Pain

A new clinical practice guideline by the American Society for Radiation Oncology (ASTRO) steers use of external beam radiation therapy (EBRT) for the palliation of symptomatic bone metastases, including recommendations concerning pain management and quality of life.

The guideline was needed to update previous recommendations and incorporate new high-quality evidence for the management of symptomatic bone metastases, Sara Alcorn, MD, PhD, of the University of Minnesota, Minneapolis, and colleagues wrote in Practical Radiation Oncology.

The focus was on the efficacy of EBRT in reducing pain, improving skeletal function, and enhancing quality of life, they wrote in the clinical practice guideline.

In developing their recommendations, the ASTRO task force reviewed evidence from 53 randomized controlled trials (RCTs) and 31 nonrandomized studies, and considered clinical experience.
 

Indications for Palliative Radiation

EBRT is strongly recommended for reducing pain from osseous metastasis and improving ambulatory status, sphincter function, and reducing pain in patients with spinal metastases causing compression of the spinal cord or cauda equina.

For patients with symptomatic bone metastases and an anticipated life expectancy of at least 4 weeks, EBRT is conditionally recommended to improve quality of life.

Implementation of other Treatments Alongside Palliative Radiation

Instead of RT alone, surgery with postoperative RT is conditionally recommended for patients with compression of the spinal cord or cauda equina.

Postoperative RT is strongly recommended for patients who have undergone surgery for non-spine bone metastases or spine metastases without involving spinal cord or cauda equina compression.

For patients with spinal bone metastases compressing the spinal cord or cauda equina, combining RT with dexamethasone is strongly recommended over RT alone.

Techniques, Dose-Fractionation, and Dose-Constraints for Initial Palliative Radiation

For patients with symptomatic bone metastases undergoing conventional palliative RT, strongly recommended doses are 800 cGy in 1 fraction, 2000 cGy in 5 fractions, 2400 cGy in 6 fractions, or 3000 cGy in 10 fractions.

For patients with spinal bone metastases causing compression of the spinal cord or cauda equina who are not candidates for initial surgical decompression and are treated with conventional palliative RT, strongly recommended doses are 800 cGy in 1 fraction, 1600 cGy in 2 fractions, 2000 cGy in 5 fractions, or 3000 cGy in 10 fractions.

When selecting dose-fractionation, consider patient and disease factors such as prognosis and radiosensitivity, the authors wrote.

Highly conformal planning and delivery techniques, such as intensity-modulated radiation therapy, are conditionally recommended for patients with spinal bone metastases compressing the spinal cord or cauda equina who are receiving dose-escalated palliative RT.

The strongly recommended stereotactic body radiotherapy (SBRT) doses for patients with symptomatic bone metastases are 1200 to 1600 cGy in 1 fraction for non-spine metastases and 2400 cGy in 2 fractions for spine metastases. Other established SBRT dose and fractionation regimens with similar biologically effective doses may be considered based on patient tumor characteristics, normal tissue factors, and physician experience.

For patients with symptomatic bone metastases who have an ECOG PS of 0-2, are not undergoing surgical intervention, and have no neurological symptoms, SBRT is conditionally recommended over conventional palliative RT. Other factors to consider include life expectancy, tumor radiosensitivity, and metastatic disease burden, the guideline says.
 

Techniques, Dose-Fractionation, and Dose-Constraints for Palliative Reirradiation

For patients with spinal bone metastases requiring reirradiation to the same site, the strongly recommended conventional palliative RT regimens are 800 cGy in 1 fraction, 2000 cGy in 5 fractions, 2400 cGy in 6 fractions, or 2000 cGy in 8 fractions. When determining the RT dose-fractionation, consider the prior RT dose, time interval, and total spinal cord tolerance, the guideline says.

Treatment with SBRT is conditionally recommended for patients with spinal bone metastases needing reirradiation at the same site. When determining if SBRT is appropriate, consider patient factors such as urgency of treatment, prognosis, and radio-resistance. In addition, consider the prior RT dose, time interval, and total spinal cord tolerance when determining the RT dose-fractionation, the authors say.

The strongly recommended options for patients with symptomatic non-spine bone metastases needing reirradiation at the same site are single-fraction RT (800 cGy in 1 fraction) or multifraction conventional palliative RT (2000 cGy in 5 fractions or 2400 cGy in 6 fractions).
 

Impact of Techniques and Dose-fractionation on Quality of Life and Toxicity

For patients with bone metastases undergoing palliative radiation, it is strongly recommended to use a shared decision-making approach to determine the dose, fractionation, and supportive measures to optimize quality of life.

“Based on published data, the ASTRO task force’s recommendations inform best clinical practices on palliative RT for symptomatic bone metastases,” the guideline panelists said.

Limitations

While the guideline provides comprehensive recommendations, the panelists underscored the importance of individualized treatment approaches. Future research is needed to address gaps in evidence, particularly regarding advanced RT techniques and reirradiation strategies.

Guideline development was funded by ASTRO, with the systematic evidence review funded by the Patient-Centered Outcomes Research Institute. The panelists disclosed relationships with AstraZeneca, Elekta, Teladoc, and others.

A new clinical practice guideline by the American Society for Radiation Oncology (ASTRO) steers use of external beam radiation therapy (EBRT) for the palliation of symptomatic bone metastases, including recommendations concerning pain management and quality of life.

The guideline was needed to update previous recommendations and incorporate new high-quality evidence for the management of symptomatic bone metastases, Sara Alcorn, MD, PhD, of the University of Minnesota, Minneapolis, and colleagues wrote in Practical Radiation Oncology.

The focus was on the efficacy of EBRT in reducing pain, improving skeletal function, and enhancing quality of life, they wrote in the clinical practice guideline.

In developing their recommendations, the ASTRO task force reviewed evidence from 53 randomized controlled trials (RCTs) and 31 nonrandomized studies, and considered clinical experience.
 

Indications for Palliative Radiation

EBRT is strongly recommended for reducing pain from osseous metastasis and improving ambulatory status, sphincter function, and reducing pain in patients with spinal metastases causing compression of the spinal cord or cauda equina.

For patients with symptomatic bone metastases and an anticipated life expectancy of at least 4 weeks, EBRT is conditionally recommended to improve quality of life.

Implementation of other Treatments Alongside Palliative Radiation

Instead of RT alone, surgery with postoperative RT is conditionally recommended for patients with compression of the spinal cord or cauda equina.

Postoperative RT is strongly recommended for patients who have undergone surgery for non-spine bone metastases or spine metastases without involving spinal cord or cauda equina compression.

For patients with spinal bone metastases compressing the spinal cord or cauda equina, combining RT with dexamethasone is strongly recommended over RT alone.

Techniques, Dose-Fractionation, and Dose-Constraints for Initial Palliative Radiation

For patients with symptomatic bone metastases undergoing conventional palliative RT, strongly recommended doses are 800 cGy in 1 fraction, 2000 cGy in 5 fractions, 2400 cGy in 6 fractions, or 3000 cGy in 10 fractions.

For patients with spinal bone metastases causing compression of the spinal cord or cauda equina who are not candidates for initial surgical decompression and are treated with conventional palliative RT, strongly recommended doses are 800 cGy in 1 fraction, 1600 cGy in 2 fractions, 2000 cGy in 5 fractions, or 3000 cGy in 10 fractions.

When selecting dose-fractionation, consider patient and disease factors such as prognosis and radiosensitivity, the authors wrote.

Highly conformal planning and delivery techniques, such as intensity-modulated radiation therapy, are conditionally recommended for patients with spinal bone metastases compressing the spinal cord or cauda equina who are receiving dose-escalated palliative RT.

The strongly recommended stereotactic body radiotherapy (SBRT) doses for patients with symptomatic bone metastases are 1200 to 1600 cGy in 1 fraction for non-spine metastases and 2400 cGy in 2 fractions for spine metastases. Other established SBRT dose and fractionation regimens with similar biologically effective doses may be considered based on patient tumor characteristics, normal tissue factors, and physician experience.

For patients with symptomatic bone metastases who have an ECOG PS of 0-2, are not undergoing surgical intervention, and have no neurological symptoms, SBRT is conditionally recommended over conventional palliative RT. Other factors to consider include life expectancy, tumor radiosensitivity, and metastatic disease burden, the guideline says.
 

Techniques, Dose-Fractionation, and Dose-Constraints for Palliative Reirradiation

For patients with spinal bone metastases requiring reirradiation to the same site, the strongly recommended conventional palliative RT regimens are 800 cGy in 1 fraction, 2000 cGy in 5 fractions, 2400 cGy in 6 fractions, or 2000 cGy in 8 fractions. When determining the RT dose-fractionation, consider the prior RT dose, time interval, and total spinal cord tolerance, the guideline says.

Treatment with SBRT is conditionally recommended for patients with spinal bone metastases needing reirradiation at the same site. When determining if SBRT is appropriate, consider patient factors such as urgency of treatment, prognosis, and radio-resistance. In addition, consider the prior RT dose, time interval, and total spinal cord tolerance when determining the RT dose-fractionation, the authors say.

The strongly recommended options for patients with symptomatic non-spine bone metastases needing reirradiation at the same site are single-fraction RT (800 cGy in 1 fraction) or multifraction conventional palliative RT (2000 cGy in 5 fractions or 2400 cGy in 6 fractions).
 

Impact of Techniques and Dose-fractionation on Quality of Life and Toxicity

For patients with bone metastases undergoing palliative radiation, it is strongly recommended to use a shared decision-making approach to determine the dose, fractionation, and supportive measures to optimize quality of life.

“Based on published data, the ASTRO task force’s recommendations inform best clinical practices on palliative RT for symptomatic bone metastases,” the guideline panelists said.

Limitations

While the guideline provides comprehensive recommendations, the panelists underscored the importance of individualized treatment approaches. Future research is needed to address gaps in evidence, particularly regarding advanced RT techniques and reirradiation strategies.

Guideline development was funded by ASTRO, with the systematic evidence review funded by the Patient-Centered Outcomes Research Institute. The panelists disclosed relationships with AstraZeneca, Elekta, Teladoc, and others.

A new clinical practice guideline by the American Society for Radiation Oncology (ASTRO) steers use of external beam radiation therapy (EBRT) for the palliation of symptomatic bone metastases, including recommendations concerning pain management and quality of life.

The guideline was needed to update previous recommendations and incorporate new high-quality evidence for the management of symptomatic bone metastases, Sara Alcorn, MD, PhD, of the University of Minnesota, Minneapolis, and colleagues wrote in Practical Radiation Oncology.

The focus was on the efficacy of EBRT in reducing pain, improving skeletal function, and enhancing quality of life, they wrote in the clinical practice guideline.

In developing their recommendations, the ASTRO task force reviewed evidence from 53 randomized controlled trials (RCTs) and 31 nonrandomized studies, and considered clinical experience.
 

Indications for Palliative Radiation

EBRT is strongly recommended for reducing pain from osseous metastasis and improving ambulatory status, sphincter function, and reducing pain in patients with spinal metastases causing compression of the spinal cord or cauda equina.

For patients with symptomatic bone metastases and an anticipated life expectancy of at least 4 weeks, EBRT is conditionally recommended to improve quality of life.

Implementation of other Treatments Alongside Palliative Radiation

Instead of RT alone, surgery with postoperative RT is conditionally recommended for patients with compression of the spinal cord or cauda equina.

Postoperative RT is strongly recommended for patients who have undergone surgery for non-spine bone metastases or spine metastases without involving spinal cord or cauda equina compression.

For patients with spinal bone metastases compressing the spinal cord or cauda equina, combining RT with dexamethasone is strongly recommended over RT alone.

Techniques, Dose-Fractionation, and Dose-Constraints for Initial Palliative Radiation

For patients with symptomatic bone metastases undergoing conventional palliative RT, strongly recommended doses are 800 cGy in 1 fraction, 2000 cGy in 5 fractions, 2400 cGy in 6 fractions, or 3000 cGy in 10 fractions.

For patients with spinal bone metastases causing compression of the spinal cord or cauda equina who are not candidates for initial surgical decompression and are treated with conventional palliative RT, strongly recommended doses are 800 cGy in 1 fraction, 1600 cGy in 2 fractions, 2000 cGy in 5 fractions, or 3000 cGy in 10 fractions.

When selecting dose-fractionation, consider patient and disease factors such as prognosis and radiosensitivity, the authors wrote.

Highly conformal planning and delivery techniques, such as intensity-modulated radiation therapy, are conditionally recommended for patients with spinal bone metastases compressing the spinal cord or cauda equina who are receiving dose-escalated palliative RT.

The strongly recommended stereotactic body radiotherapy (SBRT) doses for patients with symptomatic bone metastases are 1200 to 1600 cGy in 1 fraction for non-spine metastases and 2400 cGy in 2 fractions for spine metastases. Other established SBRT dose and fractionation regimens with similar biologically effective doses may be considered based on patient tumor characteristics, normal tissue factors, and physician experience.

For patients with symptomatic bone metastases who have an ECOG PS of 0-2, are not undergoing surgical intervention, and have no neurological symptoms, SBRT is conditionally recommended over conventional palliative RT. Other factors to consider include life expectancy, tumor radiosensitivity, and metastatic disease burden, the guideline says.
 

