might be another reason, another line of argument, that could be put forward in the United States to say, “We want to have a healthy environment and a healthy option for patients.”

I’ll let Sergey speak to mechanisms of action and those types of things.

Dr. Motov: As a general anesthetic and hydrocarbonated volatile ones, I’m just going to say that it causes this generalized diffuse cortical depression, and there are no particular channels, receptors, or enzymes we need to worry much about. In short, it’s an inhaled gas used to put patients or people to sleep.

Over the past 30 or 40 years — and I’ll go back to the past decade — there have been numerous studies in different countries (outside of the United States, of course), and with the recent study that Ken just cited, there were comparisons for managing predominantly acute traumatic injuries in pediatric and adult populations presenting to EDs in various regions of the world that compared Penthrox, or the green whistle, with either placebo or active comparators, which included parenteral opioids, oral opioids, and NSAIDs.

The recent systematic review by Fabbri, out of Italy, showed that for ultra–short-term pain — we’re talking about 5, 10, or 15 minutes — inhaled methoxyflurane was found to be equal or even superior to standard of care, primarily related to parenteral opioids, and safety was off the hook. Interestingly, with respect to analgesia, they found that geriatric patients seemed to be responding more, with respect to changing pain score, than younger adults — we’re talking about ages 18-64 vs 65 or older. Again, we need to make sure that we carefully select those elderly people without underlying renal or hepatic insufficiency.

To wrap this up, there is evidence clearly supporting its analgesic efficacy and safety, even in comparison to commonly used and traditionally accepted analgesic modalities that we use for managing acute pain.

US Military Use and Implications for Civilian Practice

Dr. Glatter: Do you think that methoxyflurane’s use in the military will help propel its use in clinical settings in the US, and possibly convince the FDA to look at this closer? The military is currently using it in deployed combat veterans in an ongoing fashion.

Dr. Motov: I’m excited that the Department of Defense in the United States has taken the lead, and they’re being very progressive. There are data that we’ve adapted to the civilian environment by use of intranasal opioids and intranasal ketamine with more doctors who came out of the military. In the military, it’s a kingdom within a kingdom. I don’t know their relationship with the FDA, but I support the military’s pharmacologic initiative by honoring and disseminating their research once it becomes available.

For us nonmilitary folks, we still need to work with the FDA. We need to convince the FDA to let us study the drug, and then we need to pile the evidence within the United States so that the FDA will start looking at this favorably. It wouldn’t hurt and it wouldn’t harm. Any piece of evidence will add to the existing body of literature that we need to allow this medication to be available to us.

Safety Considerations and Aerosolization Concerns

Dr. Glatter: Its safety in children is well established in Australia and throughout the world. I think it deserves a careful look, and the evidence that you’ve both presented argues for the use of this prehospital but also in hospital. I guess there was concern in the hospital with underventilation and healthcare workers being exposed to the fumes, and then getting headaches, dizziness, and so forth. I don’t know if that’s borne out, Ken, in any of your experience in Canada at all.

Dr. Milne: We currently don’t have it in our shop. It’s being used in British Columbia right now in the prehospital setting, and I’m not aware of anybody using it in their department. It’s used prehospital as far as I know.

Dr. Motov: I can attest to it, if I may, because I had familiarized myself with the device. I actually was able to hold it in my hands. I have not used it yet but I had the prototype. The way it’s set up, there is an activated charcoal chamber that sits right on top of the device, which serves as the scavenger for exhaled air that contains particles of methoxyflurane. In theory, but I’m telling how it is in practicality, it significantly reduces occupational exposure, based on data that lacks specifics.

Although most of the researchers did not measure the concentration of methoxyflurane in ambient air within the treatment room in the EDs, I believe the additional data sources clearly stating that it’s within or even below the detectable level that would cause any harm. Once again, we need to honor pathology. We need to make sure that pregnant women will not be exposed to it.

Dr. Milne: In 2024, we also need to be concerned about aerosolizing procedures and aerosolizing treatments, and just take that into account because we should be considering all the potential benefits and all the potential harms. Going through the COVID-19 pandemic, there was concern about transmission and whether or not it was droplet or aerosolized.

