Addiction Medicine

Women who used marijuana (cannabis) at least four times in the previous month (heavy users) were less likely to have type 2 diabetes than women who were light users or nonusers, in a nationally representative U.S. observational study.

In contrast, there were no differences in the prevalence of type 2 diabetes in men who were light or heavy cannabis users versus nonusers.
 

Kerkez/Getty Images

These findings are based on data from the 2013-2018 National Health and Nutrition Examination Survey (NHANES), whereby participants self-reported their cannabis use.

The study by Ayobami S. Ogunsola, MD, MPH, a graduate student at Texas A&M University, College Station, and colleagues was recently published in Cannabis and Cannabinoid Research. 
 

What do the findings mean?

Although overall findings linking cannabis use and diabetes have been inconsistent, the gender differences in the current study are consistent with animal studies and some clinical studies, senior author Ibraheem M. Karaye, MD, MPH, said in an interview.

However, these gender differences need to be confirmed, and “we strongly recommend that more biological or biochemical studies be conducted that could actually tell us the mechanisms,” said Dr. Karaye, an assistant professor in the department of population health, Hofstra University, Hempstead, N.Y.

“It’s indisputable that medical marijuana has some medical benefits,” he added. “Women [who use cannabis] have been shown to lose more weight than men, for example.”

“If women [cannabis users] are less likely to develop diabetes or more likely to express improvement of symptoms of diabetes,” he noted, “this means that hyperglycemic medications that are being prescribed should be watched scrupulously. Otherwise, there is a risk that [women] may overrespond.”

That is, Dr. Karaye continued, women “may be at risk of developing hypoglycemia because the cannabis is acting synergistically with the regular drug that is being used to treat the diabetes.” 

U.S. clinicians, especially in states with legalized medical marijuana, need to be aware of the potential synergy.

“One would have to consider the patient as a whole,” he stressed. “For example, a woman that uses medical marijuana may actually respond differently to hyperglycemic medication.”
 

Conflicting reports explained by sex differences?

Evidence on whether cannabis use is linked with type 2 diabetes is limited and conflicting, the researchers wrote. They hypothesized that these conflicting findings might be explained by sex differences.

To “help inform current diabetes prevention and mitigation efforts,” they investigated sex differences in cannabis use and prevalence of type 2 diabetes in 15,602 men and women in the 2013-2014, 2015-2016, and 2017-2018 NHANES surveys.

Participants were classified as having type 2 diabetes if they had a physician’s diagnosis; a 2-hour plasma glucose of at least 200 mg/dL (in a glucose tolerance test); fasting blood glucose of at least 126 mg/dL; or A1c of at least 6.5%.

About half of respondents were women (52%) and close to half (44%) were age 18-39.

More than a third (38%) had a body mass index (BMI) of at least 30 kg/m2, indicating obesity.

Roughly 1 in 10 had a diagnosis of type 2 diabetes (13.5%) or A1c of at least 6.5% (9.8%).

Close to a fifth smoked cigarettes (16%). Similarly, 14.5% used cannabis at least four times a week, 3.3% used it less often, and the rest did not use it. Half of participants were not physically active (49%).

Just over half had at least a college education (55%).

Heavy cannabis users were more likely to be younger than age 40 (57% of men, 57% of women), college graduates (54% of men, 63% of women), cigarette smokers (79% of men, 83% of women), and physically inactive (39% of men, 49% of women).

Among women, heavy cannabis users were 49% less likely to have type 2 diabetes than nonusers, after adjusting for age, sex, race/ethnicity, educational level, physical activity, tobacco use, alcohol use, marital status, difficulty walking, employment status, income, and BMI (adjusted odds ratio, 0.51; 95% confidence interval, 0.31-0.84).

There were no significant differences between light cannabis users versus nonusers and diabetes prevalence in women, or between light or heavy cannabis users versus nonusers and diabetes prevalence in men.
 

Limitations, yet biologically plausible

The researchers acknowledged several study limitations.

They do not know how long participants had used marijuana. The men and women may have underreported their cannabis use, especially in states where medical marijuana was not legal, and the NHANES data did not specify whether the cannabis was recreational or medicinal.

The study may have been underpowered to detect a smaller difference in men who used versus did not use marijuana.

And importantly, this was an observational study (a snapshot at one point in time), so it cannot say whether the heavy cannabis use in women caused a decreased likelihood of diabetes.

Nevertheless, the inverse association between cannabis use and presence of type 2 diabetes is biologically plausible, Dr. Ogunsola and colleagues wrote.

The two major cannabis compounds, cannabidiol and delta-9-tetrahydrocannabinol, stimulate CBD1 and CBD2 receptors in the central and peripheral nervous systems, respectively. And “activation of the CBD1 receptor increases insulin secretion, glucagon, and somatostatin, and activates metabolic processes in fat and skeletal muscles – mechanisms that improve glucose disposal,” they explained.

The researchers speculated that the sex differences they found for this association may be caused by differences in sex hormones, or the endocannabinoid system, or fat deposits.

Therefore, “additional studies are needed to investigate the sex-based heterogeneity reported in this study and to elucidate potential mechanisms for the observation,” they concluded.

The study did not receive any funding and the researchers have no relevant financial disclosures.

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

Women who used marijuana (cannabis) at least four times in the previous month (heavy users) were less likely to have type 2 diabetes than women who were light users or nonusers, in a nationally representative U.S. observational study.

In contrast, there were no differences in the prevalence of type 2 diabetes in men who were light or heavy cannabis users versus nonusers.
 

Kerkez/Getty Images

These findings are based on data from the 2013-2018 National Health and Nutrition Examination Survey (NHANES), whereby participants self-reported their cannabis use.

The study by Ayobami S. Ogunsola, MD, MPH, a graduate student at Texas A&M University, College Station, and colleagues was recently published in Cannabis and Cannabinoid Research. 
 

What do the findings mean?

Although overall findings linking cannabis use and diabetes have been inconsistent, the gender differences in the current study are consistent with animal studies and some clinical studies, senior author Ibraheem M. Karaye, MD, MPH, said in an interview.

However, these gender differences need to be confirmed, and “we strongly recommend that more biological or biochemical studies be conducted that could actually tell us the mechanisms,” said Dr. Karaye, an assistant professor in the department of population health, Hofstra University, Hempstead, N.Y.

“It’s indisputable that medical marijuana has some medical benefits,” he added. “Women [who use cannabis] have been shown to lose more weight than men, for example.”

“If women [cannabis users] are less likely to develop diabetes or more likely to express improvement of symptoms of diabetes,” he noted, “this means that hyperglycemic medications that are being prescribed should be watched scrupulously. Otherwise, there is a risk that [women] may overrespond.”

That is, Dr. Karaye continued, women “may be at risk of developing hypoglycemia because the cannabis is acting synergistically with the regular drug that is being used to treat the diabetes.” 

U.S. clinicians, especially in states with legalized medical marijuana, need to be aware of the potential synergy.

“One would have to consider the patient as a whole,” he stressed. “For example, a woman that uses medical marijuana may actually respond differently to hyperglycemic medication.”
 

Conflicting reports explained by sex differences?

Evidence on whether cannabis use is linked with type 2 diabetes is limited and conflicting, the researchers wrote. They hypothesized that these conflicting findings might be explained by sex differences.

To “help inform current diabetes prevention and mitigation efforts,” they investigated sex differences in cannabis use and prevalence of type 2 diabetes in 15,602 men and women in the 2013-2014, 2015-2016, and 2017-2018 NHANES surveys.

Participants were classified as having type 2 diabetes if they had a physician’s diagnosis; a 2-hour plasma glucose of at least 200 mg/dL (in a glucose tolerance test); fasting blood glucose of at least 126 mg/dL; or A1c of at least 6.5%.

About half of respondents were women (52%) and close to half (44%) were age 18-39.

More than a third (38%) had a body mass index (BMI) of at least 30 kg/m2, indicating obesity.

Roughly 1 in 10 had a diagnosis of type 2 diabetes (13.5%) or A1c of at least 6.5% (9.8%).

Close to a fifth smoked cigarettes (16%). Similarly, 14.5% used cannabis at least four times a week, 3.3% used it less often, and the rest did not use it. Half of participants were not physically active (49%).

Just over half had at least a college education (55%).

Heavy cannabis users were more likely to be younger than age 40 (57% of men, 57% of women), college graduates (54% of men, 63% of women), cigarette smokers (79% of men, 83% of women), and physically inactive (39% of men, 49% of women).

Among women, heavy cannabis users were 49% less likely to have type 2 diabetes than nonusers, after adjusting for age, sex, race/ethnicity, educational level, physical activity, tobacco use, alcohol use, marital status, difficulty walking, employment status, income, and BMI (adjusted odds ratio, 0.51; 95% confidence interval, 0.31-0.84).

There were no significant differences between light cannabis users versus nonusers and diabetes prevalence in women, or between light or heavy cannabis users versus nonusers and diabetes prevalence in men.
 

Limitations, yet biologically plausible

The researchers acknowledged several study limitations.

They do not know how long participants had used marijuana. The men and women may have underreported their cannabis use, especially in states where medical marijuana was not legal, and the NHANES data did not specify whether the cannabis was recreational or medicinal.

The study may have been underpowered to detect a smaller difference in men who used versus did not use marijuana.

And importantly, this was an observational study (a snapshot at one point in time), so it cannot say whether the heavy cannabis use in women caused a decreased likelihood of diabetes.

Nevertheless, the inverse association between cannabis use and presence of type 2 diabetes is biologically plausible, Dr. Ogunsola and colleagues wrote.

The two major cannabis compounds, cannabidiol and delta-9-tetrahydrocannabinol, stimulate CBD1 and CBD2 receptors in the central and peripheral nervous systems, respectively. And “activation of the CBD1 receptor increases insulin secretion, glucagon, and somatostatin, and activates metabolic processes in fat and skeletal muscles – mechanisms that improve glucose disposal,” they explained.

The researchers speculated that the sex differences they found for this association may be caused by differences in sex hormones, or the endocannabinoid system, or fat deposits.

Therefore, “additional studies are needed to investigate the sex-based heterogeneity reported in this study and to elucidate potential mechanisms for the observation,” they concluded.

The study did not receive any funding and the researchers have no relevant financial disclosures.

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

Women who used marijuana (cannabis) at least four times in the previous month (heavy users) were less likely to have type 2 diabetes than women who were light users or nonusers, in a nationally representative U.S. observational study.

In contrast, there were no differences in the prevalence of type 2 diabetes in men who were light or heavy cannabis users versus nonusers.
 