Techniques, Dose-Fractionation, and Dose-Constraints for Palliative Reirradiation

For patients with spinal bone metastases requiring reirradiation to the same site, the strongly recommended conventional palliative RT regimens are 800 cGy in 1 fraction, 2000 cGy in 5 fractions, 2400 cGy in 6 fractions, or 2000 cGy in 8 fractions. When determining the RT dose-fractionation, consider the prior RT dose, time interval, and total spinal cord tolerance, the guideline says.

Treatment with SBRT is conditionally recommended for patients with spinal bone metastases needing reirradiation at the same site. When determining if SBRT is appropriate, consider patient factors such as urgency of treatment, prognosis, and radio-resistance. In addition, consider the prior RT dose, time interval, and total spinal cord tolerance when determining the RT dose-fractionation, the authors say.

The strongly recommended options for patients with symptomatic non-spine bone metastases needing reirradiation at the same site are single-fraction RT (800 cGy in 1 fraction) or multifraction conventional palliative RT (2000 cGy in 5 fractions or 2400 cGy in 6 fractions).
 

Impact of Techniques and Dose-fractionation on Quality of Life and Toxicity

For patients with bone metastases undergoing palliative radiation, it is strongly recommended to use a shared decision-making approach to determine the dose, fractionation, and supportive measures to optimize quality of life.

“Based on published data, the ASTRO task force’s recommendations inform best clinical practices on palliative RT for symptomatic bone metastases,” the guideline panelists said.

Limitations

While the guideline provides comprehensive recommendations, the panelists underscored the importance of individualized treatment approaches. Future research is needed to address gaps in evidence, particularly regarding advanced RT techniques and reirradiation strategies.

Guideline development was funded by ASTRO, with the systematic evidence review funded by the Patient-Centered Outcomes Research Institute. The panelists disclosed relationships with AstraZeneca, Elekta, Teladoc, and others.

Although the prevalence of migraine in the United States has remained stable over the past three decades, migraine-related disability has nearly doubled during that time, a new systematic review showed.

“The disability trend could reflect changes in reporting, study methodology, social, and societal changes, or changes in exacerbating or remediating factors that make migraine more disabling,” wrote lead investigator Fred Cohen, MD, of Center for Headache and Facial Pain, Department of Neurology, Icahn School of Medicine, Mount Sinai, New York City, and colleagues.

The study was published online in Headache.

Researchers conducted a systematic review of population-based US epidemiologic studies focusing on the prevalence and/or burden of migraine, all published before February 2022. Studies on migraine, episodic migraine, and/or chronic migraine were included.

The primary measure of disease burden was the Migraine Disability Assessment Scale (MIDAS), which measures days lost to migraine over a 3-month period in three domains and defines groups with moderate or severe disability (grades III and IV, respectively), using cut-scores.

Of 1609 studies initially reviewed, the researchers included 26 publications from 11 US population-based studies.

For the past 30 years, the prevalence of migraine in the population has remained largely stable, ranging from 12% to 15% in the overall population, from 17% to 19% in women, and from 6% to 7% in men.

In adults overall, chronic migraine prevalence is 0.91% (1.3% in women and 0.5% in men), while in adolescents, the prevalence is 0.8%.

Although prevalence remained roughly the same during the 30 years, the proportion of people with migraine and moderate to severe MIDAS disability (grades III-IV) has trended upward across studies during part of the study period, increasing from 22% in 2005 to 42% in 2018.

Throughout the years studied, a consistently higher proportion of women versus men were assigned MIDAS grades III-IV.

Although researchers said the exact reason for the increase is unknown, possible explanations include changes in study methodology from mailed questionnaires to web surveys or the decline in participation rate in web surveys. It is also possible that people with migraine may be more willing to report disability than they used to be, authors wrote.

Increased MIDAS scores may be attributable to some environmental risk factor that exacerbates migraine without modifying its prevalence, such as worsening air quality, an increase in natural disasters, or increased opioid use for migraine, they added.

The reason for increased moderate to severe disability in women may be attributable to the fact that migraine is “most common in mid-life, a period characterized by familial and work responsibilities, which may engender a higher risk of burden for working women,” authors wrote. The link between migraine attacks and menstrual cycles may also explain observed gender differences in disability.

In general, the most frequently reported burdens associated with migraine included missed work and school and family and social functioning.

It is “surprising that improvements in treatment have not been associated with reductions in disability,” researchers noted.

No financial support was provided for this study. Dr. Cohen serves as an assistant editor for Headache. He has received honoraria from Springer Nature and MedLink Neurology. Other authors’ disclosures are listed on the original paper.
 

A version of this article appeared on Medscape.com.

Although the prevalence of migraine in the United States has remained stable over the past three decades, migraine-related disability has nearly doubled during that time, a new systematic review showed.

“The disability trend could reflect changes in reporting, study methodology, social, and societal changes, or changes in exacerbating or remediating factors that make migraine more disabling,” wrote lead investigator Fred Cohen, MD, of Center for Headache and Facial Pain, Department of Neurology, Icahn School of Medicine, Mount Sinai, New York City, and colleagues.

The study was published online in Headache.

Researchers conducted a systematic review of population-based US epidemiologic studies focusing on the prevalence and/or burden of migraine, all published before February 2022. Studies on migraine, episodic migraine, and/or chronic migraine were included.

The primary measure of disease burden was the Migraine Disability Assessment Scale (MIDAS), which measures days lost to migraine over a 3-month period in three domains and defines groups with moderate or severe disability (grades III and IV, respectively), using cut-scores.

Of 1609 studies initially reviewed, the researchers included 26 publications from 11 US population-based studies.

For the past 30 years, the prevalence of migraine in the population has remained largely stable, ranging from 12% to 15% in the overall population, from 17% to 19% in women, and from 6% to 7% in men.

In adults overall, chronic migraine prevalence is 0.91% (1.3% in women and 0.5% in men), while in adolescents, the prevalence is 0.8%.

Although prevalence remained roughly the same during the 30 years, the proportion of people with migraine and moderate to severe MIDAS disability (grades III-IV) has trended upward across studies during part of the study period, increasing from 22% in 2005 to 42% in 2018.

Throughout the years studied, a consistently higher proportion of women versus men were assigned MIDAS grades III-IV.

Although researchers said the exact reason for the increase is unknown, possible explanations include changes in study methodology from mailed questionnaires to web surveys or the decline in participation rate in web surveys. It is also possible that people with migraine may be more willing to report disability than they used to be, authors wrote.

Increased MIDAS scores may be attributable to some environmental risk factor that exacerbates migraine without modifying its prevalence, such as worsening air quality, an increase in natural disasters, or increased opioid use for migraine, they added.

The reason for increased moderate to severe disability in women may be attributable to the fact that migraine is “most common in mid-life, a period characterized by familial and work responsibilities, which may engender a higher risk of burden for working women,” authors wrote. The link between migraine attacks and menstrual cycles may also explain observed gender differences in disability.

In general, the most frequently reported burdens associated with migraine included missed work and school and family and social functioning.

It is “surprising that improvements in treatment have not been associated with reductions in disability,” researchers noted.

No financial support was provided for this study. Dr. Cohen serves as an assistant editor for Headache. He has received honoraria from Springer Nature and MedLink Neurology. Other authors’ disclosures are listed on the original paper.
 

A version of this article appeared on Medscape.com.

Although the prevalence of migraine in the United States has remained stable over the past three decades, migraine-related disability has nearly doubled during that time, a new systematic review showed.

“The disability trend could reflect changes in reporting, study methodology, social, and societal changes, or changes in exacerbating or remediating factors that make migraine more disabling,” wrote lead investigator Fred Cohen, MD, of Center for Headache and Facial Pain, Department of Neurology, Icahn School of Medicine, Mount Sinai, New York City, and colleagues.

The study was published online in Headache.

Researchers conducted a systematic review of population-based US epidemiologic studies focusing on the prevalence and/or burden of migraine, all published before February 2022. Studies on migraine, episodic migraine, and/or chronic migraine were included.

The primary measure of disease burden was the Migraine Disability Assessment Scale (MIDAS), which measures days lost to migraine over a 3-month period in three domains and defines groups with moderate or severe disability (grades III and IV, respectively), using cut-scores.

Of 1609 studies initially reviewed, the researchers included 26 publications from 11 US population-based studies.

For the past 30 years, the prevalence of migraine in the population has remained largely stable, ranging from 12% to 15% in the overall population, from 17% to 19% in women, and from 6% to 7% in men.

In adults overall, chronic migraine prevalence is 0.91% (1.3% in women and 0.5% in men), while in adolescents, the prevalence is 0.8%.

Although prevalence remained roughly the same during the 30 years, the proportion of people with migraine and moderate to severe MIDAS disability (grades III-IV) has trended upward across studies during part of the study period, increasing from 22% in 2005 to 42% in 2018.

Throughout the years studied, a consistently higher proportion of women versus men were assigned MIDAS grades III-IV.

Although researchers said the exact reason for the increase is unknown, possible explanations include changes in study methodology from mailed questionnaires to web surveys or the decline in participation rate in web surveys. It is also possible that people with migraine may be more willing to report disability than they used to be, authors wrote.

Increased MIDAS scores may be attributable to some environmental risk factor that exacerbates migraine without modifying its prevalence, such as worsening air quality, an increase in natural disasters, or increased opioid use for migraine, they added.

The reason for increased moderate to severe disability in women may be attributable to the fact that migraine is “most common in mid-life, a period characterized by familial and work responsibilities, which may engender a higher risk of burden for working women,” authors wrote. The link between migraine attacks and menstrual cycles may also explain observed gender differences in disability.

In general, the most frequently reported burdens associated with migraine included missed work and school and family and social functioning.

It is “surprising that improvements in treatment have not been associated with reductions in disability,” researchers noted.

No financial support was provided for this study. Dr. Cohen serves as an assistant editor for Headache. He has received honoraria from Springer Nature and MedLink Neurology. Other authors’ disclosures are listed on the original paper.
 

A version of this article appeared on Medscape.com.

PHOENIX — Certain minority populations may be at a higher absolute risk of being prescribed opioids after undergoing dermatologic surgery, according to a new study. The study also found that patients who do receive opioids postoperatively are at an increased risk for chronic opioid use and complications.

This report represents the largest analysis to date of opioid prescribing after dermatologic surgery, said lead author Kyle C. Lauck, MD, a dermatology resident at Baylor University Medical Center, Dallas, Texas. “Females, African Americans, and Latino patients may be at a higher risk of opioid prescription after dermatologic surgery. Surgeons should be aware of these populations and the risks they face when determining candidacy for postsurgical opioid analgesia.”

He presented the results at the annual meeting of the American College of Mohs Surgery.

The opioid epidemic is a concern across all areas of medicine, and the majority of opioid prescriptions in dermatology are given following surgery. Dr. Lauck noted that even though guidelines delegate opioids as second line for pain control, the existing data on opioid prescribing in dermatologic surgery is mixed. For example, some reports have shown that up to 58% of patients receive opioids postoperatively. “No consensus exists when we should routinely give opioids to these patients,” he said.

Even though most surgeons prescribe short courses of opioids, even brief regimens are associated with increased risks for overuse and substance abuse. Population-level data are limited concerning opioid prescriptions in dermatologic surgery, and in particular, there is an absence of data on the risk for long-term complications associated with use.

[embed:render:related:node:262964]

Certain Populations at Risk

To evaluate opioid prescription rates in dermatologic surgery, focusing on disparities between demographic populations, as well as the risk for long-term complications of postoperative opioid prescriptions, Dr. Lauck and colleagues conducted a retrospective study that included 914,721 dermatologic surgery patients, with billing codes for Mohs micrographic surgery. Patient data were obtained from TriNetX, a federated health research network.

The mean age of patients in this cohort was 54 years, and 124,494 (13.6%) were prescribed postsurgical oral opioids. The most common was oxycodone, prescribed to 43% of patients. Dr. Lauck noted that, according to their data, certain groups appeared more likely to receive a prescription for opioids following surgery. These included Black or African American patients (23.75% vs 12.86% for White patients), females (13.73% vs 13.16% for males), and Latino or Hispanic patients (17.02% vs 13.61% non-Latino/Hispanic patients).

Patients with a history of prior oral opioid prescription, prior opioid abuse or dependence, and any type of substance abuse had a significant increase in absolute risk of being prescribed postsurgical opioids (P < .0001). 

The type of surgery also was associated with prescribed postop opioids. For a malignant excision, 18.29% of patients were prescribed postop opioids compared with 14.9% for a benign excision. About a third of patients (34.9%) undergoing a graft repair received opioids.

There was an elevated rate of postop opioid prescribing that was specific to the site of surgery, with the highest rates observed with eyelids, scalp and neck, trunk, and genital sites. The highest overall rates of opioid prescriptions were for patients who underwent excisions in the genital area (54.5%).
 

Long-Term Consequences

The authors also looked at the longer-term consequences of postop opioid use. “Nearly one in three patients who were prescribed opioids needed subsequent prescriptions down the line,” said Dr. Lauck. 

From 3 months to 5 years after surgery, patients who received postsurgical opioids were at significantly higher risk for not only subsequent oral opioid prescription but also opiate abuse, any substance abuse, overdose by opioid narcotics, constipation, and chronic pain. “An opioid prescription may confer further risks of longitudinal complications of chronic opioid use,” he concluded.