There was an observational study published in 2022 in Austria by Trimmel in BMC Emergency Medicine showing similar results. It seemed to work well and potential harms didn’t get picked up. They had to stop the study early because of COVID-19.

We need to always focus in on the potential benefits, the potential harms; where does the science land? Where do the data lie? Then we move forward from that and make informed decisions.

Final Thoughts

Dr. Glatter: Are there any key takeaways you’d like to share with our audience?

Dr. Milne: One of the takeaways from this whole conversation is that science is iterative and science changes. When new evidence becomes available, and we’ve seen it accumulate around the world, we as scientists, as a researcher, as somebody committed to great patient care should revisit our positions on this. Since there is a prohibition against this medication, I think it’s time to reassess that stance and move forward to see if it still is accurate today.

Dr. Motov: I wholeheartedly agree with this. Thank you, Ken, for bringing this up. Good point.

Dr. Glatter: This has been a really informative discussion. I think our audience will certainly embrace this. Thank you very much for your time; it’s much appreciated.
 

Dr. Glatter is an assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He is a medical adviser for Medscape and hosts the Hot Topics in EM series. Dr. Milne is an emergency physician at Strathroy Middlesex General Hospital in Ontario, Canada, and the founder of the well-known podcast The Skeptics’ Guide to Emergency Medicine (SGEM). Dr. Motov is professor of emergency medicine and director of research in the Department of Emergency Medicine at Maimonides Medical Center in Brooklyn, New York. He is passionate about safe and effective pain management in the emergency department, and has numerous publications on the subject of opioid alternatives in pain management. Dr. Glatter, Dr. Milne, and Dr. Motov had no conflicts of interest to disclose.

A version of this article appeared on Medscape.com.

This discussion was recorded on March 29, 2024. The transcript has been edited for clarity.

Robert D. Glatter, MD: Joining me today to discuss the use of methoxyflurane (Penthrox), an inhaled nonopioid analgesic for the relief of acute pain, is Dr. William Kenneth (Ken) Milne, an emergency physician at Strathroy Middlesex General Hospital in Ontario, Canada, and the founder of the well-known podcast The Skeptics’ Guide to Emergency Medicine (SGEM).

Also joining me is Dr. Sergey Motov, an emergency physician and research director at Maimonides Medical Center in Brooklyn, New York, and an expert in pain management. I want to welcome both of you and thank you for joining me.
 

RAMPED Trial: Evaluating the Efficacy of Methoxyflurane

Dr. Glatter: Ken, your recent post on Twitter [now X] regarding the utility of Penthrox in the RAMPED trial really caught my attention. While the trial was from 2021, it really is relevant regarding the prehospital management of pain in the practice of emergency medicine, and certainly in-hospital practice. I was hoping you could review the study design but also get into the rationale behind the use of this novel agent.

William Kenneth (Ken) Milne, MD, MSc: Sure. I’d be happy to kick this episode off with talking about a study that was published in 2020 in Academic Emergency Medicine. It was an Australian study by Brichko et al., and they were doing a randomized controlled trial looking at methoxyflurane vs standard care.

They selected out a population of adults, which they defined as 18-75 years of age. They were in the prehospital setting and they had a pain score of greater than 8. They gave the participants methoxyflurane, which is also called the “green whistle.” They had the subjects take that for their prehospital pain, and they compared that with whatever your standard analgesic in the prehospital setting would be.

Their primary outcome was how many patients had at least 50% reduction in their pain score within 30 minutes. They recruited about 120 people, and they found that there was no statistical difference in the primary outcome between methoxyflurane and standard care. Again, that primary outcome was a reduction in pain score by greater than 50% at 30 minutes, and there wasn’t a statistical difference between the two.

There are obviously limits to any study, and it was a convenience sample. This was an unmasked trial, so people knew if they were getting this green whistle, which is popular in Australia. People would be familiar with this device, and they didn’t compare it with a sham or placebo group.

Pharmacology of Penthrox: Its Role and Mechanism of Action

Dr. Glatter: The primary outcome wasn’t met, but certainly secondary outcomes were. There was, again, a relatively small number of patients in this trial. That said, there was significant pain relief. I think there are issues with the trial, as with any trial limitations.