Kerkez/Getty Images

These findings are based on data from the 2013-2018 National Health and Nutrition Examination Survey (NHANES), whereby participants self-reported their cannabis use.

The study by Ayobami S. Ogunsola, MD, MPH, a graduate student at Texas A&M University, College Station, and colleagues was recently published in Cannabis and Cannabinoid Research. 
 

What do the findings mean?

Although overall findings linking cannabis use and diabetes have been inconsistent, the gender differences in the current study are consistent with animal studies and some clinical studies, senior author Ibraheem M. Karaye, MD, MPH, said in an interview.

However, these gender differences need to be confirmed, and “we strongly recommend that more biological or biochemical studies be conducted that could actually tell us the mechanisms,” said Dr. Karaye, an assistant professor in the department of population health, Hofstra University, Hempstead, N.Y.

“It’s indisputable that medical marijuana has some medical benefits,” he added. “Women [who use cannabis] have been shown to lose more weight than men, for example.”

“If women [cannabis users] are less likely to develop diabetes or more likely to express improvement of symptoms of diabetes,” he noted, “this means that hyperglycemic medications that are being prescribed should be watched scrupulously. Otherwise, there is a risk that [women] may overrespond.”

That is, Dr. Karaye continued, women “may be at risk of developing hypoglycemia because the cannabis is acting synergistically with the regular drug that is being used to treat the diabetes.” 

U.S. clinicians, especially in states with legalized medical marijuana, need to be aware of the potential synergy.

“One would have to consider the patient as a whole,” he stressed. “For example, a woman that uses medical marijuana may actually respond differently to hyperglycemic medication.”
 

Conflicting reports explained by sex differences?

Evidence on whether cannabis use is linked with type 2 diabetes is limited and conflicting, the researchers wrote. They hypothesized that these conflicting findings might be explained by sex differences.

To “help inform current diabetes prevention and mitigation efforts,” they investigated sex differences in cannabis use and prevalence of type 2 diabetes in 15,602 men and women in the 2013-2014, 2015-2016, and 2017-2018 NHANES surveys.

Participants were classified as having type 2 diabetes if they had a physician’s diagnosis; a 2-hour plasma glucose of at least 200 mg/dL (in a glucose tolerance test); fasting blood glucose of at least 126 mg/dL; or A1c of at least 6.5%.

About half of respondents were women (52%) and close to half (44%) were age 18-39.

More than a third (38%) had a body mass index (BMI) of at least 30 kg/m2, indicating obesity.

Roughly 1 in 10 had a diagnosis of type 2 diabetes (13.5%) or A1c of at least 6.5% (9.8%).

Close to a fifth smoked cigarettes (16%). Similarly, 14.5% used cannabis at least four times a week, 3.3% used it less often, and the rest did not use it. Half of participants were not physically active (49%).

Just over half had at least a college education (55%).

Heavy cannabis users were more likely to be younger than age 40 (57% of men, 57% of women), college graduates (54% of men, 63% of women), cigarette smokers (79% of men, 83% of women), and physically inactive (39% of men, 49% of women).

Among women, heavy cannabis users were 49% less likely to have type 2 diabetes than nonusers, after adjusting for age, sex, race/ethnicity, educational level, physical activity, tobacco use, alcohol use, marital status, difficulty walking, employment status, income, and BMI (adjusted odds ratio, 0.51; 95% confidence interval, 0.31-0.84).

There were no significant differences between light cannabis users versus nonusers and diabetes prevalence in women, or between light or heavy cannabis users versus nonusers and diabetes prevalence in men.
 

Limitations, yet biologically plausible

The researchers acknowledged several study limitations.

They do not know how long participants had used marijuana. The men and women may have underreported their cannabis use, especially in states where medical marijuana was not legal, and the NHANES data did not specify whether the cannabis was recreational or medicinal.

The study may have been underpowered to detect a smaller difference in men who used versus did not use marijuana.

And importantly, this was an observational study (a snapshot at one point in time), so it cannot say whether the heavy cannabis use in women caused a decreased likelihood of diabetes.

Nevertheless, the inverse association between cannabis use and presence of type 2 diabetes is biologically plausible, Dr. Ogunsola and colleagues wrote.

The two major cannabis compounds, cannabidiol and delta-9-tetrahydrocannabinol, stimulate CBD1 and CBD2 receptors in the central and peripheral nervous systems, respectively. And “activation of the CBD1 receptor increases insulin secretion, glucagon, and somatostatin, and activates metabolic processes in fat and skeletal muscles – mechanisms that improve glucose disposal,” they explained.

The researchers speculated that the sex differences they found for this association may be caused by differences in sex hormones, or the endocannabinoid system, or fat deposits.

Therefore, “additional studies are needed to investigate the sex-based heterogeneity reported in this study and to elucidate potential mechanisms for the observation,” they concluded.

The study did not receive any funding and the researchers have no relevant financial disclosures.

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

Young adults hospitalized for a stroke are much more likely to be admitted for a recurrent stroke if they have cannabis use disorder, new observational research suggests. “Our analysis shows young marijuana users with a history of stroke or transient ischemic attack remain at significantly high risk for future strokes,” said lead study author Akhil Jain, MD, a resident physician at Mercy Fitzgerald Hospital in Darby, Pennsylvania.

“It’s essential to raise awareness among young adults about the impact of chronic habitual use of marijuana, especially if they have established cardiovascular risk factors or previous stroke.”

The study will be presented during the International Stroke Conference, presented by the American Stroke Association, a division of the American Heart Association.

An increasing number of jurisdictions are allowing marijuana use. To date, 18 states and the District of Columbia have legalized recreational cannabis use, the investigators noted.

Research suggests cannabis use disorder – defined as the chronic habitual use of cannabis – is more prevalent in the young adult population. But Dr. Jain said the population of marijuana users is “a changing dynamic.”

Cannabis use has been linked to an increased risk for first-time stroke or transient ischemic attack (TIA). Traditional stroke risk factors include hypertension, diabetes, and diseases related to blood vessels or blood circulation, including atherosclerosis.

Young adults might have additional stroke risk factors, such as behavioral habits like substance abuse, low physical activity, and smoking, oral contraceptives use among females, and brain infections, especially in the immunocompromised, said Dr. Jain.

Research from the American Heart Association shows stroke rates are increasing among adults 18 to 45 years of age. Each year, young adults account for up to 15% of strokes in the United States.

Prevalence and risk for recurrent stroke in patients with previous stroke or TIA in cannabis users have not been clearly established, the researchers pointed out.

A higher rate of recurrent stroke

For this new study, Dr. Jain and colleagues used data from the National Inpatient Sample from October 2015 to December 2017. They identified hospitalizations among young adults 18 to 45 years of age with a previous history of stroke or TIA.

They then grouped these patients into those with cannabis use disorder (4,690) and those without cannabis use disorder (156,700). The median age in both cohorts was 37 years.

The analysis did not include those who were considered in remission from cannabis use disorder.

Results showed that 6.9% of those with cannabis use disorder were hospitalized for a recurrent stroke, compared with 5.4% of those without cannabis use disorder (P < .001).

After adjustment for demographic factors (age, sex, race, household income), and pre-existing conditions, patients with cannabis use disorder were 48% more likely to be hospitalized for recurrent stroke than those without cannabis use disorder (odds ratio, 1.48; 95% confidence interval, 1.28-1.71; P < .001).

Compared with the group without cannabis use disorder, the cannabis use disorder group had more men (55.2% vs. 40.2%), more African American people (44.6% vs. 37.2%), and more use of tobacco (73.9% vs. 39.6%) and alcohol (16.5% vs. 3.6%). They also had a greater percentage of chronic obstructive pulmonary disease, depression, and psychoses.

But a smaller percentage of those with cannabis use disorder had hypertension (51.3% vs. 55.6%; P = .001) and diabetes (16.3% vs. 22.7%; P < .001), which is an “interesting” finding, said Dr. Jain.

“We observed that even with a lower rate of cardiovascular risk factors, after controlling for all the risk factors, we still found the cannabis users had a higher rate of recurrent stroke.”

He noted this was a retrospective study without a control group. “If both groups had comparable hypertension, then this risk might actually be more evident,” said Dr. Jain. “We need a prospective study with comparable groups.”

Living in low-income neighborhoods and in northeast and southern regions of the United States was also more common in the cannabis use disorder group.
 

Hypothesis-generating research

The study did not investigate the possible mechanisms by which marijuana use might increase stroke risk, but Dr. Jain speculated that these could include factors such as impaired blood vessel function, changes in blood supply, an increased tendency of blood clotting, impaired energy production in brain cells, and an imbalance between molecules that harm healthy tissue and the antioxidant defenses that neutralize them.

As cannabis use may pose a different risk for a new stroke, as opposed a previous stroke, Dr. Jain said it would be interesting to study the amount of “residual function deficit” experienced with the first stroke.

The new study represents “foundational research” upon which other research teams can build, said Dr. Jain. “Our study is hypothesis-generating research for a future prospective randomized controlled trial.”

A limitation of the study is that it did not consider the effect of various doses, duration, and forms of cannabis abuse, or use of medicinal cannabis or other drugs.

Robert L. Page II, PharmD, professor, departments of clinical pharmacy and physical medicine/rehabilitation, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, provided a comment on this new research.

A cannabis use disorder diagnosis provides “specific criteria” with regard to chronicity of use and reflects “more of a physical and psychological dependence upon cannabis,” said Dr. Page, who chaired the writing group for the AHA 2020 cannabis and cardiovascular disease scientific statement.

He explained what sets people with cannabis use disorder apart from “run-of-the-mill” recreational cannabis users is that “these are individuals who use a cannabis product, whether it’s smoking it, vaping it, or consuming it via an edible, and are using it on a regular basis, in a chronic fashion.”

The study received no outside funding. The authors report no relevant disclosures.

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

Young adults hospitalized for a stroke are much more likely to be admitted for a recurrent stroke if they have cannabis use disorder, new observational research suggests. “Our analysis shows young marijuana users with a history of stroke or transient ischemic attack remain at significantly high risk for future strokes,” said lead study author Akhil Jain, MD, a resident physician at Mercy Fitzgerald Hospital in Darby, Pennsylvania.

“It’s essential to raise awareness among young adults about the impact of chronic habitual use of marijuana, especially if they have established cardiovascular risk factors or previous stroke.”

The study will be presented during the International Stroke Conference, presented by the American Stroke Association, a division of the American Heart Association.

An increasing number of jurisdictions are allowing marijuana use. To date, 18 states and the District of Columbia have legalized recreational cannabis use, the investigators noted.