Commenting on the study, Jesse M. Lewin, MD, chief of Mohs micrographic and dermatologic surgery at Icahn School of Medicine at Mount Sinai, New York City, noted an important finding of this study was the long-term sequelae of patients who did receive postop opioids.

“This is striking given that postsurgical opiate prescriptions are for short durations and limited number of pills,” he told this news organization. “This study highlights the potential danger of even short course of opiates and should serve as a reminder to dermatologic surgeons to be judicious about opiate prescribing.”

Dr. Lauck and Dr. Lewin had no disclosures. 
 

A version of this article appeared on Medscape.com.

PHOENIX — Certain minority populations may be at a higher absolute risk of being prescribed opioids after undergoing dermatologic surgery, according to a new study. The study also found that patients who do receive opioids postoperatively are at an increased risk for chronic opioid use and complications.

This report represents the largest analysis to date of opioid prescribing after dermatologic surgery, said lead author Kyle C. Lauck, MD, a dermatology resident at Baylor University Medical Center, Dallas, Texas. “Females, African Americans, and Latino patients may be at a higher risk of opioid prescription after dermatologic surgery. Surgeons should be aware of these populations and the risks they face when determining candidacy for postsurgical opioid analgesia.”

He presented the results at the annual meeting of the American College of Mohs Surgery.

The opioid epidemic is a concern across all areas of medicine, and the majority of opioid prescriptions in dermatology are given following surgery. Dr. Lauck noted that even though guidelines delegate opioids as second line for pain control, the existing data on opioid prescribing in dermatologic surgery is mixed. For example, some reports have shown that up to 58% of patients receive opioids postoperatively. “No consensus exists when we should routinely give opioids to these patients,” he said.

Even though most surgeons prescribe short courses of opioids, even brief regimens are associated with increased risks for overuse and substance abuse. Population-level data are limited concerning opioid prescriptions in dermatologic surgery, and in particular, there is an absence of data on the risk for long-term complications associated with use.

[embed:render:related:node:262964]

Certain Populations at Risk

To evaluate opioid prescription rates in dermatologic surgery, focusing on disparities between demographic populations, as well as the risk for long-term complications of postoperative opioid prescriptions, Dr. Lauck and colleagues conducted a retrospective study that included 914,721 dermatologic surgery patients, with billing codes for Mohs micrographic surgery. Patient data were obtained from TriNetX, a federated health research network.

The mean age of patients in this cohort was 54 years, and 124,494 (13.6%) were prescribed postsurgical oral opioids. The most common was oxycodone, prescribed to 43% of patients. Dr. Lauck noted that, according to their data, certain groups appeared more likely to receive a prescription for opioids following surgery. These included Black or African American patients (23.75% vs 12.86% for White patients), females (13.73% vs 13.16% for males), and Latino or Hispanic patients (17.02% vs 13.61% non-Latino/Hispanic patients).

Patients with a history of prior oral opioid prescription, prior opioid abuse or dependence, and any type of substance abuse had a significant increase in absolute risk of being prescribed postsurgical opioids (P < .0001). 

The type of surgery also was associated with prescribed postop opioids. For a malignant excision, 18.29% of patients were prescribed postop opioids compared with 14.9% for a benign excision. About a third of patients (34.9%) undergoing a graft repair received opioids.

There was an elevated rate of postop opioid prescribing that was specific to the site of surgery, with the highest rates observed with eyelids, scalp and neck, trunk, and genital sites. The highest overall rates of opioid prescriptions were for patients who underwent excisions in the genital area (54.5%).
 

Long-Term Consequences

The authors also looked at the longer-term consequences of postop opioid use. “Nearly one in three patients who were prescribed opioids needed subsequent prescriptions down the line,” said Dr. Lauck. 

From 3 months to 5 years after surgery, patients who received postsurgical opioids were at significantly higher risk for not only subsequent oral opioid prescription but also opiate abuse, any substance abuse, overdose by opioid narcotics, constipation, and chronic pain. “An opioid prescription may confer further risks of longitudinal complications of chronic opioid use,” he concluded.

Commenting on the study, Jesse M. Lewin, MD, chief of Mohs micrographic and dermatologic surgery at Icahn School of Medicine at Mount Sinai, New York City, noted an important finding of this study was the long-term sequelae of patients who did receive postop opioids.

“This is striking given that postsurgical opiate prescriptions are for short durations and limited number of pills,” he told this news organization. “This study highlights the potential danger of even short course of opiates and should serve as a reminder to dermatologic surgeons to be judicious about opiate prescribing.”

Dr. Lauck and Dr. Lewin had no disclosures. 
 

A version of this article appeared on Medscape.com.

PHOENIX — Certain minority populations may be at a higher absolute risk of being prescribed opioids after undergoing dermatologic surgery, according to a new study. The study also found that patients who do receive opioids postoperatively are at an increased risk for chronic opioid use and complications.

This report represents the largest analysis to date of opioid prescribing after dermatologic surgery, said lead author Kyle C. Lauck, MD, a dermatology resident at Baylor University Medical Center, Dallas, Texas. “Females, African Americans, and Latino patients may be at a higher risk of opioid prescription after dermatologic surgery. Surgeons should be aware of these populations and the risks they face when determining candidacy for postsurgical opioid analgesia.”

He presented the results at the annual meeting of the American College of Mohs Surgery.

The opioid epidemic is a concern across all areas of medicine, and the majority of opioid prescriptions in dermatology are given following surgery. Dr. Lauck noted that even though guidelines delegate opioids as second line for pain control, the existing data on opioid prescribing in dermatologic surgery is mixed. For example, some reports have shown that up to 58% of patients receive opioids postoperatively. “No consensus exists when we should routinely give opioids to these patients,” he said.

Even though most surgeons prescribe short courses of opioids, even brief regimens are associated with increased risks for overuse and substance abuse. Population-level data are limited concerning opioid prescriptions in dermatologic surgery, and in particular, there is an absence of data on the risk for long-term complications associated with use.

[embed:render:related:node:262964]

Certain Populations at Risk

To evaluate opioid prescription rates in dermatologic surgery, focusing on disparities between demographic populations, as well as the risk for long-term complications of postoperative opioid prescriptions, Dr. Lauck and colleagues conducted a retrospective study that included 914,721 dermatologic surgery patients, with billing codes for Mohs micrographic surgery. Patient data were obtained from TriNetX, a federated health research network.

The mean age of patients in this cohort was 54 years, and 124,494 (13.6%) were prescribed postsurgical oral opioids. The most common was oxycodone, prescribed to 43% of patients. Dr. Lauck noted that, according to their data, certain groups appeared more likely to receive a prescription for opioids following surgery. These included Black or African American patients (23.75% vs 12.86% for White patients), females (13.73% vs 13.16% for males), and Latino or Hispanic patients (17.02% vs 13.61% non-Latino/Hispanic patients).

Patients with a history of prior oral opioid prescription, prior opioid abuse or dependence, and any type of substance abuse had a significant increase in absolute risk of being prescribed postsurgical opioids (P < .0001). 

The type of surgery also was associated with prescribed postop opioids. For a malignant excision, 18.29% of patients were prescribed postop opioids compared with 14.9% for a benign excision. About a third of patients (34.9%) undergoing a graft repair received opioids.

There was an elevated rate of postop opioid prescribing that was specific to the site of surgery, with the highest rates observed with eyelids, scalp and neck, trunk, and genital sites. The highest overall rates of opioid prescriptions were for patients who underwent excisions in the genital area (54.5%).
 

Long-Term Consequences

The authors also looked at the longer-term consequences of postop opioid use. “Nearly one in three patients who were prescribed opioids needed subsequent prescriptions down the line,” said Dr. Lauck. 

From 3 months to 5 years after surgery, patients who received postsurgical opioids were at significantly higher risk for not only subsequent oral opioid prescription but also opiate abuse, any substance abuse, overdose by opioid narcotics, constipation, and chronic pain. “An opioid prescription may confer further risks of longitudinal complications of chronic opioid use,” he concluded.

Commenting on the study, Jesse M. Lewin, MD, chief of Mohs micrographic and dermatologic surgery at Icahn School of Medicine at Mount Sinai, New York City, noted an important finding of this study was the long-term sequelae of patients who did receive postop opioids.

“This is striking given that postsurgical opiate prescriptions are for short durations and limited number of pills,” he told this news organization. “This study highlights the potential danger of even short course of opiates and should serve as a reminder to dermatologic surgeons to be judicious about opiate prescribing.”

Dr. Lauck and Dr. Lewin had no disclosures. 
 

A version of this article appeared on Medscape.com.

Meningitis has been highlighted as a novel risk factor for trigeminal neuralgia in a nationwide, propensity-matched study of hospital admissions.

In multivariate analysis, the odds of meningitis were threefold higher in patients admitted with trigeminal neuralgia than in matched controls without trigeminal neuralgia.

This is the first nationwide population-based study of the rare, chronic pain disorder to identify the prevalence of trigeminal neuralgia admissions in the United States and risk factors contributing to trigeminal neuralgia development.

“Our results affirm known associations between trigeminal neuralgia and comorbidities like multiple sclerosis, and they also identify meningitis as a novel risk factor for trigeminal neuralgia,” said investigator Megan Tang, BS, a medical student at the Icahn School of Medicine at Mount Sinai, New York City.

The findings were presented at the American Association of Neurological Surgeons (AANS) 2024 annual meeting.
 

Strong Clinical Risk Factors

Trigeminal neuralgia is a rare pain disorder involving neurovascular compression of the trigeminal nerve. Its etiology and risk factors are poorly understood. Current literature is based on limited datasets and reports inconsistent risk factors across studies.

To better understand the disorder, researchers used International Classification of Diseases (ICD)-9 codes to identify trigeminal neuralgia admissions in the National Inpatient Sample from 2016 to 2019, and then propensity matched them 1:1 to non-trigeminal neuralgia admissions based on demographics, socioeconomic status, and Charlson comorbidity index scores.

Univariate analysis identified 136,345 trigeminal neuralgia admissions or an overall prevalence of 0.096%.

Trigeminal neuralgia admissions had lower morbidity than non-trigeminal neuralgia admissions and a higher prevalence of non-White patients, private insurance, and prolonged length of stay, Ms. Tang said.

Patients admitted for trigeminal neuralgia also had a higher prevalence of several chronic conditions, including hypertension, hyperlipidemia, and osteoarthritis; inflammatory conditions like lupus, meningitis, rheumatoid arthritis, and inflammatory bowel disease; and neurologic conditions including multiple sclerosis, epilepsy, stroke, and neurovascular compression disorders.

In multivariate analysis, investigators identified meningitis as a previously unknown risk factor for trigeminal neuralgia (odds ratio [OR], 3.1; P < .001).

Other strong risk factors were neurovascular compression disorders (OR, 39.82; P < .001) and multiple sclerosis (OR, 12.41; P < .001). Non-White race (Black; OR, 1.09; Hispanic; OR, 1.23; Other; OR, 1.24) and use of Medicaid (OR, 1.07) and other insurance (OR, 1.17) were demographic risk factors for trigeminal neuralgia.

“This finding points us toward future work exploring the potential mechanisms of predictors, most notably inflammatory conditions in trigeminal neuralgia development,” Ms. Tang concluded.

She declined to comment further on the findings, noting the investigators are still finalizing the results and interpretation.
 

Ask About Meningitis, Fever

Commenting on the findings, Michael D. Staudt, MD, MSc, University Hospitals Cleveland Medical Center, said that many patients who present with classical trigeminal neuralgia will have a blood vessel on MRI that is pressing on the trigeminal nerve.

“Obviously, the nerve is bathed in cerebrospinal fluid. So, if there’s an inflammatory marker, inflammation, or infection that could be injuring the nerve in a way that we don’t yet understand, that could be something that could cause trigeminal neuralgia without having to see a blood vessel,” said Dr. Staudt, who was not involved in the study. “It makes sense, theoretically. Something that’s inflammatory, something that’s irritating, that’s novel.”

Currently, predictive markers include clinical history, response to classical medications such as carbamazepine, and MRI findings, Dr. Staudt noted.

“Someone shows up with symptoms and MRI, and it’s basically do they have a blood vessel or not,” he said. “Treatments are generally within the same categories, but we don’t think it’s the same sort of success rate as seeing a blood vessel.”

Further research is needed, but, in the meantime, Dr. Staudt said, “We can ask patients who show up with facial pain if they’ve ever had meningitis or some sort of fever that preceded their onset of pain.”

The study had no specific funding. Ms. Tang and coauthor Jack Y. Zhang, MS, reported no relevant financial disclosures. Dr. Staudt reported serving as a consultant for Abbott and as a scientific adviser and consultant for Boston Scientific.

A version of this article appeared on Medscape.com.

Meningitis has been highlighted as a novel risk factor for trigeminal neuralgia in a nationwide, propensity-matched study of hospital admissions.

In multivariate analysis, the odds of meningitis were threefold higher in patients admitted with trigeminal neuralgia than in matched controls without trigeminal neuralgia.

This is the first nationwide population-based study of the rare, chronic pain disorder to identify the prevalence of trigeminal neuralgia admissions in the United States and risk factors contributing to trigeminal neuralgia development.