Getting to the pharmacology of Penthrox, can you describe this inhaled anesthetic and how we use it, specifically its role at the subanesthetic doses?

Sergey M. Motov, MD: Methoxyflurane is embedded in the green whistle package, and that whole contraption is called Penthrox. It’s an inhaled volatile fluorinated hydrocarbon anesthetic that was predominantly used, I’d say 40, 50 years ago, for general anesthesia and slowly but surely fell out of favor due to the fact that, when used for prolonged duration or in supratherapeutic doses, there were cases of severe or even fatal nephrotoxicity and hepatotoxicity.

In the late ‘70s and early ‘80s, all the fluranes came on board that are slightly different as general anesthetics, and methoxyflurane started slowly falling out of favor. Because of this paucity and then a subsequent slightly greater number of cases of nephrotoxicity and hepatotoxicity, [the US Food and Drug Administration] FDA made a decision to pull the drug off the market in 2005. FDA successfully accomplished its mission and since then has pretty much banned the use of inhaled methoxyflurane in any shape, form, or color in the United States.

Going back to the green whistle, it has been used in Australia probably for about 50-60 years, and has been used in Europe for probably 10-20 years. Ken can attest that it has been used in Canada for at least a decade and the track record is phenomenal.

We are using subanesthetic, even supratherapeutic doses that, based on available literature, has no incidence of this fatal hepatotoxicity or nephrotoxicity. We’re talking about 10 million doses administered worldwide, except in the United States. There are 40-plus randomized clinical trials with over 30,000 patients enrolled that prove efficacy and safety.

That’s where we are right now, in a conundrum. We have a great deal of data all over the world, except in the United States, that push for the use of this noninvasive, patient-controlled nonopioid inhaled anesthetic. We just don’t have the access in North America, with the exception of Canada.

Regulatory Hurdles: Challenges in FDA Approval

Dr. Glatter: Absolutely. The FDA wants to be cautious, but if you look at the evidence base of data on this, it really indicates otherwise. Do you think that these roadblocks can be somehow overcome?

Dr. Milne: In the 2000s and 2010s, everybody was focused on opioids and all the dangers and potential adverse events. Opioids are great drugs like many other drugs; it depends on dose and duration. If used properly, it’s an excellent drug. Well, here’s another excellent drug if it’s used properly, and the adverse events are dependent on their dose and duration. Penthrox, or methoxyflurane, is a subtherapeutic, small dose and there have been no reported cases of addiction or abuse related to these inhalers.

Dr. Glatter: That argues for the point — and I’ll turn this over to you, Sergey — of how can this not, in my mind, be an issue that the FDA can overcome.

Dr. Motov: I agree with you. It’s very hard for me to speak on behalf of the FDA, to allude to their thinking processes, but we need to be up to speed with the evidence. The first thing is, why don’t you study the drug in the United States? I’m not asking you to lift the ban, which you put in 2005, but why don’t you honor what has been done over two decades and at least open the door a little bit and let us do what we do best? Why don’t you allow us to do the research in a controlled setting with a carefully, properly selected group of patients without underlying renal or hepatic insufficiency and see where we’re at?

Let’s compare it against placebo. If that’s not ethical, let’s compare it against active comparators — God knows we have 15-20 drugs we can use — and let’s see where we’re at. Ken has been nothing short of superb when it comes to evidence. Let us put the evidence together.

Dr. Milne: If there were concerns decades ago, those need to be addressed. As science is iterative and as other information becomes available, the scientific method would say, Let’s reexamine this and let’s reexamine our position, and do that with evidence. To do that, it has to have validity within the US system. Someone like you doing the research, you are a pain research guru; you should be doing this research to say, “Does it work or not? Does this nonapproval still stand today in 2024?”

Dr. Motov: Thank you for the shout-out, and I agree with you. All of us, those who are interested, on the frontiers of emergency care — as present clinicians — we should be doing this. There is nothing that will convince the FDA more than properly and rightly conducted research, time to reassess the evidence, and time to be less rigid. I understand that you placed a ban 20 years ago, but let’s go with the science. We cannot be behind it.