Research suggests cannabis use disorder – defined as the chronic habitual use of cannabis – is more prevalent in the young adult population. But Dr. Jain said the population of marijuana users is “a changing dynamic.”

Cannabis use has been linked to an increased risk for first-time stroke or transient ischemic attack (TIA). Traditional stroke risk factors include hypertension, diabetes, and diseases related to blood vessels or blood circulation, including atherosclerosis.

Young adults might have additional stroke risk factors, such as behavioral habits like substance abuse, low physical activity, and smoking, oral contraceptives use among females, and brain infections, especially in the immunocompromised, said Dr. Jain.

Research from the American Heart Association shows stroke rates are increasing among adults 18 to 45 years of age. Each year, young adults account for up to 15% of strokes in the United States.

Prevalence and risk for recurrent stroke in patients with previous stroke or TIA in cannabis users have not been clearly established, the researchers pointed out.

A higher rate of recurrent stroke

For this new study, Dr. Jain and colleagues used data from the National Inpatient Sample from October 2015 to December 2017. They identified hospitalizations among young adults 18 to 45 years of age with a previous history of stroke or TIA.

They then grouped these patients into those with cannabis use disorder (4,690) and those without cannabis use disorder (156,700). The median age in both cohorts was 37 years.

The analysis did not include those who were considered in remission from cannabis use disorder.

Results showed that 6.9% of those with cannabis use disorder were hospitalized for a recurrent stroke, compared with 5.4% of those without cannabis use disorder (P < .001).

After adjustment for demographic factors (age, sex, race, household income), and pre-existing conditions, patients with cannabis use disorder were 48% more likely to be hospitalized for recurrent stroke than those without cannabis use disorder (odds ratio, 1.48; 95% confidence interval, 1.28-1.71; P < .001).

Compared with the group without cannabis use disorder, the cannabis use disorder group had more men (55.2% vs. 40.2%), more African American people (44.6% vs. 37.2%), and more use of tobacco (73.9% vs. 39.6%) and alcohol (16.5% vs. 3.6%). They also had a greater percentage of chronic obstructive pulmonary disease, depression, and psychoses.

But a smaller percentage of those with cannabis use disorder had hypertension (51.3% vs. 55.6%; P = .001) and diabetes (16.3% vs. 22.7%; P < .001), which is an “interesting” finding, said Dr. Jain.

“We observed that even with a lower rate of cardiovascular risk factors, after controlling for all the risk factors, we still found the cannabis users had a higher rate of recurrent stroke.”

He noted this was a retrospective study without a control group. “If both groups had comparable hypertension, then this risk might actually be more evident,” said Dr. Jain. “We need a prospective study with comparable groups.”

Living in low-income neighborhoods and in northeast and southern regions of the United States was also more common in the cannabis use disorder group.
 

Hypothesis-generating research

The study did not investigate the possible mechanisms by which marijuana use might increase stroke risk, but Dr. Jain speculated that these could include factors such as impaired blood vessel function, changes in blood supply, an increased tendency of blood clotting, impaired energy production in brain cells, and an imbalance between molecules that harm healthy tissue and the antioxidant defenses that neutralize them.

As cannabis use may pose a different risk for a new stroke, as opposed a previous stroke, Dr. Jain said it would be interesting to study the amount of “residual function deficit” experienced with the first stroke.

The new study represents “foundational research” upon which other research teams can build, said Dr. Jain. “Our study is hypothesis-generating research for a future prospective randomized controlled trial.”

A limitation of the study is that it did not consider the effect of various doses, duration, and forms of cannabis abuse, or use of medicinal cannabis or other drugs.

Robert L. Page II, PharmD, professor, departments of clinical pharmacy and physical medicine/rehabilitation, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, provided a comment on this new research.

A cannabis use disorder diagnosis provides “specific criteria” with regard to chronicity of use and reflects “more of a physical and psychological dependence upon cannabis,” said Dr. Page, who chaired the writing group for the AHA 2020 cannabis and cardiovascular disease scientific statement.

He explained what sets people with cannabis use disorder apart from “run-of-the-mill” recreational cannabis users is that “these are individuals who use a cannabis product, whether it’s smoking it, vaping it, or consuming it via an edible, and are using it on a regular basis, in a chronic fashion.”

The study received no outside funding. The authors report no relevant disclosures.

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

Young adults hospitalized for a stroke are much more likely to be admitted for a recurrent stroke if they have cannabis use disorder, new observational research suggests. “Our analysis shows young marijuana users with a history of stroke or transient ischemic attack remain at significantly high risk for future strokes,” said lead study author Akhil Jain, MD, a resident physician at Mercy Fitzgerald Hospital in Darby, Pennsylvania.

“It’s essential to raise awareness among young adults about the impact of chronic habitual use of marijuana, especially if they have established cardiovascular risk factors or previous stroke.”

The study will be presented during the International Stroke Conference, presented by the American Stroke Association, a division of the American Heart Association.

An increasing number of jurisdictions are allowing marijuana use. To date, 18 states and the District of Columbia have legalized recreational cannabis use, the investigators noted.

Research suggests cannabis use disorder – defined as the chronic habitual use of cannabis – is more prevalent in the young adult population. But Dr. Jain said the population of marijuana users is “a changing dynamic.”

Cannabis use has been linked to an increased risk for first-time stroke or transient ischemic attack (TIA). Traditional stroke risk factors include hypertension, diabetes, and diseases related to blood vessels or blood circulation, including atherosclerosis.

Young adults might have additional stroke risk factors, such as behavioral habits like substance abuse, low physical activity, and smoking, oral contraceptives use among females, and brain infections, especially in the immunocompromised, said Dr. Jain.

Research from the American Heart Association shows stroke rates are increasing among adults 18 to 45 years of age. Each year, young adults account for up to 15% of strokes in the United States.

Prevalence and risk for recurrent stroke in patients with previous stroke or TIA in cannabis users have not been clearly established, the researchers pointed out.

A higher rate of recurrent stroke

For this new study, Dr. Jain and colleagues used data from the National Inpatient Sample from October 2015 to December 2017. They identified hospitalizations among young adults 18 to 45 years of age with a previous history of stroke or TIA.

They then grouped these patients into those with cannabis use disorder (4,690) and those without cannabis use disorder (156,700). The median age in both cohorts was 37 years.

The analysis did not include those who were considered in remission from cannabis use disorder.

Results showed that 6.9% of those with cannabis use disorder were hospitalized for a recurrent stroke, compared with 5.4% of those without cannabis use disorder (P < .001).

After adjustment for demographic factors (age, sex, race, household income), and pre-existing conditions, patients with cannabis use disorder were 48% more likely to be hospitalized for recurrent stroke than those without cannabis use disorder (odds ratio, 1.48; 95% confidence interval, 1.28-1.71; P < .001).

Compared with the group without cannabis use disorder, the cannabis use disorder group had more men (55.2% vs. 40.2%), more African American people (44.6% vs. 37.2%), and more use of tobacco (73.9% vs. 39.6%) and alcohol (16.5% vs. 3.6%). They also had a greater percentage of chronic obstructive pulmonary disease, depression, and psychoses.

But a smaller percentage of those with cannabis use disorder had hypertension (51.3% vs. 55.6%; P = .001) and diabetes (16.3% vs. 22.7%; P < .001), which is an “interesting” finding, said Dr. Jain.

“We observed that even with a lower rate of cardiovascular risk factors, after controlling for all the risk factors, we still found the cannabis users had a higher rate of recurrent stroke.”

He noted this was a retrospective study without a control group. “If both groups had comparable hypertension, then this risk might actually be more evident,” said Dr. Jain. “We need a prospective study with comparable groups.”

Living in low-income neighborhoods and in northeast and southern regions of the United States was also more common in the cannabis use disorder group.
 

Hypothesis-generating research

The study did not investigate the possible mechanisms by which marijuana use might increase stroke risk, but Dr. Jain speculated that these could include factors such as impaired blood vessel function, changes in blood supply, an increased tendency of blood clotting, impaired energy production in brain cells, and an imbalance between molecules that harm healthy tissue and the antioxidant defenses that neutralize them.

As cannabis use may pose a different risk for a new stroke, as opposed a previous stroke, Dr. Jain said it would be interesting to study the amount of “residual function deficit” experienced with the first stroke.

The new study represents “foundational research” upon which other research teams can build, said Dr. Jain. “Our study is hypothesis-generating research for a future prospective randomized controlled trial.”

A limitation of the study is that it did not consider the effect of various doses, duration, and forms of cannabis abuse, or use of medicinal cannabis or other drugs.

Robert L. Page II, PharmD, professor, departments of clinical pharmacy and physical medicine/rehabilitation, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, provided a comment on this new research.

A cannabis use disorder diagnosis provides “specific criteria” with regard to chronicity of use and reflects “more of a physical and psychological dependence upon cannabis,” said Dr. Page, who chaired the writing group for the AHA 2020 cannabis and cardiovascular disease scientific statement.

He explained what sets people with cannabis use disorder apart from “run-of-the-mill” recreational cannabis users is that “these are individuals who use a cannabis product, whether it’s smoking it, vaping it, or consuming it via an edible, and are using it on a regular basis, in a chronic fashion.”

The study received no outside funding. The authors report no relevant disclosures.

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

A new study finding that samples from maternal urine and the meconium of their newborn babies frequently produce different results is raising more questions about drug testing of pregnant women.

The study found concerningly high rates of disagreement (or “discordance”) in biochemical testing between maternal urine in women with a documented history of or active drug use and the meconium in their newborns. In some cases, such discordance might be triggering the inappropriate intervention of childcare protective services, including the separation of infants from their mothers, according to the researchers, who presented their findings Feb. 4 at the meeting sponsored by the Society for Maternal-Fetal Medicine.

“There’s a very big debate right now in the obstetrics and perinatology communities about the utility of biochemical testing and the identification of high-risk women,” lead author Cassandra Heiselman, DO, MPH, clinical assistant professor in the department of obstetrics, gynecology and reproductive medicine at Stony Brook (N.Y.) University, said in an interview. “We know that each biochemical test has limitations, which can include basically the inability to detect all substances, especially synthetic opioids like fentanyl, [and] the possibility for false results.”

Inaccuracies in testing can potentially result in inappropriate separation of mother and baby. “Careful scrutiny of results is needed,” Dr. Heiselman said.

The Stony Brook team conducted a retrospective cohort study that identified women presenting for delivery from January 2017 to March 2021 with indications for drug testing, including a known history of or current substance use disorder/misuse, and late or no prenatal care. A standardized panel was used for testing maternal urine and newborn meconium.