“Our results affirm known associations between trigeminal neuralgia and comorbidities like multiple sclerosis, and they also identify meningitis as a novel risk factor for trigeminal neuralgia,” said investigator Megan Tang, BS, a medical student at the Icahn School of Medicine at Mount Sinai, New York City.

The findings were presented at the American Association of Neurological Surgeons (AANS) 2024 annual meeting.
 

Strong Clinical Risk Factors

Trigeminal neuralgia is a rare pain disorder involving neurovascular compression of the trigeminal nerve. Its etiology and risk factors are poorly understood. Current literature is based on limited datasets and reports inconsistent risk factors across studies.

To better understand the disorder, researchers used International Classification of Diseases (ICD)-9 codes to identify trigeminal neuralgia admissions in the National Inpatient Sample from 2016 to 2019, and then propensity matched them 1:1 to non-trigeminal neuralgia admissions based on demographics, socioeconomic status, and Charlson comorbidity index scores.

Univariate analysis identified 136,345 trigeminal neuralgia admissions or an overall prevalence of 0.096%.

Trigeminal neuralgia admissions had lower morbidity than non-trigeminal neuralgia admissions and a higher prevalence of non-White patients, private insurance, and prolonged length of stay, Ms. Tang said.

Patients admitted for trigeminal neuralgia also had a higher prevalence of several chronic conditions, including hypertension, hyperlipidemia, and osteoarthritis; inflammatory conditions like lupus, meningitis, rheumatoid arthritis, and inflammatory bowel disease; and neurologic conditions including multiple sclerosis, epilepsy, stroke, and neurovascular compression disorders.

In multivariate analysis, investigators identified meningitis as a previously unknown risk factor for trigeminal neuralgia (odds ratio [OR], 3.1; P < .001).

Other strong risk factors were neurovascular compression disorders (OR, 39.82; P < .001) and multiple sclerosis (OR, 12.41; P < .001). Non-White race (Black; OR, 1.09; Hispanic; OR, 1.23; Other; OR, 1.24) and use of Medicaid (OR, 1.07) and other insurance (OR, 1.17) were demographic risk factors for trigeminal neuralgia.

“This finding points us toward future work exploring the potential mechanisms of predictors, most notably inflammatory conditions in trigeminal neuralgia development,” Ms. Tang concluded.

She declined to comment further on the findings, noting the investigators are still finalizing the results and interpretation.
 

Ask About Meningitis, Fever

Commenting on the findings, Michael D. Staudt, MD, MSc, University Hospitals Cleveland Medical Center, said that many patients who present with classical trigeminal neuralgia will have a blood vessel on MRI that is pressing on the trigeminal nerve.

“Obviously, the nerve is bathed in cerebrospinal fluid. So, if there’s an inflammatory marker, inflammation, or infection that could be injuring the nerve in a way that we don’t yet understand, that could be something that could cause trigeminal neuralgia without having to see a blood vessel,” said Dr. Staudt, who was not involved in the study. “It makes sense, theoretically. Something that’s inflammatory, something that’s irritating, that’s novel.”

Currently, predictive markers include clinical history, response to classical medications such as carbamazepine, and MRI findings, Dr. Staudt noted.

“Someone shows up with symptoms and MRI, and it’s basically do they have a blood vessel or not,” he said. “Treatments are generally within the same categories, but we don’t think it’s the same sort of success rate as seeing a blood vessel.”

Further research is needed, but, in the meantime, Dr. Staudt said, “We can ask patients who show up with facial pain if they’ve ever had meningitis or some sort of fever that preceded their onset of pain.”

The study had no specific funding. Ms. Tang and coauthor Jack Y. Zhang, MS, reported no relevant financial disclosures. Dr. Staudt reported serving as a consultant for Abbott and as a scientific adviser and consultant for Boston Scientific.

A version of this article appeared on Medscape.com.

Meningitis has been highlighted as a novel risk factor for trigeminal neuralgia in a nationwide, propensity-matched study of hospital admissions.

In multivariate analysis, the odds of meningitis were threefold higher in patients admitted with trigeminal neuralgia than in matched controls without trigeminal neuralgia.

This is the first nationwide population-based study of the rare, chronic pain disorder to identify the prevalence of trigeminal neuralgia admissions in the United States and risk factors contributing to trigeminal neuralgia development.

“Our results affirm known associations between trigeminal neuralgia and comorbidities like multiple sclerosis, and they also identify meningitis as a novel risk factor for trigeminal neuralgia,” said investigator Megan Tang, BS, a medical student at the Icahn School of Medicine at Mount Sinai, New York City.

The findings were presented at the American Association of Neurological Surgeons (AANS) 2024 annual meeting.
 

Strong Clinical Risk Factors

Trigeminal neuralgia is a rare pain disorder involving neurovascular compression of the trigeminal nerve. Its etiology and risk factors are poorly understood. Current literature is based on limited datasets and reports inconsistent risk factors across studies.

To better understand the disorder, researchers used International Classification of Diseases (ICD)-9 codes to identify trigeminal neuralgia admissions in the National Inpatient Sample from 2016 to 2019, and then propensity matched them 1:1 to non-trigeminal neuralgia admissions based on demographics, socioeconomic status, and Charlson comorbidity index scores.

Univariate analysis identified 136,345 trigeminal neuralgia admissions or an overall prevalence of 0.096%.

Trigeminal neuralgia admissions had lower morbidity than non-trigeminal neuralgia admissions and a higher prevalence of non-White patients, private insurance, and prolonged length of stay, Ms. Tang said.

Patients admitted for trigeminal neuralgia also had a higher prevalence of several chronic conditions, including hypertension, hyperlipidemia, and osteoarthritis; inflammatory conditions like lupus, meningitis, rheumatoid arthritis, and inflammatory bowel disease; and neurologic conditions including multiple sclerosis, epilepsy, stroke, and neurovascular compression disorders.

In multivariate analysis, investigators identified meningitis as a previously unknown risk factor for trigeminal neuralgia (odds ratio [OR], 3.1; P < .001).

Other strong risk factors were neurovascular compression disorders (OR, 39.82; P < .001) and multiple sclerosis (OR, 12.41; P < .001). Non-White race (Black; OR, 1.09; Hispanic; OR, 1.23; Other; OR, 1.24) and use of Medicaid (OR, 1.07) and other insurance (OR, 1.17) were demographic risk factors for trigeminal neuralgia.

“This finding points us toward future work exploring the potential mechanisms of predictors, most notably inflammatory conditions in trigeminal neuralgia development,” Ms. Tang concluded.

She declined to comment further on the findings, noting the investigators are still finalizing the results and interpretation.
 

Ask About Meningitis, Fever

Commenting on the findings, Michael D. Staudt, MD, MSc, University Hospitals Cleveland Medical Center, said that many patients who present with classical trigeminal neuralgia will have a blood vessel on MRI that is pressing on the trigeminal nerve.

“Obviously, the nerve is bathed in cerebrospinal fluid. So, if there’s an inflammatory marker, inflammation, or infection that could be injuring the nerve in a way that we don’t yet understand, that could be something that could cause trigeminal neuralgia without having to see a blood vessel,” said Dr. Staudt, who was not involved in the study. “It makes sense, theoretically. Something that’s inflammatory, something that’s irritating, that’s novel.”

Currently, predictive markers include clinical history, response to classical medications such as carbamazepine, and MRI findings, Dr. Staudt noted.

“Someone shows up with symptoms and MRI, and it’s basically do they have a blood vessel or not,” he said. “Treatments are generally within the same categories, but we don’t think it’s the same sort of success rate as seeing a blood vessel.”

Further research is needed, but, in the meantime, Dr. Staudt said, “We can ask patients who show up with facial pain if they’ve ever had meningitis or some sort of fever that preceded their onset of pain.”

The study had no specific funding. Ms. Tang and coauthor Jack Y. Zhang, MS, reported no relevant financial disclosures. Dr. Staudt reported serving as a consultant for Abbott and as a scientific adviser and consultant for Boston Scientific.

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.

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.

The US Drug Enforcement Agency (DEA) is moving forward with plans to move marijuana from a Schedule I to a Schedule III controlled substance under the Controlled Substance Act (CSA), the US Department of Justice officials announced this week. 

First reported by the Associated Press and since confirmed by this news organization through a US Department of Justice spokesperson, the news made international headlines. Despite the media splash, the final rule is still months away.

How did we get here? What happens next? What impact might rescheduling have on clinicians, patients, researchers, and the medical cannabis industry? 

Why Reschedule? Why Now? 

The DEA’s decision is based on a 2023 determination from the US Food and Drug Administration (FDA) that marijuana has a legitimate medical use and should be moved to Schedule III. 

DEA defines Schedule I drugs as those with no currently accepted medical use and a high potential for abuse. That class includes heroin, LSD, and ecstasy. Schedule III drugs have a moderate to low potential for physical and psychological dependence and have a currently accepted medical use. This class includes ketamine, acetaminophen with codeine, and buprenorphine. 

Even though the manufacturing, distribution, sale, and use of marijuana has long violated federal law, 38 states and Washington, DC, have legalized medical cannabis, and 24 states and DC have legalized its recreational use.

Congress has allowed states leeway for the distribution and use of medical marijuana, and current and previous presidential administrations have chosen not to aggressively pursue prosecution of state-allowed marijuana use, the Congressional Research Service (CRS) reports. 

Pressure to address the conflict between federal and state laws and an increasing interest in drug development of cannabis and cannabis-derived products probably contributed to the DEA’s decision, said Stephen Strakowski, MD, professor, and vice chair of psychiatry at Indiana University in Indianapolis, and professor and associate vice president at University of Texas in Austin.

“The trend toward legalization is everywhere and even though nationally the feds in this instance are lagging the states, the pressure to legalize has been intense for 50 years and it’s not surprising that the DEA is finally following that lead,” Dr. Strakowski told this news organization. 

How Does Rescheduling Work? What’s the Timeline?

The DEA will submit a formal rule proposing that marijuana be moved from Schedule I to Schedule III to the White House Office of Management and Budget. The timing of the submission is unclear. 

Once the proposed rule is posted to the Federal Register, there will be a public comment period, which usually lasts 30-60 days.

“This will likely generate a lot of public comment,” Robert Mikos, JD, LaRoche Family Chair in Law at Vanderbilt University Law School in Nashville, Tennessee, told this news organization. “Then the agency has to go back and wade through those comments and decide if they want to proceed with the rule as proposed or modify it.”

A final rule will probably be posted before the end of the current presidential term in January, Mr. Mikos said. While a lawsuit blocking its implementation is possible, there is a “low chance that a court would block this,” he added.

How Will Rescheduling Affect Medical Marijuana?

For medical marijuana, changing the drug to a Schedule III means that it can legally be prescribed but only in states that have legalized medical cannabis, Mr. Mikos said. 

“If you’re a patient in a state with a medical marijuana law and your physician gives you a prescription for medical marijuana and you possess it, you will no longer be guilty of a federal crime,” he said.

Rescheduling could also benefit patients who receive care through the Veterans Administration (VA), Mr. Mikos said. For several years, the VA has had a policy that blocked clinicians from prescribing medical marijuana because as a Schedule I drug, it was determined to have no accepted medical use. 

“It’s possible the VA may drop that policy once the drug gets rescheduled. If you’re in a medical marijuana state, if you’re a VA patient, and you don’t want to spend the extra money to go outside that system, this will have meaningful impact on their lives,” Mr. Mikos said.

But what about patients living in states that have not legalized medical cannabis? 

“You still wouldn’t be committing a federal crime, but you could be violating state law,” Mr. Mikos said. “That’s a much more salient consideration because if you look at who goes after individuals who possess small amounts of drugs, the state handles 99% of those cases.” 

The manufacture, distribution, and possession of recreational marijuana would remain illegal under federal law.

What Does It Mean for Medical Marijuana Dispensaries?

Though rescheduling makes it legal for clinicians to prescribe medical marijuana and for patients to use it, the actual sale of the drug will remain illegal under federal law because rescheduling only changes prescribing under the CSA, Mr. Mikos said.

“If you’re a dispensary and you sell it, even if it’s to somebody who’s got a prescription, you’re still probably violating the Food, Drug and Cosmetics Act. Rescheduling doesn’t change that,” he said. 

“Even assuming the DEA follows through with this and it doesn’t come undone at some future date, the industry is still going struggle to comply with the Controlled Substances Act post rescheduling because that statute is going to continue to impose a number of regulations on the industry,” Mr. Mikos added.

However, rescheduling would change the tax status of the estimated 12,000-15,000 state-licensed cannabis dispensaries in the United States, allowing access to certain tax deductions that are unavailable to sales involving Schedule I controlled substances, James Daily, JD, MS, with Center for Empirical Research in the Law at Washington University School of Law in St. Louis, told this news organization.

“Many cannabis businesses do in fact pay federal taxes, but the inability to take any federal tax credits or deductions means that their effective tax rate is much higher than it would otherwise be,” Mr. Daily said. 

Although new federal tax deductions would likely available to cannabis businesses if marijuana were rescheduled to Schedule III, “their business would still be in violation of federal law,” he said. 