Exploring the Ecological Footprint of Methoxyflurane

Dr. Milne: There was an Austrian study in 2022 and a very interesting study out of the UK looking at life-cycle impact assessment on the environment. If we’re not just concerned about patient care —obviously, we want to provide patients with a safe and effective product, compared with other products that are available that might not have as good a safety profile — this looks at the impact on the environment.

Dr. Glatter: Ken, can you tell me about some of your recent research regarding the environmental effects related to use of Penthrox, but also its utility pharmacologically and its mechanism of action?

Dr. Milne: There was a really interesting study published this year by Martindale in the Emergency Medicine Journal. It took a different approach to this question about could we be using this drug, and why should we be using this drug? Sergey and I have already talked about the potential benefits and the potential harms. I mentioned opioids and some of the concerns about that. For this drug, if we’re using it in the prehospital setting in this little green whistle, the potential benefits look really good, and we haven’t seen any of the potential harms come through in the literature.

This was another line of evidence of why this might be a good drug, because of the environmental impact of this low-dose methoxyflurane. They compared it with nitrous oxide and said, “Well, what about the life-cycle impact on the environment of using this and the overall cradle-to-grave environmental impacts?”

Obviously, Sergey and I are interested in patient care, and we treat patients one at a time. But we have a larger responsibility to social determinants of health, like our environment. If you look at the overall cradle-to-grave environmental impact of this drug, it was better than for nitrous oxide when looking specifically at climate-change impact. That might be another reason, another line of argument, that could be put forward in the United States to say, “We want to have a healthy environment and a healthy option for patients.”

I’ll let Sergey speak to mechanisms of action and those types of things.

Dr. Motov: As a general anesthetic and hydrocarbonated volatile ones, I’m just going to say that it causes this generalized diffuse cortical depression, and there are no particular channels, receptors, or enzymes we need to worry much about. In short, it’s an inhaled gas used to put patients or people to sleep.

Over the past 30 or 40 years — and I’ll go back to the past decade — there have been numerous studies in different countries (outside of the United States, of course), and with the recent study that Ken just cited, there were comparisons for managing predominantly acute traumatic injuries in pediatric and adult populations presenting to EDs in various regions of the world that compared Penthrox, or the green whistle, with either placebo or active comparators, which included parenteral opioids, oral opioids, and NSAIDs.

The recent systematic review by Fabbri, out of Italy, showed that for ultra–short-term pain — we’re talking about 5, 10, or 15 minutes — inhaled methoxyflurane was found to be equal or even superior to standard of care, primarily related to parenteral opioids, and safety was off the hook. Interestingly, with respect to analgesia, they found that geriatric patients seemed to be responding more, with respect to changing pain score, than younger adults — we’re talking about ages 18-64 vs 65 or older. Again, we need to make sure that we carefully select those elderly people without underlying renal or hepatic insufficiency.

To wrap this up, there is evidence clearly supporting its analgesic efficacy and safety, even in comparison to commonly used and traditionally accepted analgesic modalities that we use for managing acute pain.

US Military Use and Implications for Civilian Practice

Dr. Glatter: Do you think that methoxyflurane’s use in the military will help propel its use in clinical settings in the US, and possibly convince the FDA to look at this closer? The military is currently using it in deployed combat veterans in an ongoing fashion.

Dr. Motov: I’m excited that the Department of Defense in the United States has taken the lead, and they’re being very progressive. There are data that we’ve adapted to the civilian environment by use of intranasal opioids and intranasal ketamine with more doctors who came out of the military. In the military, it’s a kingdom within a kingdom. I don’t know their relationship with the FDA, but I support the military’s pharmacologic initiative by honoring and disseminating their research once it becomes available.

For us nonmilitary folks, we still need to work with the FDA. We need to convince the FDA to let us study the drug, and then we need to pile the evidence within the United States so that the FDA will start looking at this favorably. It wouldn’t hurt and it wouldn’t harm. Any piece of evidence will add to the existing body of literature that we need to allow this medication to be available to us.

Safety Considerations and Aerosolization Concerns

Dr. Glatter: Its safety in children is well established in Australia and throughout the world. I think it deserves a careful look, and the evidence that you’ve both presented argues for the use of this prehospital but also in hospital. I guess there was concern in the hospital with underventilation and healthcare workers being exposed to the fumes, and then getting headaches, dizziness, and so forth. I don’t know if that’s borne out, Ken, in any of your experience in Canada at all.