Urine tests of 327 women resulted in 187 (57%) positive and 98 (30%) negative results, along with 42 (13%) samples with incomplete data, the researchers reported. In contrast, drug testing of newborn meconium was positive in 273 (83%) cases, negative in 42 (13%), and was not performed in 12 (4%) – for a rate of concordance of 41%.

Concordance of urine/meconium occurred more frequently in male newborns (65%), compared with females (35%). “It is unclear biologically why there is such a difference based on the sex of the infants’ test and is an area that needs further investigation,” Dr. Heiselman said.

Comparing urine and meconium tests for 11 substances resulted in 195/483 (40%) concordance, the researchers said; 18% were discordant with positive maternal urine, and 41% were discordant with newborn positive meconium.

Oxycodone and fentanyl were significantly discordant with positive maternal urine. Cannabis use was the most common factor associated with a positive test of meconium, according to the researchers.

“Some studies have shown cannabis use in the second trimester can show up in meconium testing even if the mother has stopped that behavior,” Dr. Heiselman said. “Then there is also cross-reactivity with other substances that can lead to higher false positive results, especially in the urine toxicology.”

The reasons for the discordant results are not clear and vary by substance, Dr. Heiselman said.

“Cannabis and methadone were the significant factors leading to discordance with positive newborn meconium, which may reflect prior use earlier in pregnancy without recent use before delivery,” she said in an interview. “Urine and meconium reflect potentially different timing in perinatal exposure and the potential differences in windows of detection for different substances. Therefore, we would expect some discordance in our comparisons, just not the extent that we saw.”

Some test results might also have been false positives. Many commonly used medications, from cough syrups to proton pump inhibitors, have the potential to generate positive results for illicit drugs, Dr. Heiselman said.

“The issue of discordance is a complex one, where there are limitations of the tests being performed, possible cross-reactivity with false positives, and the difference in what test reflects as far as timing of prenatal exposure. Furthermore, a negative test does not rule out sporadic use, nor does a positive result diagnose substance use disorder or its severity,” she said.
 

Lack of standards

Dr. Heiselman said states and the federal government lack standards to biochemically evaluate women at risk for drug abuse and their newborns.

“My institution uses a risk-based protocol. Basically, we test cases where we have a known history of substance use disorder or active use, a history in the last 3 years of any kind of substance use, initiation of late prenatal care after 20 weeks, or no prenatal care at all,” she said. “And then the pediatricians on the other side will test neonates if the mother has any of that history or if the neonates themselves have unexplained complications or drug withdrawal symptoms.”

High rates of discordance can result in the inappropriate intervention by childcare protective service agencies when the mother may not have a substance use disorder, she noted.

Perinatologist Kecia Gaither, MD, MPH, associate professor of clinical obstetrics and gynecology at Weill Cornell Medicine, New York, called the findings “no surprise,” but added that negative findings in neonates “do not exclude the possibility of substance abuse by the mother. It is important to recognize the limitations inherent with screening tests for illicit substances in neonates from substance-abusing mothers.”

Dr. Heiselman added that understanding what maternal and infant drug tests truly reflect “can help us as clinicians in deciding when we test, whether it’s medically necessary, instead of just thinking biochemical tests are the best screening tool, because we know that we are screening. We must engage these women in empathetic and nonjudgmental discussions, which often will elucidate a substance use disorder history more so than just biochemical testing, negative or positive.”

The researchers disclosed no relevant financial relationships.

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

A new study finding that samples from maternal urine and the meconium of their newborn babies frequently produce different results is raising more questions about drug testing of pregnant women.

The study found concerningly high rates of disagreement (or “discordance”) in biochemical testing between maternal urine in women with a documented history of or active drug use and the meconium in their newborns. In some cases, such discordance might be triggering the inappropriate intervention of childcare protective services, including the separation of infants from their mothers, according to the researchers, who presented their findings Feb. 4 at the meeting sponsored by the Society for Maternal-Fetal Medicine.

“There’s a very big debate right now in the obstetrics and perinatology communities about the utility of biochemical testing and the identification of high-risk women,” lead author Cassandra Heiselman, DO, MPH, clinical assistant professor in the department of obstetrics, gynecology and reproductive medicine at Stony Brook (N.Y.) University, said in an interview. “We know that each biochemical test has limitations, which can include basically the inability to detect all substances, especially synthetic opioids like fentanyl, [and] the possibility for false results.”

Inaccuracies in testing can potentially result in inappropriate separation of mother and baby. “Careful scrutiny of results is needed,” Dr. Heiselman said.

The Stony Brook team conducted a retrospective cohort study that identified women presenting for delivery from January 2017 to March 2021 with indications for drug testing, including a known history of or current substance use disorder/misuse, and late or no prenatal care. A standardized panel was used for testing maternal urine and newborn meconium.

Urine tests of 327 women resulted in 187 (57%) positive and 98 (30%) negative results, along with 42 (13%) samples with incomplete data, the researchers reported. In contrast, drug testing of newborn meconium was positive in 273 (83%) cases, negative in 42 (13%), and was not performed in 12 (4%) – for a rate of concordance of 41%.

Concordance of urine/meconium occurred more frequently in male newborns (65%), compared with females (35%). “It is unclear biologically why there is such a difference based on the sex of the infants’ test and is an area that needs further investigation,” Dr. Heiselman said.

Comparing urine and meconium tests for 11 substances resulted in 195/483 (40%) concordance, the researchers said; 18% were discordant with positive maternal urine, and 41% were discordant with newborn positive meconium.

Oxycodone and fentanyl were significantly discordant with positive maternal urine. Cannabis use was the most common factor associated with a positive test of meconium, according to the researchers.

“Some studies have shown cannabis use in the second trimester can show up in meconium testing even if the mother has stopped that behavior,” Dr. Heiselman said. “Then there is also cross-reactivity with other substances that can lead to higher false positive results, especially in the urine toxicology.”

The reasons for the discordant results are not clear and vary by substance, Dr. Heiselman said.

“Cannabis and methadone were the significant factors leading to discordance with positive newborn meconium, which may reflect prior use earlier in pregnancy without recent use before delivery,” she said in an interview. “Urine and meconium reflect potentially different timing in perinatal exposure and the potential differences in windows of detection for different substances. Therefore, we would expect some discordance in our comparisons, just not the extent that we saw.”

Some test results might also have been false positives. Many commonly used medications, from cough syrups to proton pump inhibitors, have the potential to generate positive results for illicit drugs, Dr. Heiselman said.

“The issue of discordance is a complex one, where there are limitations of the tests being performed, possible cross-reactivity with false positives, and the difference in what test reflects as far as timing of prenatal exposure. Furthermore, a negative test does not rule out sporadic use, nor does a positive result diagnose substance use disorder or its severity,” she said.
 

Lack of standards

Dr. Heiselman said states and the federal government lack standards to biochemically evaluate women at risk for drug abuse and their newborns.

“My institution uses a risk-based protocol. Basically, we test cases where we have a known history of substance use disorder or active use, a history in the last 3 years of any kind of substance use, initiation of late prenatal care after 20 weeks, or no prenatal care at all,” she said. “And then the pediatricians on the other side will test neonates if the mother has any of that history or if the neonates themselves have unexplained complications or drug withdrawal symptoms.”

High rates of discordance can result in the inappropriate intervention by childcare protective service agencies when the mother may not have a substance use disorder, she noted.

Perinatologist Kecia Gaither, MD, MPH, associate professor of clinical obstetrics and gynecology at Weill Cornell Medicine, New York, called the findings “no surprise,” but added that negative findings in neonates “do not exclude the possibility of substance abuse by the mother. It is important to recognize the limitations inherent with screening tests for illicit substances in neonates from substance-abusing mothers.”

Dr. Heiselman added that understanding what maternal and infant drug tests truly reflect “can help us as clinicians in deciding when we test, whether it’s medically necessary, instead of just thinking biochemical tests are the best screening tool, because we know that we are screening. We must engage these women in empathetic and nonjudgmental discussions, which often will elucidate a substance use disorder history more so than just biochemical testing, negative or positive.”

The researchers disclosed no relevant financial relationships.

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

A new study finding that samples from maternal urine and the meconium of their newborn babies frequently produce different results is raising more questions about drug testing of pregnant women.

The study found concerningly high rates of disagreement (or “discordance”) in biochemical testing between maternal urine in women with a documented history of or active drug use and the meconium in their newborns. In some cases, such discordance might be triggering the inappropriate intervention of childcare protective services, including the separation of infants from their mothers, according to the researchers, who presented their findings Feb. 4 at the meeting sponsored by the Society for Maternal-Fetal Medicine.

“There’s a very big debate right now in the obstetrics and perinatology communities about the utility of biochemical testing and the identification of high-risk women,” lead author Cassandra Heiselman, DO, MPH, clinical assistant professor in the department of obstetrics, gynecology and reproductive medicine at Stony Brook (N.Y.) University, said in an interview. “We know that each biochemical test has limitations, which can include basically the inability to detect all substances, especially synthetic opioids like fentanyl, [and] the possibility for false results.”

Inaccuracies in testing can potentially result in inappropriate separation of mother and baby. “Careful scrutiny of results is needed,” Dr. Heiselman said.

The Stony Brook team conducted a retrospective cohort study that identified women presenting for delivery from January 2017 to March 2021 with indications for drug testing, including a known history of or current substance use disorder/misuse, and late or no prenatal care. A standardized panel was used for testing maternal urine and newborn meconium.

Urine tests of 327 women resulted in 187 (57%) positive and 98 (30%) negative results, along with 42 (13%) samples with incomplete data, the researchers reported. In contrast, drug testing of newborn meconium was positive in 273 (83%) cases, negative in 42 (13%), and was not performed in 12 (4%) – for a rate of concordance of 41%.

Concordance of urine/meconium occurred more frequently in male newborns (65%), compared with females (35%). “It is unclear biologically why there is such a difference based on the sex of the infants’ test and is an area that needs further investigation,” Dr. Heiselman said.

Comparing urine and meconium tests for 11 substances resulted in 195/483 (40%) concordance, the researchers said; 18% were discordant with positive maternal urine, and 41% were discordant with newborn positive meconium.

Oxycodone and fentanyl were significantly discordant with positive maternal urine. Cannabis use was the most common factor associated with a positive test of meconium, according to the researchers.

“Some studies have shown cannabis use in the second trimester can show up in meconium testing even if the mother has stopped that behavior,” Dr. Heiselman said. “Then there is also cross-reactivity with other substances that can lead to higher false positive results, especially in the urine toxicology.”

The reasons for the discordant results are not clear and vary by substance, Dr. Heiselman said.