“This creates a further tension between state and federal law, which could be resolved by further legalization or it could be resolved by extending the prohibition on tax deductions to include cannabis and not just Schedule I and II drugs,” he added.

Will Rescheduling Make It Easier to Conduct Cannabis-Related Research? 

Research on medical cannabis has been stymied by FDA and DEA regulations regarding the study of Schedule I controlled substances. Although rescheduling could lift that barrier, other challenges would remain.

“Schedule III drugs can be more easily researched, but it’s unclear if, for example, a clinical trial could lawfully obtain the cannabis from a dispensary or if they would still have to go through the one legal federal supplier of cannabis,” Daily said. 

The FDA reports having received more than 800 investigational new drug applications for and pre-investigational new drug applications related to cannabis and cannabis-derived products since the 1970s, the agency reports. To date, the FDA has not approved any marketing drug applications for cannabis for the treatment of any disease or condition. 

In January 2023, the agency published updated guidelines for researchers and sponsors interested in developing drugs containing cannabis or cannabis-derived compounds. 

It’s unclear whether those guidelines would be updated if the rescheduling moves forward. 

Does Rescheduling Marijuana Pose Any Risk? 

In its report to the DEA that marijuana be rescheduled, the FDA was careful to note that the agency’s recommendation is “not meant to imply that safety and effectiveness have been established for marijuana that would support FDA approval of a marijuana drug product for a particular indication.”

That’s a notation that clinicians and patients should take to heart, Dr. Strakowski said. 

“It’s important to remind people that Schedule III drugs, by definition, have addiction and other side effect risks,” he said. “The celebrity marketing that sits behind a lot of this is incompletely informed. It’s portrayed as fun and harmless in almost every movie and conversation you see, and we know that’s not true.”

Previous studies have linked cannabis to increased risk for mania, anxiety disorders, and schizophrenia. 

“It is increasingly clear that marijuana use is linked to poor outcomes in people who struggle with mental illness,” Dr. Strakowski said. “We have no evidence that it can help you but there is evidence that it can harm you.”

Dr. Strakowski likens cannabis use to alcohol, which is a known depressant that is associated with worse outcomes in people with mental illness. 

“I think with cannabis, we don’t know enough about it yet, but we do know that it does have some anxiety risks,” he said. “The risks in people with mental illness are simply different than in people who don’t have mental illness.”

Dr. Strakowski, Mr. Mikos, and Mr. Daily report no relevant disclosures. 
 

A version of this article appeared on Medscape.com.

The US Drug Enforcement Agency (DEA) is moving forward with plans to move marijuana from a Schedule I to a Schedule III controlled substance under the Controlled Substance Act (CSA), the US Department of Justice officials announced this week. 

First reported by the Associated Press and since confirmed by this news organization through a US Department of Justice spokesperson, the news made international headlines. Despite the media splash, the final rule is still months away.

How did we get here? What happens next? What impact might rescheduling have on clinicians, patients, researchers, and the medical cannabis industry? 

Why Reschedule? Why Now? 

The DEA’s decision is based on a 2023 determination from the US Food and Drug Administration (FDA) that marijuana has a legitimate medical use and should be moved to Schedule III. 

DEA defines Schedule I drugs as those with no currently accepted medical use and a high potential for abuse. That class includes heroin, LSD, and ecstasy. Schedule III drugs have a moderate to low potential for physical and psychological dependence and have a currently accepted medical use. This class includes ketamine, acetaminophen with codeine, and buprenorphine. 

Even though the manufacturing, distribution, sale, and use of marijuana has long violated federal law, 38 states and Washington, DC, have legalized medical cannabis, and 24 states and DC have legalized its recreational use.

Congress has allowed states leeway for the distribution and use of medical marijuana, and current and previous presidential administrations have chosen not to aggressively pursue prosecution of state-allowed marijuana use, the Congressional Research Service (CRS) reports. 

Pressure to address the conflict between federal and state laws and an increasing interest in drug development of cannabis and cannabis-derived products probably contributed to the DEA’s decision, said Stephen Strakowski, MD, professor, and vice chair of psychiatry at Indiana University in Indianapolis, and professor and associate vice president at University of Texas in Austin.

“The trend toward legalization is everywhere and even though nationally the feds in this instance are lagging the states, the pressure to legalize has been intense for 50 years and it’s not surprising that the DEA is finally following that lead,” Dr. Strakowski told this news organization. 

How Does Rescheduling Work? What’s the Timeline?

The DEA will submit a formal rule proposing that marijuana be moved from Schedule I to Schedule III to the White House Office of Management and Budget. The timing of the submission is unclear. 

Once the proposed rule is posted to the Federal Register, there will be a public comment period, which usually lasts 30-60 days.

“This will likely generate a lot of public comment,” Robert Mikos, JD, LaRoche Family Chair in Law at Vanderbilt University Law School in Nashville, Tennessee, told this news organization. “Then the agency has to go back and wade through those comments and decide if they want to proceed with the rule as proposed or modify it.”

A final rule will probably be posted before the end of the current presidential term in January, Mr. Mikos said. While a lawsuit blocking its implementation is possible, there is a “low chance that a court would block this,” he added.

How Will Rescheduling Affect Medical Marijuana?

For medical marijuana, changing the drug to a Schedule III means that it can legally be prescribed but only in states that have legalized medical cannabis, Mr. Mikos said. 

“If you’re a patient in a state with a medical marijuana law and your physician gives you a prescription for medical marijuana and you possess it, you will no longer be guilty of a federal crime,” he said.

Rescheduling could also benefit patients who receive care through the Veterans Administration (VA), Mr. Mikos said. For several years, the VA has had a policy that blocked clinicians from prescribing medical marijuana because as a Schedule I drug, it was determined to have no accepted medical use. 

“It’s possible the VA may drop that policy once the drug gets rescheduled. If you’re in a medical marijuana state, if you’re a VA patient, and you don’t want to spend the extra money to go outside that system, this will have meaningful impact on their lives,” Mr. Mikos said.

But what about patients living in states that have not legalized medical cannabis? 

“You still wouldn’t be committing a federal crime, but you could be violating state law,” Mr. Mikos said. “That’s a much more salient consideration because if you look at who goes after individuals who possess small amounts of drugs, the state handles 99% of those cases.” 

The manufacture, distribution, and possession of recreational marijuana would remain illegal under federal law.

What Does It Mean for Medical Marijuana Dispensaries?

Though rescheduling makes it legal for clinicians to prescribe medical marijuana and for patients to use it, the actual sale of the drug will remain illegal under federal law because rescheduling only changes prescribing under the CSA, Mr. Mikos said.

“If you’re a dispensary and you sell it, even if it’s to somebody who’s got a prescription, you’re still probably violating the Food, Drug and Cosmetics Act. Rescheduling doesn’t change that,” he said. 

“Even assuming the DEA follows through with this and it doesn’t come undone at some future date, the industry is still going struggle to comply with the Controlled Substances Act post rescheduling because that statute is going to continue to impose a number of regulations on the industry,” Mr. Mikos added.

However, rescheduling would change the tax status of the estimated 12,000-15,000 state-licensed cannabis dispensaries in the United States, allowing access to certain tax deductions that are unavailable to sales involving Schedule I controlled substances, James Daily, JD, MS, with Center for Empirical Research in the Law at Washington University School of Law in St. Louis, told this news organization.

“Many cannabis businesses do in fact pay federal taxes, but the inability to take any federal tax credits or deductions means that their effective tax rate is much higher than it would otherwise be,” Mr. Daily said. 

Although new federal tax deductions would likely available to cannabis businesses if marijuana were rescheduled to Schedule III, “their business would still be in violation of federal law,” he said. 

“This creates a further tension between state and federal law, which could be resolved by further legalization or it could be resolved by extending the prohibition on tax deductions to include cannabis and not just Schedule I and II drugs,” he added.

Will Rescheduling Make It Easier to Conduct Cannabis-Related Research? 

Research on medical cannabis has been stymied by FDA and DEA regulations regarding the study of Schedule I controlled substances. Although rescheduling could lift that barrier, other challenges would remain.

“Schedule III drugs can be more easily researched, but it’s unclear if, for example, a clinical trial could lawfully obtain the cannabis from a dispensary or if they would still have to go through the one legal federal supplier of cannabis,” Daily said. 

The FDA reports having received more than 800 investigational new drug applications for and pre-investigational new drug applications related to cannabis and cannabis-derived products since the 1970s, the agency reports. To date, the FDA has not approved any marketing drug applications for cannabis for the treatment of any disease or condition. 

In January 2023, the agency published updated guidelines for researchers and sponsors interested in developing drugs containing cannabis or cannabis-derived compounds. 

It’s unclear whether those guidelines would be updated if the rescheduling moves forward. 

Does Rescheduling Marijuana Pose Any Risk? 

In its report to the DEA that marijuana be rescheduled, the FDA was careful to note that the agency’s recommendation is “not meant to imply that safety and effectiveness have been established for marijuana that would support FDA approval of a marijuana drug product for a particular indication.”

That’s a notation that clinicians and patients should take to heart, Dr. Strakowski said. 

“It’s important to remind people that Schedule III drugs, by definition, have addiction and other side effect risks,” he said. “The celebrity marketing that sits behind a lot of this is incompletely informed. It’s portrayed as fun and harmless in almost every movie and conversation you see, and we know that’s not true.”

Previous studies have linked cannabis to increased risk for mania, anxiety disorders, and schizophrenia. 

“It is increasingly clear that marijuana use is linked to poor outcomes in people who struggle with mental illness,” Dr. Strakowski said. “We have no evidence that it can help you but there is evidence that it can harm you.”

Dr. Strakowski likens cannabis use to alcohol, which is a known depressant that is associated with worse outcomes in people with mental illness. 

“I think with cannabis, we don’t know enough about it yet, but we do know that it does have some anxiety risks,” he said. “The risks in people with mental illness are simply different than in people who don’t have mental illness.”

Dr. Strakowski, Mr. Mikos, and Mr. Daily report no relevant disclosures. 
 

A version of this article appeared on Medscape.com.

The US Drug Enforcement Agency (DEA) is moving forward with plans to move marijuana from a Schedule I to a Schedule III controlled substance under the Controlled Substance Act (CSA), the US Department of Justice officials announced this week. 

First reported by the Associated Press and since confirmed by this news organization through a US Department of Justice spokesperson, the news made international headlines. Despite the media splash, the final rule is still months away.

How did we get here? What happens next? What impact might rescheduling have on clinicians, patients, researchers, and the medical cannabis industry? 

Why Reschedule? Why Now? 

The DEA’s decision is based on a 2023 determination from the US Food and Drug Administration (FDA) that marijuana has a legitimate medical use and should be moved to Schedule III. 

DEA defines Schedule I drugs as those with no currently accepted medical use and a high potential for abuse. That class includes heroin, LSD, and ecstasy. Schedule III drugs have a moderate to low potential for physical and psychological dependence and have a currently accepted medical use. This class includes ketamine, acetaminophen with codeine, and buprenorphine. 

Even though the manufacturing, distribution, sale, and use of marijuana has long violated federal law, 38 states and Washington, DC, have legalized medical cannabis, and 24 states and DC have legalized its recreational use.

Congress has allowed states leeway for the distribution and use of medical marijuana, and current and previous presidential administrations have chosen not to aggressively pursue prosecution of state-allowed marijuana use, the Congressional Research Service (CRS) reports. 

Pressure to address the conflict between federal and state laws and an increasing interest in drug development of cannabis and cannabis-derived products probably contributed to the DEA’s decision, said Stephen Strakowski, MD, professor, and vice chair of psychiatry at Indiana University in Indianapolis, and professor and associate vice president at University of Texas in Austin.

“The trend toward legalization is everywhere and even though nationally the feds in this instance are lagging the states, the pressure to legalize has been intense for 50 years and it’s not surprising that the DEA is finally following that lead,” Dr. Strakowski told this news organization. 

How Does Rescheduling Work? What’s the Timeline?

The DEA will submit a formal rule proposing that marijuana be moved from Schedule I to Schedule III to the White House Office of Management and Budget. The timing of the submission is unclear. 

Once the proposed rule is posted to the Federal Register, there will be a public comment period, which usually lasts 30-60 days.

“This will likely generate a lot of public comment,” Robert Mikos, JD, LaRoche Family Chair in Law at Vanderbilt University Law School in Nashville, Tennessee, told this news organization. “Then the agency has to go back and wade through those comments and decide if they want to proceed with the rule as proposed or modify it.”

A final rule will probably be posted before the end of the current presidential term in January, Mr. Mikos said. While a lawsuit blocking its implementation is possible, there is a “low chance that a court would block this,” he added.

How Will Rescheduling Affect Medical Marijuana?

For medical marijuana, changing the drug to a Schedule III means that it can legally be prescribed but only in states that have legalized medical cannabis, Mr. Mikos said. 

“If you’re a patient in a state with a medical marijuana law and your physician gives you a prescription for medical marijuana and you possess it, you will no longer be guilty of a federal crime,” he said.

Rescheduling could also benefit patients who receive care through the Veterans Administration (VA), Mr. Mikos said. For several years, the VA has had a policy that blocked clinicians from prescribing medical marijuana because as a Schedule I drug, it was determined to have no accepted medical use. 