Dr. Milne: We currently don’t have it in our shop. It’s being used in British Columbia right now in the prehospital setting, and I’m not aware of anybody using it in their department. It’s used prehospital as far as I know.

Dr. Motov: I can attest to it, if I may, because I had familiarized myself with the device. I actually was able to hold it in my hands. I have not used it yet but I had the prototype. The way it’s set up, there is an activated charcoal chamber that sits right on top of the device, which serves as the scavenger for exhaled air that contains particles of methoxyflurane. In theory, but I’m telling how it is in practicality, it significantly reduces occupational exposure, based on data that lacks specifics.

Although most of the researchers did not measure the concentration of methoxyflurane in ambient air within the treatment room in the EDs, I believe the additional data sources clearly stating that it’s within or even below the detectable level that would cause any harm. Once again, we need to honor pathology. We need to make sure that pregnant women will not be exposed to it.

Dr. Milne: In 2024, we also need to be concerned about aerosolizing procedures and aerosolizing treatments, and just take that into account because we should be considering all the potential benefits and all the potential harms. Going through the COVID-19 pandemic, there was concern about transmission and whether or not it was droplet or aerosolized.

There was an observational study published in 2022 in Austria by Trimmel in BMC Emergency Medicine showing similar results. It seemed to work well and potential harms didn’t get picked up. They had to stop the study early because of COVID-19.

We need to always focus in on the potential benefits, the potential harms; where does the science land? Where do the data lie? Then we move forward from that and make informed decisions.

Final Thoughts

Dr. Glatter: Are there any key takeaways you’d like to share with our audience?

Dr. Milne: One of the takeaways from this whole conversation is that science is iterative and science changes. When new evidence becomes available, and we’ve seen it accumulate around the world, we as scientists, as a researcher, as somebody committed to great patient care should revisit our positions on this. Since there is a prohibition against this medication, I think it’s time to reassess that stance and move forward to see if it still is accurate today.

Dr. Motov: I wholeheartedly agree with this. Thank you, Ken, for bringing this up. Good point.

Dr. Glatter: This has been a really informative discussion. I think our audience will certainly embrace this. Thank you very much for your time; it’s much appreciated.
 

Dr. Glatter is an assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He is a medical adviser for Medscape and hosts the Hot Topics in EM series. Dr. Milne is an emergency physician at Strathroy Middlesex General Hospital in Ontario, Canada, and the founder of the well-known podcast The Skeptics’ Guide to Emergency Medicine (SGEM). Dr. Motov is professor of emergency medicine and director of research in the Department of Emergency Medicine at Maimonides Medical Center in Brooklyn, New York. He is passionate about safe and effective pain management in the emergency department, and has numerous publications on the subject of opioid alternatives in pain management. Dr. Glatter, Dr. Milne, and Dr. Motov had no conflicts of interest to disclose.

A version of this article appeared on Medscape.com.

This discussion was recorded on March 29, 2024. The transcript has been edited for clarity.

Robert D. Glatter, MD: Joining me today to discuss the use of methoxyflurane (Penthrox), an inhaled nonopioid analgesic for the relief of acute pain, is Dr. William Kenneth (Ken) Milne, an emergency physician at Strathroy Middlesex General Hospital in Ontario, Canada, and the founder of the well-known podcast The Skeptics’ Guide to Emergency Medicine (SGEM).

Also joining me is Dr. Sergey Motov, an emergency physician and research director at Maimonides Medical Center in Brooklyn, New York, and an expert in pain management. I want to welcome both of you and thank you for joining me.
 

RAMPED Trial: Evaluating the Efficacy of Methoxyflurane

Dr. Glatter: Ken, your recent post on Twitter [now X] regarding the utility of Penthrox in the RAMPED trial really caught my attention. While the trial was from 2021, it really is relevant regarding the prehospital management of pain in the practice of emergency medicine, and certainly in-hospital practice. I was hoping you could review the study design but also get into the rationale behind the use of this novel agent.

William Kenneth (Ken) Milne, MD, MSc: Sure. I’d be happy to kick this episode off with talking about a study that was published in 2020 in Academic Emergency Medicine. It was an Australian study by Brichko et al., and they were doing a randomized controlled trial looking at methoxyflurane vs standard care.