“Cannabis and methadone were the significant factors leading to discordance with positive newborn meconium, which may reflect prior use earlier in pregnancy without recent use before delivery,” she said in an interview. “Urine and meconium reflect potentially different timing in perinatal exposure and the potential differences in windows of detection for different substances. Therefore, we would expect some discordance in our comparisons, just not the extent that we saw.”

Some test results might also have been false positives. Many commonly used medications, from cough syrups to proton pump inhibitors, have the potential to generate positive results for illicit drugs, Dr. Heiselman said.

“The issue of discordance is a complex one, where there are limitations of the tests being performed, possible cross-reactivity with false positives, and the difference in what test reflects as far as timing of prenatal exposure. Furthermore, a negative test does not rule out sporadic use, nor does a positive result diagnose substance use disorder or its severity,” she said.
 

Lack of standards

Dr. Heiselman said states and the federal government lack standards to biochemically evaluate women at risk for drug abuse and their newborns.

“My institution uses a risk-based protocol. Basically, we test cases where we have a known history of substance use disorder or active use, a history in the last 3 years of any kind of substance use, initiation of late prenatal care after 20 weeks, or no prenatal care at all,” she said. “And then the pediatricians on the other side will test neonates if the mother has any of that history or if the neonates themselves have unexplained complications or drug withdrawal symptoms.”

High rates of discordance can result in the inappropriate intervention by childcare protective service agencies when the mother may not have a substance use disorder, she noted.

Perinatologist Kecia Gaither, MD, MPH, associate professor of clinical obstetrics and gynecology at Weill Cornell Medicine, New York, called the findings “no surprise,” but added that negative findings in neonates “do not exclude the possibility of substance abuse by the mother. It is important to recognize the limitations inherent with screening tests for illicit substances in neonates from substance-abusing mothers.”

Dr. Heiselman added that understanding what maternal and infant drug tests truly reflect “can help us as clinicians in deciding when we test, whether it’s medically necessary, instead of just thinking biochemical tests are the best screening tool, because we know that we are screening. We must engage these women in empathetic and nonjudgmental discussions, which often will elucidate a substance use disorder history more so than just biochemical testing, negative or positive.”

The researchers disclosed no relevant financial relationships.

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

Hundreds of Native American tribes have tentatively settled in what one of the lead attorneys describes as “an epic deal”: The top 3 pharmaceutical distributors in the US and Johnson & Johnson have agreed to pay $665 million for deceptive marketing practices and overdistribution of opioids. Native Americans were among those hardest hit by the opioid epidemic. Between 2006 and 2014, Native Americans were nearly 50% more likely than non-Natives to die of an opioid overdose. In 2014, they ranked number 1 for death by opioid overdose.

Overprescribing was rampant. In some areas, such as southwestern Virginia, eastern Kentucky, and Alabama, prescriptions were 5 to 6 times higher than the national average. The overprescribing was largely due to massive and aggressive billion-dollar marketing campaigns, which misrepresented the safety of opioid medications. Purdue Pharma, for instance, trained sales representatives to claim that the risk of addiction was “less than 1 percent.” In an interview with Smithsonian Magazine, Caleb Alexander, MD, codirector of Johns Hopkins’ Center for Drug Safety and Effectiveness, said, “When I was in residency training, we were taught that one needn’t worry about the addictive potential of opioids if a patient had true pain.” He said it was no accident that physicians were cultivated to overestimate the effectiveness for chronic, noncancer pain while underestimating the risks.

Native Americans were not only in the target group for prescriptions, but also apparently singularly targeted. “We were preyed upon,” said Chickasaw Nation Governor Bill Anoatubby in the Washington Post. “It was unconscionable.” A Washington Post analysis found that, between 2006 and 2014, opioid distributors shipped an average of 36 pills per person in the US. States in the so-called opioid belt (mostly Southern states), received an average of 60 to 66 pills per person. The distributors shipped 57 pills per person to Oklahoma, home to nearly 322,000 Native Americans. (The opioid death rate for Native Americans in Oklahoma from 2006 to 2014 was more than triple the nationwide rate for non-Natives.) In South Dakota as recently as 2015, enough opioids were prescribed to medicate every adult around-the-clock for 19 consecutive days. Native Americans comprise 9% of South Dakota’s population; however, almost 30% of the patients are being treated for opioid use disorder.

In the settlement, which is a first for tribes, McKesson, Cardinal Health, and AmerisourceBergen would pay $515 million over 7 years. Johnson & Johnson would contribute $150 million in 2 years to the federally recognized tribes. “This settlement is a real turning point in history,” said Lloyd Miller, one of the attorneys representing one-third of the litigating tribes.

But the money is still small compensation for ravaging millions of lives. “Flooding the Native community with Western medicine—sedating a population rather than seeking to understand its needs and challenges—is not an acceptable means of handling its trauma,” the Lakota People’s Law Project says in an article on its website. Thus, the money dispersal will be overseen by a panel of tribal health experts, to go toward programs that aid drug users and their communities.

The funds will be managed in a way that will consider the long-term damage, Native American leaders vow. Children, for instance, have not been exempt from the sequelae of the overprescribing. Foster care systems are “overrun” with children of addicted parents, the Law Project says, and the children are placed in homes outside the tribe. “In the long run, this has the potential to curtail tribal membership, break down familial lines, and degrade cultural values.”

Dealing with the problem has drained tribal resources—doubly strained by the COVID-19 epidemic. Chairman Douglas Yankton, of the Spirit Lake Nation in North Dakota, said in a statement, “The dollars that will flow to Tribes under this initial settlement will help fund crucial, on-reservation, culturally appropriate opioid treatment services.”

However, Chairman Kristopher Peters, of the Squaxin Island Tribe in Washington State, told the Washington Post, “There is no amount of money that’s going to solve the generational issues that have been created from this. Our hope is that we can use these funds to help revitalize our culture and help heal our people.”

Johnson & Johnson says it no longer sells prescription opioids in the US

Hundreds of Native American tribes have tentatively settled in what one of the lead attorneys describes as “an epic deal”: The top 3 pharmaceutical distributors in the US and Johnson & Johnson have agreed to pay $665 million for deceptive marketing practices and overdistribution of opioids. Native Americans were among those hardest hit by the opioid epidemic. Between 2006 and 2014, Native Americans were nearly 50% more likely than non-Natives to die of an opioid overdose. In 2014, they ranked number 1 for death by opioid overdose.

Overprescribing was rampant. In some areas, such as southwestern Virginia, eastern Kentucky, and Alabama, prescriptions were 5 to 6 times higher than the national average. The overprescribing was largely due to massive and aggressive billion-dollar marketing campaigns, which misrepresented the safety of opioid medications. Purdue Pharma, for instance, trained sales representatives to claim that the risk of addiction was “less than 1 percent.” In an interview with Smithsonian Magazine, Caleb Alexander, MD, codirector of Johns Hopkins’ Center for Drug Safety and Effectiveness, said, “When I was in residency training, we were taught that one needn’t worry about the addictive potential of opioids if a patient had true pain.” He said it was no accident that physicians were cultivated to overestimate the effectiveness for chronic, noncancer pain while underestimating the risks.

Native Americans were not only in the target group for prescriptions, but also apparently singularly targeted. “We were preyed upon,” said Chickasaw Nation Governor Bill Anoatubby in the Washington Post. “It was unconscionable.” A Washington Post analysis found that, between 2006 and 2014, opioid distributors shipped an average of 36 pills per person in the US. States in the so-called opioid belt (mostly Southern states), received an average of 60 to 66 pills per person. The distributors shipped 57 pills per person to Oklahoma, home to nearly 322,000 Native Americans. (The opioid death rate for Native Americans in Oklahoma from 2006 to 2014 was more than triple the nationwide rate for non-Natives.) In South Dakota as recently as 2015, enough opioids were prescribed to medicate every adult around-the-clock for 19 consecutive days. Native Americans comprise 9% of South Dakota’s population; however, almost 30% of the patients are being treated for opioid use disorder.

In the settlement, which is a first for tribes, McKesson, Cardinal Health, and AmerisourceBergen would pay $515 million over 7 years. Johnson & Johnson would contribute $150 million in 2 years to the federally recognized tribes. “This settlement is a real turning point in history,” said Lloyd Miller, one of the attorneys representing one-third of the litigating tribes.

But the money is still small compensation for ravaging millions of lives. “Flooding the Native community with Western medicine—sedating a population rather than seeking to understand its needs and challenges—is not an acceptable means of handling its trauma,” the Lakota People’s Law Project says in an article on its website. Thus, the money dispersal will be overseen by a panel of tribal health experts, to go toward programs that aid drug users and their communities.

The funds will be managed in a way that will consider the long-term damage, Native American leaders vow. Children, for instance, have not been exempt from the sequelae of the overprescribing. Foster care systems are “overrun” with children of addicted parents, the Law Project says, and the children are placed in homes outside the tribe. “In the long run, this has the potential to curtail tribal membership, break down familial lines, and degrade cultural values.”

Dealing with the problem has drained tribal resources—doubly strained by the COVID-19 epidemic. Chairman Douglas Yankton, of the Spirit Lake Nation in North Dakota, said in a statement, “The dollars that will flow to Tribes under this initial settlement will help fund crucial, on-reservation, culturally appropriate opioid treatment services.”

However, Chairman Kristopher Peters, of the Squaxin Island Tribe in Washington State, told the Washington Post, “There is no amount of money that’s going to solve the generational issues that have been created from this. Our hope is that we can use these funds to help revitalize our culture and help heal our people.”

Johnson & Johnson says it no longer sells prescription opioids in the US

Hundreds of Native American tribes have tentatively settled in what one of the lead attorneys describes as “an epic deal”: The top 3 pharmaceutical distributors in the US and Johnson & Johnson have agreed to pay $665 million for deceptive marketing practices and overdistribution of opioids. Native Americans were among those hardest hit by the opioid epidemic. Between 2006 and 2014, Native Americans were nearly 50% more likely than non-Natives to die of an opioid overdose. In 2014, they ranked number 1 for death by opioid overdose.

Overprescribing was rampant. In some areas, such as southwestern Virginia, eastern Kentucky, and Alabama, prescriptions were 5 to 6 times higher than the national average. The overprescribing was largely due to massive and aggressive billion-dollar marketing campaigns, which misrepresented the safety of opioid medications. Purdue Pharma, for instance, trained sales representatives to claim that the risk of addiction was “less than 1 percent.” In an interview with Smithsonian Magazine, Caleb Alexander, MD, codirector of Johns Hopkins’ Center for Drug Safety and Effectiveness, said, “When I was in residency training, we were taught that one needn’t worry about the addictive potential of opioids if a patient had true pain.” He said it was no accident that physicians were cultivated to overestimate the effectiveness for chronic, noncancer pain while underestimating the risks.