“It’s possible the VA may drop that policy once the drug gets rescheduled. If you’re in a medical marijuana state, if you’re a VA patient, and you don’t want to spend the extra money to go outside that system, this will have meaningful impact on their lives,” Mr. Mikos said.

But what about patients living in states that have not legalized medical cannabis? 

“You still wouldn’t be committing a federal crime, but you could be violating state law,” Mr. Mikos said. “That’s a much more salient consideration because if you look at who goes after individuals who possess small amounts of drugs, the state handles 99% of those cases.” 

The manufacture, distribution, and possession of recreational marijuana would remain illegal under federal law.

What Does It Mean for Medical Marijuana Dispensaries?

Though rescheduling makes it legal for clinicians to prescribe medical marijuana and for patients to use it, the actual sale of the drug will remain illegal under federal law because rescheduling only changes prescribing under the CSA, Mr. Mikos said.

“If you’re a dispensary and you sell it, even if it’s to somebody who’s got a prescription, you’re still probably violating the Food, Drug and Cosmetics Act. Rescheduling doesn’t change that,” he said. 

“Even assuming the DEA follows through with this and it doesn’t come undone at some future date, the industry is still going struggle to comply with the Controlled Substances Act post rescheduling because that statute is going to continue to impose a number of regulations on the industry,” Mr. Mikos added.

However, rescheduling would change the tax status of the estimated 12,000-15,000 state-licensed cannabis dispensaries in the United States, allowing access to certain tax deductions that are unavailable to sales involving Schedule I controlled substances, James Daily, JD, MS, with Center for Empirical Research in the Law at Washington University School of Law in St. Louis, told this news organization.

“Many cannabis businesses do in fact pay federal taxes, but the inability to take any federal tax credits or deductions means that their effective tax rate is much higher than it would otherwise be,” Mr. Daily said. 

Although new federal tax deductions would likely available to cannabis businesses if marijuana were rescheduled to Schedule III, “their business would still be in violation of federal law,” he said. 

“This creates a further tension between state and federal law, which could be resolved by further legalization or it could be resolved by extending the prohibition on tax deductions to include cannabis and not just Schedule I and II drugs,” he added.

Will Rescheduling Make It Easier to Conduct Cannabis-Related Research? 

Research on medical cannabis has been stymied by FDA and DEA regulations regarding the study of Schedule I controlled substances. Although rescheduling could lift that barrier, other challenges would remain.

“Schedule III drugs can be more easily researched, but it’s unclear if, for example, a clinical trial could lawfully obtain the cannabis from a dispensary or if they would still have to go through the one legal federal supplier of cannabis,” Daily said. 

The FDA reports having received more than 800 investigational new drug applications for and pre-investigational new drug applications related to cannabis and cannabis-derived products since the 1970s, the agency reports. To date, the FDA has not approved any marketing drug applications for cannabis for the treatment of any disease or condition. 

In January 2023, the agency published updated guidelines for researchers and sponsors interested in developing drugs containing cannabis or cannabis-derived compounds. 

It’s unclear whether those guidelines would be updated if the rescheduling moves forward. 

Does Rescheduling Marijuana Pose Any Risk? 

In its report to the DEA that marijuana be rescheduled, the FDA was careful to note that the agency’s recommendation is “not meant to imply that safety and effectiveness have been established for marijuana that would support FDA approval of a marijuana drug product for a particular indication.”

That’s a notation that clinicians and patients should take to heart, Dr. Strakowski said. 

“It’s important to remind people that Schedule III drugs, by definition, have addiction and other side effect risks,” he said. “The celebrity marketing that sits behind a lot of this is incompletely informed. It’s portrayed as fun and harmless in almost every movie and conversation you see, and we know that’s not true.”

Previous studies have linked cannabis to increased risk for mania, anxiety disorders, and schizophrenia. 

“It is increasingly clear that marijuana use is linked to poor outcomes in people who struggle with mental illness,” Dr. Strakowski said. “We have no evidence that it can help you but there is evidence that it can harm you.”

Dr. Strakowski likens cannabis use to alcohol, which is a known depressant that is associated with worse outcomes in people with mental illness. 

“I think with cannabis, we don’t know enough about it yet, but we do know that it does have some anxiety risks,” he said. “The risks in people with mental illness are simply different than in people who don’t have mental illness.”

Dr. Strakowski, Mr. Mikos, and Mr. Daily report no relevant disclosures. 
 

A version of this article appeared on Medscape.com.

BOSTON — Patients with acute colonic diverticulitis are more likely to be seen by primary care providers than by emergency physicians, representing a shift in the way clinicians detect and treat the condition.

Acute colonic diverticulitis affects roughly 180 per 100,000 people per year in the United States.

CT of the abdomen and pelvis may not be a first-line method to detect diverticulitis in the primary care setting as it has been in emergent care, according to Kaveh Sharzehi, MD, MS, associate professor of medicine in the Division of Gastroenterology and Hepatology at Oregon Health & Science University in Portland.

Indeed, clinical guidelines by multiple physician groups recommend that providers use a more individualized approach to detecting and treating the condition. 

“There is still great value in proper and thorough physical history and some adjunct testing,” Dr. Sharzehi told attendees during a presentation on April 20 at the American College of Physicians Internal Medicine Meeting 2024. These two methods can detect the disease up to 65% of the time, Dr. Sharzehi added.

An initial evaluation of a patient with suspected acute diverticulitis should first assess the patient’s history of abdominal pain, fever, and leukocytosis, Dr. Sharzehi said. 

A C-reactive protein level > 50 mg/L “almost doubles the odds of having diverticulitis,” Dr. Sharzehi said. Studies also suggest increased levels of procalcitonin and fecal calprotectin can indicate the presence of the condition.

The American Gastroenterological Association (AGA) and the American College of Physicians recommend abdominal CT if clinicians are uncertain of the diagnosis, and to evaluate potential complications in severe cases. Ultrasound and MRI can be useful alternatives, according to guidelines from the American Society of Colon and Rectal Surgeons.

The chances of developing diverticulitis increase with age. More than 60% of Americans aged 60 years or older have diverticulosis, a condition characterized by small pouches in the colon lining that can weaken the colon wall. Less than 5% of people with diverticulosis go on to develop diverticulitis. 

“Aspirin and opioid use are also risk factors, likely from their effect on the colonic transit time and causing constipation that might contribute to diverticulitis, but that›s not very well understood,” Dr. Sharzehi said. 

Medical management has shifted from predominantly inpatient to predominantly outpatient care, Dr. Sharzehi told attendees 

“Unfortunately, there are not that many supportive guidelines for what diet a patient should have in the acute setting of diverticulitis,” he said. 

Patients with a mild case may benefit from a clear liquid diet; for some patients, high-fiber diets, regular physical activity, and statins may protect against recurrence. 

Current guidelines recommend against prescribing antibiotics for most cases because evidence suggests that diverticulitis is primarily an inflammatory process that can result in small tears in the diverticulum, rather than the disease being a complication of existing tears. 

Patients should also not be treated with probiotics or 5-aminosalicylic acid agents, Dr. Sharzehi said.

“My practice is in the Pacific Northwest, where there’s a lot of belief in naturopathic remedies, so we get a lot of questions about supplements and probiotics in preventing diverticulitis,” he said. “We don’t think it does help, and this is unanimous among all the main [physician] societies.” 

The AGA recommends referring patients for a colonoscopy within a year after diverticulitis symptoms have resided. 

Severe or unresolved cases could require inpatient procedures such as percutaneous drainage or surgery. An estimated 15%-30% of patients admitted to hospital with acute diverticulitis require surgery, Dr. Sharzehi said. 

Surgery may become an option for patients who have recurrent cases of the disease, even if not severe, Dr. Sharzehi said.

Dr. Sharzehi reported no relevant disclosures.
 

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

BOSTON — Patients with acute colonic diverticulitis are more likely to be seen by primary care providers than by emergency physicians, representing a shift in the way clinicians detect and treat the condition.

Acute colonic diverticulitis affects roughly 180 per 100,000 people per year in the United States.

CT of the abdomen and pelvis may not be a first-line method to detect diverticulitis in the primary care setting as it has been in emergent care, according to Kaveh Sharzehi, MD, MS, associate professor of medicine in the Division of Gastroenterology and Hepatology at Oregon Health & Science University in Portland.

Indeed, clinical guidelines by multiple physician groups recommend that providers use a more individualized approach to detecting and treating the condition. 

“There is still great value in proper and thorough physical history and some adjunct testing,” Dr. Sharzehi told attendees during a presentation on April 20 at the American College of Physicians Internal Medicine Meeting 2024. These two methods can detect the disease up to 65% of the time, Dr. Sharzehi added.

An initial evaluation of a patient with suspected acute diverticulitis should first assess the patient’s history of abdominal pain, fever, and leukocytosis, Dr. Sharzehi said. 

A C-reactive protein level > 50 mg/L “almost doubles the odds of having diverticulitis,” Dr. Sharzehi said. Studies also suggest increased levels of procalcitonin and fecal calprotectin can indicate the presence of the condition.

The American Gastroenterological Association (AGA) and the American College of Physicians recommend abdominal CT if clinicians are uncertain of the diagnosis, and to evaluate potential complications in severe cases. Ultrasound and MRI can be useful alternatives, according to guidelines from the American Society of Colon and Rectal Surgeons.

The chances of developing diverticulitis increase with age. More than 60% of Americans aged 60 years or older have diverticulosis, a condition characterized by small pouches in the colon lining that can weaken the colon wall. Less than 5% of people with diverticulosis go on to develop diverticulitis. 

“Aspirin and opioid use are also risk factors, likely from their effect on the colonic transit time and causing constipation that might contribute to diverticulitis, but that›s not very well understood,” Dr. Sharzehi said. 

Medical management has shifted from predominantly inpatient to predominantly outpatient care, Dr. Sharzehi told attendees 

“Unfortunately, there are not that many supportive guidelines for what diet a patient should have in the acute setting of diverticulitis,” he said. 

Patients with a mild case may benefit from a clear liquid diet; for some patients, high-fiber diets, regular physical activity, and statins may protect against recurrence. 

Current guidelines recommend against prescribing antibiotics for most cases because evidence suggests that diverticulitis is primarily an inflammatory process that can result in small tears in the diverticulum, rather than the disease being a complication of existing tears. 

Patients should also not be treated with probiotics or 5-aminosalicylic acid agents, Dr. Sharzehi said.

“My practice is in the Pacific Northwest, where there’s a lot of belief in naturopathic remedies, so we get a lot of questions about supplements and probiotics in preventing diverticulitis,” he said. “We don’t think it does help, and this is unanimous among all the main [physician] societies.” 

The AGA recommends referring patients for a colonoscopy within a year after diverticulitis symptoms have resided. 

Severe or unresolved cases could require inpatient procedures such as percutaneous drainage or surgery. An estimated 15%-30% of patients admitted to hospital with acute diverticulitis require surgery, Dr. Sharzehi said. 

Surgery may become an option for patients who have recurrent cases of the disease, even if not severe, Dr. Sharzehi said.

Dr. Sharzehi reported no relevant disclosures.
 

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

BOSTON — Patients with acute colonic diverticulitis are more likely to be seen by primary care providers than by emergency physicians, representing a shift in the way clinicians detect and treat the condition.

Acute colonic diverticulitis affects roughly 180 per 100,000 people per year in the United States.

CT of the abdomen and pelvis may not be a first-line method to detect diverticulitis in the primary care setting as it has been in emergent care, according to Kaveh Sharzehi, MD, MS, associate professor of medicine in the Division of Gastroenterology and Hepatology at Oregon Health & Science University in Portland.

Indeed, clinical guidelines by multiple physician groups recommend that providers use a more individualized approach to detecting and treating the condition. 

“There is still great value in proper and thorough physical history and some adjunct testing,” Dr. Sharzehi told attendees during a presentation on April 20 at the American College of Physicians Internal Medicine Meeting 2024. These two methods can detect the disease up to 65% of the time, Dr. Sharzehi added.

An initial evaluation of a patient with suspected acute diverticulitis should first assess the patient’s history of abdominal pain, fever, and leukocytosis, Dr. Sharzehi said. 

A C-reactive protein level > 50 mg/L “almost doubles the odds of having diverticulitis,” Dr. Sharzehi said. Studies also suggest increased levels of procalcitonin and fecal calprotectin can indicate the presence of the condition.

The American Gastroenterological Association (AGA) and the American College of Physicians recommend abdominal CT if clinicians are uncertain of the diagnosis, and to evaluate potential complications in severe cases. Ultrasound and MRI can be useful alternatives, according to guidelines from the American Society of Colon and Rectal Surgeons.

The chances of developing diverticulitis increase with age. More than 60% of Americans aged 60 years or older have diverticulosis, a condition characterized by small pouches in the colon lining that can weaken the colon wall. Less than 5% of people with diverticulosis go on to develop diverticulitis. 

“Aspirin and opioid use are also risk factors, likely from their effect on the colonic transit time and causing constipation that might contribute to diverticulitis, but that›s not very well understood,” Dr. Sharzehi said. 

Medical management has shifted from predominantly inpatient to predominantly outpatient care, Dr. Sharzehi told attendees 

“Unfortunately, there are not that many supportive guidelines for what diet a patient should have in the acute setting of diverticulitis,” he said. 