They selected out a population of adults, which they defined as 18-75 years of age. They were in the prehospital setting and they had a pain score of greater than 8. They gave the participants methoxyflurane, which is also called the “green whistle.” They had the subjects take that for their prehospital pain, and they compared that with whatever your standard analgesic in the prehospital setting would be.

Their primary outcome was how many patients had at least 50% reduction in their pain score within 30 minutes. They recruited about 120 people, and they found that there was no statistical difference in the primary outcome between methoxyflurane and standard care. Again, that primary outcome was a reduction in pain score by greater than 50% at 30 minutes, and there wasn’t a statistical difference between the two.

There are obviously limits to any study, and it was a convenience sample. This was an unmasked trial, so people knew if they were getting this green whistle, which is popular in Australia. People would be familiar with this device, and they didn’t compare it with a sham or placebo group.

Pharmacology of Penthrox: Its Role and Mechanism of Action

Dr. Glatter: The primary outcome wasn’t met, but certainly secondary outcomes were. There was, again, a relatively small number of patients in this trial. That said, there was significant pain relief. I think there are issues with the trial, as with any trial limitations.

Getting to the pharmacology of Penthrox, can you describe this inhaled anesthetic and how we use it, specifically its role at the subanesthetic doses?

Sergey M. Motov, MD: Methoxyflurane is embedded in the green whistle package, and that whole contraption is called Penthrox. It’s an inhaled volatile fluorinated hydrocarbon anesthetic that was predominantly used, I’d say 40, 50 years ago, for general anesthesia and slowly but surely fell out of favor due to the fact that, when used for prolonged duration or in supratherapeutic doses, there were cases of severe or even fatal nephrotoxicity and hepatotoxicity.

In the late ‘70s and early ‘80s, all the fluranes came on board that are slightly different as general anesthetics, and methoxyflurane started slowly falling out of favor. Because of this paucity and then a subsequent slightly greater number of cases of nephrotoxicity and hepatotoxicity, [the US Food and Drug Administration] FDA made a decision to pull the drug off the market in 2005. FDA successfully accomplished its mission and since then has pretty much banned the use of inhaled methoxyflurane in any shape, form, or color in the United States.

Going back to the green whistle, it has been used in Australia probably for about 50-60 years, and has been used in Europe for probably 10-20 years. Ken can attest that it has been used in Canada for at least a decade and the track record is phenomenal.

We are using subanesthetic, even supratherapeutic doses that, based on available literature, has no incidence of this fatal hepatotoxicity or nephrotoxicity. We’re talking about 10 million doses administered worldwide, except in the United States. There are 40-plus randomized clinical trials with over 30,000 patients enrolled that prove efficacy and safety.

That’s where we are right now, in a conundrum. We have a great deal of data all over the world, except in the United States, that push for the use of this noninvasive, patient-controlled nonopioid inhaled anesthetic. We just don’t have the access in North America, with the exception of Canada.

Regulatory Hurdles: Challenges in FDA Approval

Dr. Glatter: Absolutely. The FDA wants to be cautious, but if you look at the evidence base of data on this, it really indicates otherwise. Do you think that these roadblocks can be somehow overcome?

Dr. Milne: In the 2000s and 2010s, everybody was focused on opioids and all the dangers and potential adverse events. Opioids are great drugs like many other drugs; it depends on dose and duration. If used properly, it’s an excellent drug. Well, here’s another excellent drug if it’s used properly, and the adverse events are dependent on their dose and duration. Penthrox, or methoxyflurane, is a subtherapeutic, small dose and there have been no reported cases of addiction or abuse related to these inhalers.

Dr. Glatter: That argues for the point — and I’ll turn this over to you, Sergey — of how can this not, in my mind, be an issue that the FDA can overcome.

Dr. Motov: I agree with you. It’s very hard for me to speak on behalf of the FDA, to allude to their thinking processes, but we need to be up to speed with the evidence. The first thing is, why don’t you study the drug in the United States? I’m not asking you to lift the ban, which you put in 2005, but why don’t you honor what has been done over two decades and at least open the door a little bit and let us do what we do best? Why don’t you allow us to do the research in a controlled setting with a carefully, properly selected group of patients without underlying renal or hepatic insufficiency and see where we’re at?