Native Americans were not only in the target group for prescriptions, but also apparently singularly targeted. “We were preyed upon,” said Chickasaw Nation Governor Bill Anoatubby in the Washington Post. “It was unconscionable.” A Washington Post analysis found that, between 2006 and 2014, opioid distributors shipped an average of 36 pills per person in the US. States in the so-called opioid belt (mostly Southern states), received an average of 60 to 66 pills per person. The distributors shipped 57 pills per person to Oklahoma, home to nearly 322,000 Native Americans. (The opioid death rate for Native Americans in Oklahoma from 2006 to 2014 was more than triple the nationwide rate for non-Natives.) In South Dakota as recently as 2015, enough opioids were prescribed to medicate every adult around-the-clock for 19 consecutive days. Native Americans comprise 9% of South Dakota’s population; however, almost 30% of the patients are being treated for opioid use disorder.

In the settlement, which is a first for tribes, McKesson, Cardinal Health, and AmerisourceBergen would pay $515 million over 7 years. Johnson & Johnson would contribute $150 million in 2 years to the federally recognized tribes. “This settlement is a real turning point in history,” said Lloyd Miller, one of the attorneys representing one-third of the litigating tribes.

But the money is still small compensation for ravaging millions of lives. “Flooding the Native community with Western medicine—sedating a population rather than seeking to understand its needs and challenges—is not an acceptable means of handling its trauma,” the Lakota People’s Law Project says in an article on its website. Thus, the money dispersal will be overseen by a panel of tribal health experts, to go toward programs that aid drug users and their communities.

The funds will be managed in a way that will consider the long-term damage, Native American leaders vow. Children, for instance, have not been exempt from the sequelae of the overprescribing. Foster care systems are “overrun” with children of addicted parents, the Law Project says, and the children are placed in homes outside the tribe. “In the long run, this has the potential to curtail tribal membership, break down familial lines, and degrade cultural values.”

Dealing with the problem has drained tribal resources—doubly strained by the COVID-19 epidemic. Chairman Douglas Yankton, of the Spirit Lake Nation in North Dakota, said in a statement, “The dollars that will flow to Tribes under this initial settlement will help fund crucial, on-reservation, culturally appropriate opioid treatment services.”

However, Chairman Kristopher Peters, of the Squaxin Island Tribe in Washington State, told the Washington Post, “There is no amount of money that’s going to solve the generational issues that have been created from this. Our hope is that we can use these funds to help revitalize our culture and help heal our people.”

Johnson & Johnson says it no longer sells prescription opioids in the US

Exposure to opioid analgesics during the first trimester of pregnancy appears to increase the risk of congenital anomalies diagnosed in the first year of life, researchers report.

While the absolute risk of congenital anomalies was low, these findings add to an increasing body of evidence suggesting that prenatal exposure to opioids may confer harm to infants post partum.

“We undertook a population-based cohort study to estimate associations between opioid analgesic exposure during the first trimester and congenital anomalies using health administrative data capturing all narcotic prescriptions during pregnancy,” lead author Alexa C. Bowie, MPH, of Queen’s University in Kingston, Ont., and colleagues reported in CMAJ.

The researchers retrospectively reviewed administrative health data in a single-payer health care system from 2013 to 2018. They identified parent-infant pair records for all live births and stillbirths that occurred at more than 20 weeks’ gestation.

The exposure of interest was a prescription for any opioid analgesic with a fill date between the estimated date of conception and less than 14 weeks’ gestation. The referent group included any infant not exposed to an opioid analgesic during the index pregnancy period.
 

Results

The study cohort included a total of 599,579 gestational parent-infant pairs. Of these, 11,903 (2.0%) were exposed to opioid analgesics, and most were exposed during the first trimester only (75.8%).

Overall, 2.0% of these infants developed a congenital anomaly during the first year of life; the prevalence of congenital anomalies was 2.0% in unexposed infants and 2.8% in exposed infants.

Relative to unexposed infants, the researchers observed greater risks among infants who were exposed for some anomaly groups, including many specific anomalies, such as ankyloglossia (any opioid: adjusted risk ratio, 1.88; 95% confidence interval, 1.30-2.72; codeine: aRR, 2.14; 95% CI, 1.35-3.40), as well as gastrointestinal anomalies (any opioid: aRR, 1.46; 95% CI, 1.15-1.85; codeine: aRR, 1.53; 95% CI, 1.12-2.09; tramadol: aRR, 2.69; 95% CI 1.34-5.38).

After sensitivity analyses, which included exposure 4 weeks before conception or excluded individuals with exposure to opioid analgesics before pregnancy, the findings remained unchanged.

“Although the overall risk was low, we observed an increased risk of any congenital anomaly with tramadol, and a previously unreported risk with morphine,” the researchers wrote.

“Previous studies reported elevated risks of heart anomalies with first-trimester exposure to any opioid analgesic, codeine, and tramadol, but others reported no association with any opioid analgesic or codeine,” they explained.
 

Interpreting the results

Study author Susan Brogly, PhD, of Queen’s University said “Our population-based study confirms evidence of a small increased risk of birth defects from opioid analgesic exposure in the first trimester that was observed in a recent study of private insurance and Medicaid beneficiaries in the U.S. We further show that this small increased risk is not due to other risk factors for fetal harm in women who may take these medications.”

“An opioid prescription dispensed in the first trimester would imply that there was an acute injury or chronic condition also present in the first trimester, which may also be associated with congenital abnormalities,” commented Elisabeth Poorman, MD, MPH, a clinical instructor and primary care physician at the University of Washington in Seattle.

“Opioid use disorder is often diagnosed incorrectly; since the researchers used diagnostic billing codes to exclude individuals with opioid use disorder, some women may have been missed,” Dr. Poorman explained.

Ms. Bowie and colleagues acknowledged that a key limitation of the study was the identification of cases using diagnostic billing codes. As a result, exposure-dependent recording bias could be present and limit the applicability of the findings.

“The diagnosis and documentation of minor anomalies and those with subtle medical significance could be vulnerable to exposure-dependent recording bias,” Ms. Bowie wrote.

Dr. Poorman recommended that these results should be interpreted with caution given these and other limitations. “Overall, results from this study may imply that there is limited evidence to suspect opioids are related to congenital abnormalities due to a very small difference observed in relatively unequal groups,” she concluded.

This study received funding from the Eunice Kennedy Shriver National Institutes of Child Health and Human Development and was also supported by the Institute for Clinical Evaluative Sciences, which is funded by an annual grant from the Ontario Ministry of Health. One author reported receiving honoraria from the National Institutes of Health and a grant from the Canadian Institute of Health Research, outside the submitted work. No other competing interests were declared.

Exposure to opioid analgesics during the first trimester of pregnancy appears to increase the risk of congenital anomalies diagnosed in the first year of life, researchers report.

While the absolute risk of congenital anomalies was low, these findings add to an increasing body of evidence suggesting that prenatal exposure to opioids may confer harm to infants post partum.

“We undertook a population-based cohort study to estimate associations between opioid analgesic exposure during the first trimester and congenital anomalies using health administrative data capturing all narcotic prescriptions during pregnancy,” lead author Alexa C. Bowie, MPH, of Queen’s University in Kingston, Ont., and colleagues reported in CMAJ.

The researchers retrospectively reviewed administrative health data in a single-payer health care system from 2013 to 2018. They identified parent-infant pair records for all live births and stillbirths that occurred at more than 20 weeks’ gestation.

The exposure of interest was a prescription for any opioid analgesic with a fill date between the estimated date of conception and less than 14 weeks’ gestation. The referent group included any infant not exposed to an opioid analgesic during the index pregnancy period.
 

Results

The study cohort included a total of 599,579 gestational parent-infant pairs. Of these, 11,903 (2.0%) were exposed to opioid analgesics, and most were exposed during the first trimester only (75.8%).

Overall, 2.0% of these infants developed a congenital anomaly during the first year of life; the prevalence of congenital anomalies was 2.0% in unexposed infants and 2.8% in exposed infants.

Relative to unexposed infants, the researchers observed greater risks among infants who were exposed for some anomaly groups, including many specific anomalies, such as ankyloglossia (any opioid: adjusted risk ratio, 1.88; 95% confidence interval, 1.30-2.72; codeine: aRR, 2.14; 95% CI, 1.35-3.40), as well as gastrointestinal anomalies (any opioid: aRR, 1.46; 95% CI, 1.15-1.85; codeine: aRR, 1.53; 95% CI, 1.12-2.09; tramadol: aRR, 2.69; 95% CI 1.34-5.38).

After sensitivity analyses, which included exposure 4 weeks before conception or excluded individuals with exposure to opioid analgesics before pregnancy, the findings remained unchanged.

“Although the overall risk was low, we observed an increased risk of any congenital anomaly with tramadol, and a previously unreported risk with morphine,” the researchers wrote.

“Previous studies reported elevated risks of heart anomalies with first-trimester exposure to any opioid analgesic, codeine, and tramadol, but others reported no association with any opioid analgesic or codeine,” they explained.
 

Interpreting the results

Study author Susan Brogly, PhD, of Queen’s University said “Our population-based study confirms evidence of a small increased risk of birth defects from opioid analgesic exposure in the first trimester that was observed in a recent study of private insurance and Medicaid beneficiaries in the U.S. We further show that this small increased risk is not due to other risk factors for fetal harm in women who may take these medications.”

“An opioid prescription dispensed in the first trimester would imply that there was an acute injury or chronic condition also present in the first trimester, which may also be associated with congenital abnormalities,” commented Elisabeth Poorman, MD, MPH, a clinical instructor and primary care physician at the University of Washington in Seattle.

“Opioid use disorder is often diagnosed incorrectly; since the researchers used diagnostic billing codes to exclude individuals with opioid use disorder, some women may have been missed,” Dr. Poorman explained.

Ms. Bowie and colleagues acknowledged that a key limitation of the study was the identification of cases using diagnostic billing codes. As a result, exposure-dependent recording bias could be present and limit the applicability of the findings.

“The diagnosis and documentation of minor anomalies and those with subtle medical significance could be vulnerable to exposure-dependent recording bias,” Ms. Bowie wrote.

Dr. Poorman recommended that these results should be interpreted with caution given these and other limitations. “Overall, results from this study may imply that there is limited evidence to suspect opioids are related to congenital abnormalities due to a very small difference observed in relatively unequal groups,” she concluded.