Patients with a mild case may benefit from a clear liquid diet; for some patients, high-fiber diets, regular physical activity, and statins may protect against recurrence. 

Current guidelines recommend against prescribing antibiotics for most cases because evidence suggests that diverticulitis is primarily an inflammatory process that can result in small tears in the diverticulum, rather than the disease being a complication of existing tears. 

Patients should also not be treated with probiotics or 5-aminosalicylic acid agents, Dr. Sharzehi said.

“My practice is in the Pacific Northwest, where there’s a lot of belief in naturopathic remedies, so we get a lot of questions about supplements and probiotics in preventing diverticulitis,” he said. “We don’t think it does help, and this is unanimous among all the main [physician] societies.” 

The AGA recommends referring patients for a colonoscopy within a year after diverticulitis symptoms have resided. 

Severe or unresolved cases could require inpatient procedures such as percutaneous drainage or surgery. An estimated 15%-30% of patients admitted to hospital with acute diverticulitis require surgery, Dr. Sharzehi said. 

Surgery may become an option for patients who have recurrent cases of the disease, even if not severe, Dr. Sharzehi said.

Dr. Sharzehi reported no relevant disclosures.
 

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

The utility of cannabinoids to treat most medical conditions remains uncertain at best, but for at least three indications the data lean in favor of effectiveness, Ellie Grossman, MD, MPH, told attendees recently at the 2024 American College of Physicians Internal Medicine meeting.

Those are neuropathic pain, chemotherapy-induced nausea or vomiting, and spasticity in people with multiple sclerosis, said Dr. Grossman, an instructor at Harvard Medical School in Boston and medical director for primary care/behavioral health integration at Cambridge Health Alliance in Somerville, Massachusetts.

Dearth of Research Persists

Research is sorely lacking and of low quality in the field for many reasons, Dr. Grossman said. Most of the products tested come from outside the United States and often are synthetic and taken orally — which does not match the real-world use when patients go to dispensaries for cannabis derived directly from plants (or the plant product itself). And studies often rely on self-report.

Chronic pain is by far the top reason patients say they use medical cannabis, Dr. Grossman said. A Cochrane review of 16 studies found only that the potential benefits of cannabis may outweigh the potential harms for chronic neuropathic pain.
 

No Evidence in OUD

Dr. Grossman said she is frequently asked if cannabis can help people quit taking opioids. The answer seems to be no. A study published earlier this year in states with legalized medical or recreational cannabis found no difference between rates of opioid overdose compared with states with no such laws. “It seems like it doesn’t do anything to help us with our opioid problem,” she said.

Nor does high-quality evidence exist showing use of cannabis can improve sleep, she said. A 2022 systematic review found fewer than half of studies showed the substance useful for sleep outcomes. “Where studies were positives, it was in people who had chronic pain,” Dr. Grossman noted. Research indicates cannabis may have substantial benefit for chronic pain compared with placebo.
 

Potential Harms

If the medical benefits of cannabis are murky, the evidence for its potential harms, at least in the short term, are clearer, according to Dr. Grossman. A simplified guideline for prescribing medical cannabinoids in primary care includes sedation, feeling high, dizziness, speech disorders, muscle twitching, hypotension, and several other conditions among the potential hazards of the drug. 

But the potential for long-term harm is uncertain. “All the evidence comes from people who have been using it for recreational reasons,” where there may be co-use of tobacco, self-reported outcomes, and recall bias, she said. The characteristics of people using cannabis recreationally often differ from those using it medicinally.
 

Use With Other Controlled Substances

Dr. Grossman said clinicians should consider whether the co-use of cannabis and other controlled substances, such as benzodiazepines, opioids, or Adderall, raises the potential risks associated with those drugs. “Ultimately it comes down to talking to your patients,” she said. If a toxicity screen shows the presence of controlled substances, ask about their experience with the drugs they are using and let them know your main concern is their safety.

Dr. Grossman reported no relevant financial conflicts of interest.

A version of this article appeared on Medscape.com.

The utility of cannabinoids to treat most medical conditions remains uncertain at best, but for at least three indications the data lean in favor of effectiveness, Ellie Grossman, MD, MPH, told attendees recently at the 2024 American College of Physicians Internal Medicine meeting.

Those are neuropathic pain, chemotherapy-induced nausea or vomiting, and spasticity in people with multiple sclerosis, said Dr. Grossman, an instructor at Harvard Medical School in Boston and medical director for primary care/behavioral health integration at Cambridge Health Alliance in Somerville, Massachusetts.

Dearth of Research Persists

Research is sorely lacking and of low quality in the field for many reasons, Dr. Grossman said. Most of the products tested come from outside the United States and often are synthetic and taken orally — which does not match the real-world use when patients go to dispensaries for cannabis derived directly from plants (or the plant product itself). And studies often rely on self-report.

Chronic pain is by far the top reason patients say they use medical cannabis, Dr. Grossman said. A Cochrane review of 16 studies found only that the potential benefits of cannabis may outweigh the potential harms for chronic neuropathic pain.
 

No Evidence in OUD

Dr. Grossman said she is frequently asked if cannabis can help people quit taking opioids. The answer seems to be no. A study published earlier this year in states with legalized medical or recreational cannabis found no difference between rates of opioid overdose compared with states with no such laws. “It seems like it doesn’t do anything to help us with our opioid problem,” she said.

Nor does high-quality evidence exist showing use of cannabis can improve sleep, she said. A 2022 systematic review found fewer than half of studies showed the substance useful for sleep outcomes. “Where studies were positives, it was in people who had chronic pain,” Dr. Grossman noted. Research indicates cannabis may have substantial benefit for chronic pain compared with placebo.
 

Potential Harms

If the medical benefits of cannabis are murky, the evidence for its potential harms, at least in the short term, are clearer, according to Dr. Grossman. A simplified guideline for prescribing medical cannabinoids in primary care includes sedation, feeling high, dizziness, speech disorders, muscle twitching, hypotension, and several other conditions among the potential hazards of the drug. 

But the potential for long-term harm is uncertain. “All the evidence comes from people who have been using it for recreational reasons,” where there may be co-use of tobacco, self-reported outcomes, and recall bias, she said. The characteristics of people using cannabis recreationally often differ from those using it medicinally.
 

Use With Other Controlled Substances

Dr. Grossman said clinicians should consider whether the co-use of cannabis and other controlled substances, such as benzodiazepines, opioids, or Adderall, raises the potential risks associated with those drugs. “Ultimately it comes down to talking to your patients,” she said. If a toxicity screen shows the presence of controlled substances, ask about their experience with the drugs they are using and let them know your main concern is their safety.

Dr. Grossman reported no relevant financial conflicts of interest.

A version of this article appeared on Medscape.com.

The utility of cannabinoids to treat most medical conditions remains uncertain at best, but for at least three indications the data lean in favor of effectiveness, Ellie Grossman, MD, MPH, told attendees recently at the 2024 American College of Physicians Internal Medicine meeting.

Those are neuropathic pain, chemotherapy-induced nausea or vomiting, and spasticity in people with multiple sclerosis, said Dr. Grossman, an instructor at Harvard Medical School in Boston and medical director for primary care/behavioral health integration at Cambridge Health Alliance in Somerville, Massachusetts.

Dearth of Research Persists

Research is sorely lacking and of low quality in the field for many reasons, Dr. Grossman said. Most of the products tested come from outside the United States and often are synthetic and taken orally — which does not match the real-world use when patients go to dispensaries for cannabis derived directly from plants (or the plant product itself). And studies often rely on self-report.

Chronic pain is by far the top reason patients say they use medical cannabis, Dr. Grossman said. A Cochrane review of 16 studies found only that the potential benefits of cannabis may outweigh the potential harms for chronic neuropathic pain.
 

No Evidence in OUD

Dr. Grossman said she is frequently asked if cannabis can help people quit taking opioids. The answer seems to be no. A study published earlier this year in states with legalized medical or recreational cannabis found no difference between rates of opioid overdose compared with states with no such laws. “It seems like it doesn’t do anything to help us with our opioid problem,” she said.

Nor does high-quality evidence exist showing use of cannabis can improve sleep, she said. A 2022 systematic review found fewer than half of studies showed the substance useful for sleep outcomes. “Where studies were positives, it was in people who had chronic pain,” Dr. Grossman noted. Research indicates cannabis may have substantial benefit for chronic pain compared with placebo.
 

Potential Harms

If the medical benefits of cannabis are murky, the evidence for its potential harms, at least in the short term, are clearer, according to Dr. Grossman. A simplified guideline for prescribing medical cannabinoids in primary care includes sedation, feeling high, dizziness, speech disorders, muscle twitching, hypotension, and several other conditions among the potential hazards of the drug. 

But the potential for long-term harm is uncertain. “All the evidence comes from people who have been using it for recreational reasons,” where there may be co-use of tobacco, self-reported outcomes, and recall bias, she said. The characteristics of people using cannabis recreationally often differ from those using it medicinally.
 

Use With Other Controlled Substances

Dr. Grossman said clinicians should consider whether the co-use of cannabis and other controlled substances, such as benzodiazepines, opioids, or Adderall, raises the potential risks associated with those drugs. “Ultimately it comes down to talking to your patients,” she said. If a toxicity screen shows the presence of controlled substances, ask about their experience with the drugs they are using and let them know your main concern is their safety.

Dr. Grossman reported no relevant financial conflicts of interest.

A version of this article appeared on Medscape.com.

VIENNA — The glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide (Wegovy) not only induced weight loss but also improved knee pain in people with knee osteoarthritis (OA) and obesity, according to results from the STEP 9 study reported at the Osteoarthritis Research Society International (OARSI) 2024  World Congress.

From baseline to week 68, the mean change in knee pain assessed using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score was a reduction of 41.7 points for semaglutide and a decrease of 27.5 points for a matching placebo. The estimated treatment difference of 14.1 points between the groups was statistically significant (P < .001).

As for weight loss, this also fell by a significantly greater amount in the people treated with semaglutide vs those given placebo, with respective reductions of 13.7% and 3.2% from baseline, with an estimated 10.5% greater weight loss with semaglutide.

167824_Bliddal_Henning_web.jpg

“The interesting thing is whether there’s a specific action of GLP-1 receptor agonists on the joint, not through the weight loss but by itself,” principal study investigator Henning Bliddal, MD, DMSc, told this news organization ahead of reporting the results at OARSI 2024.

Weight loss is “obviously good” because “the knees suffer from the weight. But whether it’s good for the knee or just for the health or the well-being of the person is another matter,” said Dr. Bliddal, who is director of the Parker Institute at Bispebjerg Frederiksberg Hospital in Copenhagen, Denmark.
 

Not Approved in OA

Semaglutide and other potentially weight loss-inducing drugs are not currently indicated for use specifically in OA, Tonia Vincent, MBBS, PhD, told this news organization, and so “I think we have to be very cautious,” she said.

“Weight loss is one of the few things that has been shown to be successful in clinical trials,” said Dr. Vincent, who is a professor of musculoskeletal biology and an honorary rheumatologist at the Kennedy Institute of Rheumatology at Oxford University in Oxford, England.

“People always feel better too when they lose weight, so that helps manage pain. So, I’d be very surprised if there isn’t a benefit,” she added.

“I just think we need to know more about the long-term use of these drugs, whether the healthcare system can afford them, and how we would ration them.”
 

Previous Work

The STEP 9 study is not the first time that Dr. Bliddal has investigated the effects of a GLP-1 receptor agonist in people with knee OA, but it is the first to have shown a significant effect on knee pain.

Previously, results from the LOSEIT trial with liraglutide demonstrated that, after an 8-week dietary intervention run-in phase, people who were treated with the GLP-1 receptor agonist lost an average of 2.8 kg in body weight over a period of 1 year, vs a 1.2 kg gain in the placebo group. Knee injury and Osteoarthritis Outcome Scores, however, were largely unaffected.

“The study was more or less negative for knee pain because at that time we had to pretreat patients with some kind of weight loss before they were allowed to have the liraglutide,” Dr. Bliddal said.

“There’s so many different considerations with diets and the different ways that [dietary modification] is performed, that could be part of the explanation why some people didn’t find the pain relief,” Dr. Bliddal suggested.
 

STEP 9 Study Design

No pre-study dietary intervention was required in the STEP 9 trial, although a reduced-calorie diet and increased physical exercise were used alongside both semaglutide and placebo treatment.

STEP 9 was a multicenter, multinational phase 3 clinical trial that enrolled people if they had a body mass index (BMI) of > 30, had a clinical diagnosis of knee OA with moderate radiographic changes (Kellgren-Lawrence grade of 2-3), and were experiencing knee pain.

In addition to a baseline WOMAC pain score of at least 40 points (where 0 represents no and 100 the worst pain), the participants had to have a WOMAC numerical rating scale (NRS) score of ≥ 3.1.

A total of 407 participants were recruited and randomly allocated, 2:1, to receive once-weekly subcutaneous injections of either semaglutide 2.4 mg or placebo for a total of 68 weeks.

Dr. Bliddal presented demographic information only for the study population as a whole, showing that the mean was 56 years, 81.6% were women, 60.9% were White, 11.8% Native American, 7.6% Black, and 19.7% of other ethnic origin.