Let’s compare it against placebo. If that’s not ethical, let’s compare it against active comparators — God knows we have 15-20 drugs we can use — and let’s see where we’re at. Ken has been nothing short of superb when it comes to evidence. Let us put the evidence together.

Dr. Milne: If there were concerns decades ago, those need to be addressed. As science is iterative and as other information becomes available, the scientific method would say, Let’s reexamine this and let’s reexamine our position, and do that with evidence. To do that, it has to have validity within the US system. Someone like you doing the research, you are a pain research guru; you should be doing this research to say, “Does it work or not? Does this nonapproval still stand today in 2024?”

Dr. Motov: Thank you for the shout-out, and I agree with you. All of us, those who are interested, on the frontiers of emergency care — as present clinicians — we should be doing this. There is nothing that will convince the FDA more than properly and rightly conducted research, time to reassess the evidence, and time to be less rigid. I understand that you placed a ban 20 years ago, but let’s go with the science. We cannot be behind it.

Exploring the Ecological Footprint of Methoxyflurane

Dr. Milne: There was an Austrian study in 2022 and a very interesting study out of the UK looking at life-cycle impact assessment on the environment. If we’re not just concerned about patient care —obviously, we want to provide patients with a safe and effective product, compared with other products that are available that might not have as good a safety profile — this looks at the impact on the environment.

Dr. Glatter: Ken, can you tell me about some of your recent research regarding the environmental effects related to use of Penthrox, but also its utility pharmacologically and its mechanism of action?

Dr. Milne: There was a really interesting study published this year by Martindale in the Emergency Medicine Journal. It took a different approach to this question about could we be using this drug, and why should we be using this drug? Sergey and I have already talked about the potential benefits and the potential harms. I mentioned opioids and some of the concerns about that. For this drug, if we’re using it in the prehospital setting in this little green whistle, the potential benefits look really good, and we haven’t seen any of the potential harms come through in the literature.

This was another line of evidence of why this might be a good drug, because of the environmental impact of this low-dose methoxyflurane. They compared it with nitrous oxide and said, “Well, what about the life-cycle impact on the environment of using this and the overall cradle-to-grave environmental impacts?”

Obviously, Sergey and I are interested in patient care, and we treat patients one at a time. But we have a larger responsibility to social determinants of health, like our environment. If you look at the overall cradle-to-grave environmental impact of this drug, it was better than for nitrous oxide when looking specifically at climate-change impact. That might be another reason, another line of argument, that could be put forward in the United States to say, “We want to have a healthy environment and a healthy option for patients.”

I’ll let Sergey speak to mechanisms of action and those types of things.

Dr. Motov: As a general anesthetic and hydrocarbonated volatile ones, I’m just going to say that it causes this generalized diffuse cortical depression, and there are no particular channels, receptors, or enzymes we need to worry much about. In short, it’s an inhaled gas used to put patients or people to sleep.

Over the past 30 or 40 years — and I’ll go back to the past decade — there have been numerous studies in different countries (outside of the United States, of course), and with the recent study that Ken just cited, there were comparisons for managing predominantly acute traumatic injuries in pediatric and adult populations presenting to EDs in various regions of the world that compared Penthrox, or the green whistle, with either placebo or active comparators, which included parenteral opioids, oral opioids, and NSAIDs.

The recent systematic review by Fabbri, out of Italy, showed that for ultra–short-term pain — we’re talking about 5, 10, or 15 minutes — inhaled methoxyflurane was found to be equal or even superior to standard of care, primarily related to parenteral opioids, and safety was off the hook. Interestingly, with respect to analgesia, they found that geriatric patients seemed to be responding more, with respect to changing pain score, than younger adults — we’re talking about ages 18-64 vs 65 or older. Again, we need to make sure that we carefully select those elderly people without underlying renal or hepatic insufficiency.

To wrap this up, there is evidence clearly supporting its analgesic efficacy and safety, even in comparison to commonly used and traditionally accepted analgesic modalities that we use for managing acute pain.