This study received funding from the Eunice Kennedy Shriver National Institutes of Child Health and Human Development and was also supported by the Institute for Clinical Evaluative Sciences, which is funded by an annual grant from the Ontario Ministry of Health. One author reported receiving honoraria from the National Institutes of Health and a grant from the Canadian Institute of Health Research, outside the submitted work. No other competing interests were declared.

Exposure to opioid analgesics during the first trimester of pregnancy appears to increase the risk of congenital anomalies diagnosed in the first year of life, researchers report.

While the absolute risk of congenital anomalies was low, these findings add to an increasing body of evidence suggesting that prenatal exposure to opioids may confer harm to infants post partum.

“We undertook a population-based cohort study to estimate associations between opioid analgesic exposure during the first trimester and congenital anomalies using health administrative data capturing all narcotic prescriptions during pregnancy,” lead author Alexa C. Bowie, MPH, of Queen’s University in Kingston, Ont., and colleagues reported in CMAJ.

The researchers retrospectively reviewed administrative health data in a single-payer health care system from 2013 to 2018. They identified parent-infant pair records for all live births and stillbirths that occurred at more than 20 weeks’ gestation.

The exposure of interest was a prescription for any opioid analgesic with a fill date between the estimated date of conception and less than 14 weeks’ gestation. The referent group included any infant not exposed to an opioid analgesic during the index pregnancy period.
 

Results

The study cohort included a total of 599,579 gestational parent-infant pairs. Of these, 11,903 (2.0%) were exposed to opioid analgesics, and most were exposed during the first trimester only (75.8%).

Overall, 2.0% of these infants developed a congenital anomaly during the first year of life; the prevalence of congenital anomalies was 2.0% in unexposed infants and 2.8% in exposed infants.

Relative to unexposed infants, the researchers observed greater risks among infants who were exposed for some anomaly groups, including many specific anomalies, such as ankyloglossia (any opioid: adjusted risk ratio, 1.88; 95% confidence interval, 1.30-2.72; codeine: aRR, 2.14; 95% CI, 1.35-3.40), as well as gastrointestinal anomalies (any opioid: aRR, 1.46; 95% CI, 1.15-1.85; codeine: aRR, 1.53; 95% CI, 1.12-2.09; tramadol: aRR, 2.69; 95% CI 1.34-5.38).

After sensitivity analyses, which included exposure 4 weeks before conception or excluded individuals with exposure to opioid analgesics before pregnancy, the findings remained unchanged.

“Although the overall risk was low, we observed an increased risk of any congenital anomaly with tramadol, and a previously unreported risk with morphine,” the researchers wrote.

“Previous studies reported elevated risks of heart anomalies with first-trimester exposure to any opioid analgesic, codeine, and tramadol, but others reported no association with any opioid analgesic or codeine,” they explained.
 

Interpreting the results

Study author Susan Brogly, PhD, of Queen’s University said “Our population-based study confirms evidence of a small increased risk of birth defects from opioid analgesic exposure in the first trimester that was observed in a recent study of private insurance and Medicaid beneficiaries in the U.S. We further show that this small increased risk is not due to other risk factors for fetal harm in women who may take these medications.”

“An opioid prescription dispensed in the first trimester would imply that there was an acute injury or chronic condition also present in the first trimester, which may also be associated with congenital abnormalities,” commented Elisabeth Poorman, MD, MPH, a clinical instructor and primary care physician at the University of Washington in Seattle.

“Opioid use disorder is often diagnosed incorrectly; since the researchers used diagnostic billing codes to exclude individuals with opioid use disorder, some women may have been missed,” Dr. Poorman explained.

Ms. Bowie and colleagues acknowledged that a key limitation of the study was the identification of cases using diagnostic billing codes. As a result, exposure-dependent recording bias could be present and limit the applicability of the findings.

“The diagnosis and documentation of minor anomalies and those with subtle medical significance could be vulnerable to exposure-dependent recording bias,” Ms. Bowie wrote.

Dr. Poorman recommended that these results should be interpreted with caution given these and other limitations. “Overall, results from this study may imply that there is limited evidence to suspect opioids are related to congenital abnormalities due to a very small difference observed in relatively unequal groups,” she concluded.

This study received funding from the Eunice Kennedy Shriver National Institutes of Child Health and Human Development and was also supported by the Institute for Clinical Evaluative Sciences, which is funded by an annual grant from the Ontario Ministry of Health. One author reported receiving honoraria from the National Institutes of Health and a grant from the Canadian Institute of Health Research, outside the submitted work. No other competing interests were declared.

Two illicit drugs are contributing to a sharp rise in fentanyl-related deaths, a new study from the Centers for Disease Control and Prevention shows.

Para-fluorofentanyl, a schedule I substance often found in heroin packets and counterfeit pills, is making a comeback on the illicit drug market, Jordan Trecki, PhD, and associates reported in the Centers for Disease Control and Prevention’s Morbidity and Mortality Weekly Report (2022 Jan 28;71[4]:153-5). U.S. medical examiner reports and national law enforcement seizure data point to a rise in encounters of this drug along with metonitazene, a benzimidazole-opioid, in combination with fentanyl.

On their own, para-fluorofentanyl and metonitazene can kill the user through respiratory depression. Combinations of these substances and other opioids, including fentanyl-related compounds or adulterants, “pose an even greater potential harm to the patient than previously observed,” reported Dr. Trecki, a pharmacologist affiliated with the Drug Enforcement Administration, and colleagues.

Opioids contribute to about 75% of all U.S. drug overdose deaths, which rose by 28.5% during 2020-2021, according to the National Center for Health Statistics. And fentanyl is replacing heroin as the primary drug of use, said addiction specialist Brian Fuehrlein, MD, PhD, in an interview.

“For patients with stimulant use disorder and even cannabis use disorder, fentanyl is becoming more and more common as an adulterant in those substances, often resulting in inadvertent use. Hence, fentanyl and fentanyl-like drugs and fentanyl analogues are becoming increasingly common and important,” said Dr. Fuehrlein, director of the psychiatric emergency room at the VA Connecticut Healthcare System. He was not involved with the MMWR study.
 

Tennessee data reflect national problem

Recent data from a medical examiner in Knoxville, Tenn., illustrate what might be happening nationwide with those two emerging substances.

Over the last 2 years, the Knox County Regional Forensic Center has identified para-fluorofentanyl in the toxicology results of drug overdose victims, and metonitazene – either on its own or in combination with fentanyl and para-fluorofentanyl. Fentanyl appeared in 562 or 73% of 770 unintentional drug overdose deaths from November 2020 to August 2021. Forty-eight of these cases involved para-fluorofentanyl, and 26 involved metonitazene.

“Although the percentage of law enforcement encounters with these substances in Tennessee decreased relative to the national total percentage within this time frame, the increase in encounters both within Tennessee and nationally reflect an increased distribution of para-fluorofentanyl and metonitazene throughout the United States,” the authors reported.
 

How to identify substances, manage overdoses

The authors encouraged physicians, labs, and medical examiners to be on the lookout for these two substances either in the emergency department or when identifying the cause of drug overdose deaths.

They also advised that stronger opioids, such as fentanyl, para-fluorofentanyl, metonitazene, or other benzimidazoles may warrant additional doses of the opioid-reversal drug naloxone.

While he hasn’t personally seen any of these drugs in his practice, “I would assume that these are on the rise due to inexpensive cost to manufacture and potency of effect,” said Dr. Fuehrlein, also an associate professor of psychiatry at Yale University, New Haven, Conn.

The need for additional naloxone to manage acute overdoses is a key takeaway of the MMWR paper, he added. Clinicians should also educate patients about harm reduction strategies to avoid overdose death when using potentially powerful and unknown drugs. “Things like start low and go slow, buy from the same supplier, do not use opioids with alcohol or benzos, have Narcan available, do not use alone, etc.”

Dr. Fuehrlein had no disclosures.

Two illicit drugs are contributing to a sharp rise in fentanyl-related deaths, a new study from the Centers for Disease Control and Prevention shows.

Para-fluorofentanyl, a schedule I substance often found in heroin packets and counterfeit pills, is making a comeback on the illicit drug market, Jordan Trecki, PhD, and associates reported in the Centers for Disease Control and Prevention’s Morbidity and Mortality Weekly Report (2022 Jan 28;71[4]:153-5). U.S. medical examiner reports and national law enforcement seizure data point to a rise in encounters of this drug along with metonitazene, a benzimidazole-opioid, in combination with fentanyl.

On their own, para-fluorofentanyl and metonitazene can kill the user through respiratory depression. Combinations of these substances and other opioids, including fentanyl-related compounds or adulterants, “pose an even greater potential harm to the patient than previously observed,” reported Dr. Trecki, a pharmacologist affiliated with the Drug Enforcement Administration, and colleagues.

Opioids contribute to about 75% of all U.S. drug overdose deaths, which rose by 28.5% during 2020-2021, according to the National Center for Health Statistics. And fentanyl is replacing heroin as the primary drug of use, said addiction specialist Brian Fuehrlein, MD, PhD, in an interview.

“For patients with stimulant use disorder and even cannabis use disorder, fentanyl is becoming more and more common as an adulterant in those substances, often resulting in inadvertent use. Hence, fentanyl and fentanyl-like drugs and fentanyl analogues are becoming increasingly common and important,” said Dr. Fuehrlein, director of the psychiatric emergency room at the VA Connecticut Healthcare System. He was not involved with the MMWR study.
 

Tennessee data reflect national problem

Recent data from a medical examiner in Knoxville, Tenn., illustrate what might be happening nationwide with those two emerging substances.

Over the last 2 years, the Knox County Regional Forensic Center has identified para-fluorofentanyl in the toxicology results of drug overdose victims, and metonitazene – either on its own or in combination with fentanyl and para-fluorofentanyl. Fentanyl appeared in 562 or 73% of 770 unintentional drug overdose deaths from November 2020 to August 2021. Forty-eight of these cases involved para-fluorofentanyl, and 26 involved metonitazene.

“Although the percentage of law enforcement encounters with these substances in Tennessee decreased relative to the national total percentage within this time frame, the increase in encounters both within Tennessee and nationally reflect an increased distribution of para-fluorofentanyl and metonitazene throughout the United States,” the authors reported.
 

How to identify substances, manage overdoses

The authors encouraged physicians, labs, and medical examiners to be on the lookout for these two substances either in the emergency department or when identifying the cause of drug overdose deaths.

They also advised that stronger opioids, such as fentanyl, para-fluorofentanyl, metonitazene, or other benzimidazoles may warrant additional doses of the opioid-reversal drug naloxone.