Moreover, the mean bodyweight at baseline was 108.6 kg, and the mean baseline BMI was 40.3, with 75% of participants having a BMI ≥ 35. The mean waist circumference was 118.7 cm. The mean baseline WOMAC pain score was 70.9.
 

Other Findings

In addition to the reductions seen in the coprimary endpoints of weight loss and knee pain, the WOMAC physical function score was also reduced from baseline to week 68 to a greater degree in the semaglutide than placebo arm, by a respective 41.5 vs 26.7 points, with a significant estimated treatment difference of -14.9 points.

“The use of pain medication went down as well; you can see the drop was faster in the semaglutide group than the placebo group, and it was maintained throughout the study,” Dr. Bliddal said during his presentation. He noted that patients had to temporarily stop taking pain relievers such as acetaminophen 3 days before their pain was assessed.

Additional findings reported in the abstract, but not presented at the meeting, were a significant estimated treatment difference of -1.0 in NRS pain intensity, more people treated with semaglutide than placebo achieving ≥ 5% (87.0% vs 29.2%) or ≥ 10% (70.4% vs 9.2%) weight loss.

“Safety and tolerability with semaglutide were consistent with the global STEP program and the GLP-1 receptor agonist class in general,” Dr. Bliddal reported.

Serious adverse events occurred in a respective 10.0% and 8.1% of participants, and adverse events leading to discontinuation were recorded in 6.7% and 3%. Around one third (2.2%) of those leading to discontinuation in the semaglutide arm were gastrointestinal adverse events.

The STEP 9 study was funded by Novo Nordisk. Henning is a principal investigator for the trial and acknowledged that research grants were received from Novo Nordisk to his institution, as well as consulting fees and honoraria. He has also received congress and travel support from Contura. Dr. Vincent was not involved in the study and had no relevant conflicts of interest to disclose.

A version of this article appeared on Medscape.com.

VIENNA — The glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide (Wegovy) not only induced weight loss but also improved knee pain in people with knee osteoarthritis (OA) and obesity, according to results from the STEP 9 study reported at the Osteoarthritis Research Society International (OARSI) 2024  World Congress.

From baseline to week 68, the mean change in knee pain assessed using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score was a reduction of 41.7 points for semaglutide and a decrease of 27.5 points for a matching placebo. The estimated treatment difference of 14.1 points between the groups was statistically significant (P < .001).

As for weight loss, this also fell by a significantly greater amount in the people treated with semaglutide vs those given placebo, with respective reductions of 13.7% and 3.2% from baseline, with an estimated 10.5% greater weight loss with semaglutide.

167824_Bliddal_Henning_web.jpg

“The interesting thing is whether there’s a specific action of GLP-1 receptor agonists on the joint, not through the weight loss but by itself,” principal study investigator Henning Bliddal, MD, DMSc, told this news organization ahead of reporting the results at OARSI 2024.

Weight loss is “obviously good” because “the knees suffer from the weight. But whether it’s good for the knee or just for the health or the well-being of the person is another matter,” said Dr. Bliddal, who is director of the Parker Institute at Bispebjerg Frederiksberg Hospital in Copenhagen, Denmark.
 

Not Approved in OA

Semaglutide and other potentially weight loss-inducing drugs are not currently indicated for use specifically in OA, Tonia Vincent, MBBS, PhD, told this news organization, and so “I think we have to be very cautious,” she said.

“Weight loss is one of the few things that has been shown to be successful in clinical trials,” said Dr. Vincent, who is a professor of musculoskeletal biology and an honorary rheumatologist at the Kennedy Institute of Rheumatology at Oxford University in Oxford, England.

“People always feel better too when they lose weight, so that helps manage pain. So, I’d be very surprised if there isn’t a benefit,” she added.

“I just think we need to know more about the long-term use of these drugs, whether the healthcare system can afford them, and how we would ration them.”
 

Previous Work

The STEP 9 study is not the first time that Dr. Bliddal has investigated the effects of a GLP-1 receptor agonist in people with knee OA, but it is the first to have shown a significant effect on knee pain.

Previously, results from the LOSEIT trial with liraglutide demonstrated that, after an 8-week dietary intervention run-in phase, people who were treated with the GLP-1 receptor agonist lost an average of 2.8 kg in body weight over a period of 1 year, vs a 1.2 kg gain in the placebo group. Knee injury and Osteoarthritis Outcome Scores, however, were largely unaffected.

“The study was more or less negative for knee pain because at that time we had to pretreat patients with some kind of weight loss before they were allowed to have the liraglutide,” Dr. Bliddal said.

“There’s so many different considerations with diets and the different ways that [dietary modification] is performed, that could be part of the explanation why some people didn’t find the pain relief,” Dr. Bliddal suggested.
 

STEP 9 Study Design

No pre-study dietary intervention was required in the STEP 9 trial, although a reduced-calorie diet and increased physical exercise were used alongside both semaglutide and placebo treatment.

STEP 9 was a multicenter, multinational phase 3 clinical trial that enrolled people if they had a body mass index (BMI) of > 30, had a clinical diagnosis of knee OA with moderate radiographic changes (Kellgren-Lawrence grade of 2-3), and were experiencing knee pain.

In addition to a baseline WOMAC pain score of at least 40 points (where 0 represents no and 100 the worst pain), the participants had to have a WOMAC numerical rating scale (NRS) score of ≥ 3.1.

A total of 407 participants were recruited and randomly allocated, 2:1, to receive once-weekly subcutaneous injections of either semaglutide 2.4 mg or placebo for a total of 68 weeks.

Dr. Bliddal presented demographic information only for the study population as a whole, showing that the mean was 56 years, 81.6% were women, 60.9% were White, 11.8% Native American, 7.6% Black, and 19.7% of other ethnic origin.

Moreover, the mean bodyweight at baseline was 108.6 kg, and the mean baseline BMI was 40.3, with 75% of participants having a BMI ≥ 35. The mean waist circumference was 118.7 cm. The mean baseline WOMAC pain score was 70.9.
 

Other Findings

In addition to the reductions seen in the coprimary endpoints of weight loss and knee pain, the WOMAC physical function score was also reduced from baseline to week 68 to a greater degree in the semaglutide than placebo arm, by a respective 41.5 vs 26.7 points, with a significant estimated treatment difference of -14.9 points.

“The use of pain medication went down as well; you can see the drop was faster in the semaglutide group than the placebo group, and it was maintained throughout the study,” Dr. Bliddal said during his presentation. He noted that patients had to temporarily stop taking pain relievers such as acetaminophen 3 days before their pain was assessed.

Additional findings reported in the abstract, but not presented at the meeting, were a significant estimated treatment difference of -1.0 in NRS pain intensity, more people treated with semaglutide than placebo achieving ≥ 5% (87.0% vs 29.2%) or ≥ 10% (70.4% vs 9.2%) weight loss.

“Safety and tolerability with semaglutide were consistent with the global STEP program and the GLP-1 receptor agonist class in general,” Dr. Bliddal reported.

Serious adverse events occurred in a respective 10.0% and 8.1% of participants, and adverse events leading to discontinuation were recorded in 6.7% and 3%. Around one third (2.2%) of those leading to discontinuation in the semaglutide arm were gastrointestinal adverse events.

The STEP 9 study was funded by Novo Nordisk. Henning is a principal investigator for the trial and acknowledged that research grants were received from Novo Nordisk to his institution, as well as consulting fees and honoraria. He has also received congress and travel support from Contura. Dr. Vincent was not involved in the study and had no relevant conflicts of interest to disclose.

A version of this article appeared on Medscape.com.

VIENNA — The glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide (Wegovy) not only induced weight loss but also improved knee pain in people with knee osteoarthritis (OA) and obesity, according to results from the STEP 9 study reported at the Osteoarthritis Research Society International (OARSI) 2024  World Congress.

From baseline to week 68, the mean change in knee pain assessed using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score was a reduction of 41.7 points for semaglutide and a decrease of 27.5 points for a matching placebo. The estimated treatment difference of 14.1 points between the groups was statistically significant (P < .001).

As for weight loss, this also fell by a significantly greater amount in the people treated with semaglutide vs those given placebo, with respective reductions of 13.7% and 3.2% from baseline, with an estimated 10.5% greater weight loss with semaglutide.

167824_Bliddal_Henning_web.jpg

“The interesting thing is whether there’s a specific action of GLP-1 receptor agonists on the joint, not through the weight loss but by itself,” principal study investigator Henning Bliddal, MD, DMSc, told this news organization ahead of reporting the results at OARSI 2024.

Weight loss is “obviously good” because “the knees suffer from the weight. But whether it’s good for the knee or just for the health or the well-being of the person is another matter,” said Dr. Bliddal, who is director of the Parker Institute at Bispebjerg Frederiksberg Hospital in Copenhagen, Denmark.
 

Not Approved in OA

Semaglutide and other potentially weight loss-inducing drugs are not currently indicated for use specifically in OA, Tonia Vincent, MBBS, PhD, told this news organization, and so “I think we have to be very cautious,” she said.

“Weight loss is one of the few things that has been shown to be successful in clinical trials,” said Dr. Vincent, who is a professor of musculoskeletal biology and an honorary rheumatologist at the Kennedy Institute of Rheumatology at Oxford University in Oxford, England.

“People always feel better too when they lose weight, so that helps manage pain. So, I’d be very surprised if there isn’t a benefit,” she added.

“I just think we need to know more about the long-term use of these drugs, whether the healthcare system can afford them, and how we would ration them.”
 

Previous Work

The STEP 9 study is not the first time that Dr. Bliddal has investigated the effects of a GLP-1 receptor agonist in people with knee OA, but it is the first to have shown a significant effect on knee pain.

Previously, results from the LOSEIT trial with liraglutide demonstrated that, after an 8-week dietary intervention run-in phase, people who were treated with the GLP-1 receptor agonist lost an average of 2.8 kg in body weight over a period of 1 year, vs a 1.2 kg gain in the placebo group. Knee injury and Osteoarthritis Outcome Scores, however, were largely unaffected.

“The study was more or less negative for knee pain because at that time we had to pretreat patients with some kind of weight loss before they were allowed to have the liraglutide,” Dr. Bliddal said.

“There’s so many different considerations with diets and the different ways that [dietary modification] is performed, that could be part of the explanation why some people didn’t find the pain relief,” Dr. Bliddal suggested.
 

STEP 9 Study Design

No pre-study dietary intervention was required in the STEP 9 trial, although a reduced-calorie diet and increased physical exercise were used alongside both semaglutide and placebo treatment.

STEP 9 was a multicenter, multinational phase 3 clinical trial that enrolled people if they had a body mass index (BMI) of > 30, had a clinical diagnosis of knee OA with moderate radiographic changes (Kellgren-Lawrence grade of 2-3), and were experiencing knee pain.

In addition to a baseline WOMAC pain score of at least 40 points (where 0 represents no and 100 the worst pain), the participants had to have a WOMAC numerical rating scale (NRS) score of ≥ 3.1.

A total of 407 participants were recruited and randomly allocated, 2:1, to receive once-weekly subcutaneous injections of either semaglutide 2.4 mg or placebo for a total of 68 weeks.

Dr. Bliddal presented demographic information only for the study population as a whole, showing that the mean was 56 years, 81.6% were women, 60.9% were White, 11.8% Native American, 7.6% Black, and 19.7% of other ethnic origin.

Moreover, the mean bodyweight at baseline was 108.6 kg, and the mean baseline BMI was 40.3, with 75% of participants having a BMI ≥ 35. The mean waist circumference was 118.7 cm. The mean baseline WOMAC pain score was 70.9.
 

Other Findings

In addition to the reductions seen in the coprimary endpoints of weight loss and knee pain, the WOMAC physical function score was also reduced from baseline to week 68 to a greater degree in the semaglutide than placebo arm, by a respective 41.5 vs 26.7 points, with a significant estimated treatment difference of -14.9 points.

“The use of pain medication went down as well; you can see the drop was faster in the semaglutide group than the placebo group, and it was maintained throughout the study,” Dr. Bliddal said during his presentation. He noted that patients had to temporarily stop taking pain relievers such as acetaminophen 3 days before their pain was assessed.

Additional findings reported in the abstract, but not presented at the meeting, were a significant estimated treatment difference of -1.0 in NRS pain intensity, more people treated with semaglutide than placebo achieving ≥ 5% (87.0% vs 29.2%) or ≥ 10% (70.4% vs 9.2%) weight loss.

“Safety and tolerability with semaglutide were consistent with the global STEP program and the GLP-1 receptor agonist class in general,” Dr. Bliddal reported.

Serious adverse events occurred in a respective 10.0% and 8.1% of participants, and adverse events leading to discontinuation were recorded in 6.7% and 3%. Around one third (2.2%) of those leading to discontinuation in the semaglutide arm were gastrointestinal adverse events.

The STEP 9 study was funded by Novo Nordisk. Henning is a principal investigator for the trial and acknowledged that research grants were received from Novo Nordisk to his institution, as well as consulting fees and honoraria. He has also received congress and travel support from Contura. Dr. Vincent was not involved in the study and had no relevant conflicts of interest to disclose.

A version of this article appeared on Medscape.com.