US Military Use and Implications for Civilian Practice

Dr. Glatter: Do you think that methoxyflurane’s use in the military will help propel its use in clinical settings in the US, and possibly convince the FDA to look at this closer? The military is currently using it in deployed combat veterans in an ongoing fashion.

Dr. Motov: I’m excited that the Department of Defense in the United States has taken the lead, and they’re being very progressive. There are data that we’ve adapted to the civilian environment by use of intranasal opioids and intranasal ketamine with more doctors who came out of the military. In the military, it’s a kingdom within a kingdom. I don’t know their relationship with the FDA, but I support the military’s pharmacologic initiative by honoring and disseminating their research once it becomes available.

For us nonmilitary folks, we still need to work with the FDA. We need to convince the FDA to let us study the drug, and then we need to pile the evidence within the United States so that the FDA will start looking at this favorably. It wouldn’t hurt and it wouldn’t harm. Any piece of evidence will add to the existing body of literature that we need to allow this medication to be available to us.

Safety Considerations and Aerosolization Concerns

Dr. Glatter: Its safety in children is well established in Australia and throughout the world. I think it deserves a careful look, and the evidence that you’ve both presented argues for the use of this prehospital but also in hospital. I guess there was concern in the hospital with underventilation and healthcare workers being exposed to the fumes, and then getting headaches, dizziness, and so forth. I don’t know if that’s borne out, Ken, in any of your experience in Canada at all.

Dr. Milne: We currently don’t have it in our shop. It’s being used in British Columbia right now in the prehospital setting, and I’m not aware of anybody using it in their department. It’s used prehospital as far as I know.

Dr. Motov: I can attest to it, if I may, because I had familiarized myself with the device. I actually was able to hold it in my hands. I have not used it yet but I had the prototype. The way it’s set up, there is an activated charcoal chamber that sits right on top of the device, which serves as the scavenger for exhaled air that contains particles of methoxyflurane. In theory, but I’m telling how it is in practicality, it significantly reduces occupational exposure, based on data that lacks specifics.

Although most of the researchers did not measure the concentration of methoxyflurane in ambient air within the treatment room in the EDs, I believe the additional data sources clearly stating that it’s within or even below the detectable level that would cause any harm. Once again, we need to honor pathology. We need to make sure that pregnant women will not be exposed to it.

Dr. Milne: In 2024, we also need to be concerned about aerosolizing procedures and aerosolizing treatments, and just take that into account because we should be considering all the potential benefits and all the potential harms. Going through the COVID-19 pandemic, there was concern about transmission and whether or not it was droplet or aerosolized.

There was an observational study published in 2022 in Austria by Trimmel in BMC Emergency Medicine showing similar results. It seemed to work well and potential harms didn’t get picked up. They had to stop the study early because of COVID-19.

We need to always focus in on the potential benefits, the potential harms; where does the science land? Where do the data lie? Then we move forward from that and make informed decisions.

Final Thoughts

Dr. Glatter: Are there any key takeaways you’d like to share with our audience?

Dr. Milne: One of the takeaways from this whole conversation is that science is iterative and science changes. When new evidence becomes available, and we’ve seen it accumulate around the world, we as scientists, as a researcher, as somebody committed to great patient care should revisit our positions on this. Since there is a prohibition against this medication, I think it’s time to reassess that stance and move forward to see if it still is accurate today.

Dr. Motov: I wholeheartedly agree with this. Thank you, Ken, for bringing this up. Good point.

Dr. Glatter: This has been a really informative discussion. I think our audience will certainly embrace this. Thank you very much for your time; it’s much appreciated.
 

Dr. Glatter is an assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He is a medical adviser for Medscape and hosts the Hot Topics in EM series. Dr. Milne is an emergency physician at Strathroy Middlesex General Hospital in Ontario, Canada, and the founder of the well-known podcast The Skeptics’ Guide to Emergency Medicine (SGEM). Dr. Motov is professor of emergency medicine and director of research in the Department of Emergency Medicine at Maimonides Medical Center in Brooklyn, New York. He is passionate about safe and effective pain management in the emergency department, and has numerous publications on the subject of opioid alternatives in pain management. Dr. Glatter, Dr. Milne, and Dr. Motov had no conflicts of interest to disclose.

A version of this article appeared on Medscape.com.