While he hasn’t personally seen any of these drugs in his practice, “I would assume that these are on the rise due to inexpensive cost to manufacture and potency of effect,” said Dr. Fuehrlein, also an associate professor of psychiatry at Yale University, New Haven, Conn.

The need for additional naloxone to manage acute overdoses is a key takeaway of the MMWR paper, he added. Clinicians should also educate patients about harm reduction strategies to avoid overdose death when using potentially powerful and unknown drugs. “Things like start low and go slow, buy from the same supplier, do not use opioids with alcohol or benzos, have Narcan available, do not use alone, etc.”

Dr. Fuehrlein had no disclosures.

Two illicit drugs are contributing to a sharp rise in fentanyl-related deaths, a new study from the Centers for Disease Control and Prevention shows.

Para-fluorofentanyl, a schedule I substance often found in heroin packets and counterfeit pills, is making a comeback on the illicit drug market, Jordan Trecki, PhD, and associates reported in the Centers for Disease Control and Prevention’s Morbidity and Mortality Weekly Report (2022 Jan 28;71[4]:153-5). U.S. medical examiner reports and national law enforcement seizure data point to a rise in encounters of this drug along with metonitazene, a benzimidazole-opioid, in combination with fentanyl.

On their own, para-fluorofentanyl and metonitazene can kill the user through respiratory depression. Combinations of these substances and other opioids, including fentanyl-related compounds or adulterants, “pose an even greater potential harm to the patient than previously observed,” reported Dr. Trecki, a pharmacologist affiliated with the Drug Enforcement Administration, and colleagues.

Opioids contribute to about 75% of all U.S. drug overdose deaths, which rose by 28.5% during 2020-2021, according to the National Center for Health Statistics. And fentanyl is replacing heroin as the primary drug of use, said addiction specialist Brian Fuehrlein, MD, PhD, in an interview.

“For patients with stimulant use disorder and even cannabis use disorder, fentanyl is becoming more and more common as an adulterant in those substances, often resulting in inadvertent use. Hence, fentanyl and fentanyl-like drugs and fentanyl analogues are becoming increasingly common and important,” said Dr. Fuehrlein, director of the psychiatric emergency room at the VA Connecticut Healthcare System. He was not involved with the MMWR study.
 

Tennessee data reflect national problem

Recent data from a medical examiner in Knoxville, Tenn., illustrate what might be happening nationwide with those two emerging substances.

Over the last 2 years, the Knox County Regional Forensic Center has identified para-fluorofentanyl in the toxicology results of drug overdose victims, and metonitazene – either on its own or in combination with fentanyl and para-fluorofentanyl. Fentanyl appeared in 562 or 73% of 770 unintentional drug overdose deaths from November 2020 to August 2021. Forty-eight of these cases involved para-fluorofentanyl, and 26 involved metonitazene.

“Although the percentage of law enforcement encounters with these substances in Tennessee decreased relative to the national total percentage within this time frame, the increase in encounters both within Tennessee and nationally reflect an increased distribution of para-fluorofentanyl and metonitazene throughout the United States,” the authors reported.
 

How to identify substances, manage overdoses

The authors encouraged physicians, labs, and medical examiners to be on the lookout for these two substances either in the emergency department or when identifying the cause of drug overdose deaths.

They also advised that stronger opioids, such as fentanyl, para-fluorofentanyl, metonitazene, or other benzimidazoles may warrant additional doses of the opioid-reversal drug naloxone.

While he hasn’t personally seen any of these drugs in his practice, “I would assume that these are on the rise due to inexpensive cost to manufacture and potency of effect,” said Dr. Fuehrlein, also an associate professor of psychiatry at Yale University, New Haven, Conn.

The need for additional naloxone to manage acute overdoses is a key takeaway of the MMWR paper, he added. Clinicians should also educate patients about harm reduction strategies to avoid overdose death when using potentially powerful and unknown drugs. “Things like start low and go slow, buy from the same supplier, do not use opioids with alcohol or benzos, have Narcan available, do not use alone, etc.”

Dr. Fuehrlein had no disclosures.

Use of marijuana during pregnancy was associated with symptoms of nausea and vomiting and with use of prescribed antiemetics, according to a study presented Feb. 3 at the meeting sponsored by the Society for Maternal-Fetal Medicine. It’s unclear, however, whether the association suggests that pregnant individuals are using marijuana in an attempt to treat their symptoms or whether the marijuana use is contributing to nausea and vomiting – or neither, Torri D. Metz, MD, of the University of Utah Health in Salt Lake City, told attendees.

“Cannabis use has been increasing among pregnant individuals,” Dr. Metz said. “Reported reasons for use range from habit to perceived benefit for treatment of medical conditions, including nausea and vomiting.” She noted a previous study that found that dispensary employees in Colorado recommended cannabis to pregnant callers for treating of nausea despite no clinical evidence of it being an effective treatment.

”Anecdotally, I can say that many patients have told me that marijuana is the only thing that makes them feel better in the first trimester, but that could also be closely tied to marijuana alleviating their other symptoms, such as anxiety or sleep disturbances,” Ilina Pluym, MD, of the department of maternal-fetal medicine at the University of California, Los Angeles, said in an interview. ”In the brain, marijuana acts to alleviate nausea and vomiting, and it has been used successfully to treat nausea [caused by] chemotherapy,” said Dr. Pluym, who attended the abstract presentation but was not involved in the research. “But in the gut, with long-term marijuana use, it can have the opposite effect, which is what is seen in cannabinoid hyperemesis syndrome.”

Past research that has identified a link between cannabis use and nausea in pregnancy has typically relied on administrative data or self-reporting that are subject to recall and social desirability bias instead of a biomarker to assess cannabis use. This study therefore assessed marijuana use based on the presence of THC-COOH in urine samples and added the element of investigating antiemetic use in the population.

The study enrolled 10,038 nulliparous pregnant patients from eight U.S. centers from 2010 to 2013 who were an average 11 weeks pregnant. All participants completed the Pregnancy-Unique Quantification of Emesis (PUQE) tool at their first study visit and consented to testing of their previously frozen urine samples. The PUQE tool asks participants how often they have experienced nausea, vomiting, or retching or dry heaves within the previous 12 hours. A score of 1-6 is mild, a score of 7-12 is moderate, and a score of 13 or higher is severe.

Overall, 15.8% of participants reported moderate to severe nausea and 38.2% reported mild nausea. A total of 5.8% of participants tested positive for marijuana use based on THC levels in urine. Those with incrementally higher levels of THC, at least 500 ng/mg of creatinine, were 1.6 times more likely to report moderate to severe nausea after accounting for maternal age, body mass index, antiemetic drug use, and gestational age (adjusted odds ratio, 1.6; P < .001). An association did not exist, however, with any level of nausea overall. Those with higher creatinine levels were also 1.9 times more likely to report vomiting and 1.6 times more likely to report dry heaves or retching (P < .001).

About 1 in 10 participants (9.6%) overall had used a prescription antiemetic drug. Antiemetics were more common among those who had used marijuana: 18% of those with detectable THC had used antiemetics, compared with 12% of those without evidence of cannabis use (P < .001). However, most of those who used marijuana (83%) took only one antiemetic.

Among the study’s limitations were its lack of data on the reasons for cannabis use and the fact that it took place before widespread cannabidiol products became available, which meant most participants were using marijuana by smoking it.

Dr. Pluym also pointed out that the overall rate of marijuana use during pregnancy is likely higher today than it was in 2010-2013, before many states legalized its use. “But legalization shouldn’t equal normalization in pregnancy,” she added.

In addition, while the PUQE score assesses symptoms within the previous 12 hours, THC can remain in urine samples anywhere from several days to several weeks after marijuana is used.

”We’re unable to establish cause and effect,” Dr. Metz said, “but what we can conclude is that marijuana use was associated with early pregnancy nausea and vomiting.”

The findings emphasize the need for physicians to ask patients about their use of marijuana and seek to find out why they’re using it, Dr. Metz said. If it’s to treat nausea and vomiting of pregnancy, ob.gyns. should ensure patients are aware of the potential adverse effects of marijuana use in pregnancy and mention safe, effective alternatives. Research from the National Academy of Sciences has shown consistent evidence of decreased fetal growth with marijuana use in pregnancy, but there hasn’t been enough evidence to assess potential long-term neurological effects.

The research was funded by the National Institute on Drug Abuse and the National Institute of Child Health and Human Development. Dr. Metz and Dr. Pluym reported no disclosures.

Use of marijuana during pregnancy was associated with symptoms of nausea and vomiting and with use of prescribed antiemetics, according to a study presented Feb. 3 at the meeting sponsored by the Society for Maternal-Fetal Medicine. It’s unclear, however, whether the association suggests that pregnant individuals are using marijuana in an attempt to treat their symptoms or whether the marijuana use is contributing to nausea and vomiting – or neither, Torri D. Metz, MD, of the University of Utah Health in Salt Lake City, told attendees.

“Cannabis use has been increasing among pregnant individuals,” Dr. Metz said. “Reported reasons for use range from habit to perceived benefit for treatment of medical conditions, including nausea and vomiting.” She noted a previous study that found that dispensary employees in Colorado recommended cannabis to pregnant callers for treating of nausea despite no clinical evidence of it being an effective treatment.

”Anecdotally, I can say that many patients have told me that marijuana is the only thing that makes them feel better in the first trimester, but that could also be closely tied to marijuana alleviating their other symptoms, such as anxiety or sleep disturbances,” Ilina Pluym, MD, of the department of maternal-fetal medicine at the University of California, Los Angeles, said in an interview. ”In the brain, marijuana acts to alleviate nausea and vomiting, and it has been used successfully to treat nausea [caused by] chemotherapy,” said Dr. Pluym, who attended the abstract presentation but was not involved in the research. “But in the gut, with long-term marijuana use, it can have the opposite effect, which is what is seen in cannabinoid hyperemesis syndrome.”

Past research that has identified a link between cannabis use and nausea in pregnancy has typically relied on administrative data or self-reporting that are subject to recall and social desirability bias instead of a biomarker to assess cannabis use. This study therefore assessed marijuana use based on the presence of THC-COOH in urine samples and added the element of investigating antiemetic use in the population.

The study enrolled 10,038 nulliparous pregnant patients from eight U.S. centers from 2010 to 2013 who were an average 11 weeks pregnant. All participants completed the Pregnancy-Unique Quantification of Emesis (PUQE) tool at their first study visit and consented to testing of their previously frozen urine samples. The PUQE tool asks participants how often they have experienced nausea, vomiting, or retching or dry heaves within the previous 12 hours. A score of 1-6 is mild, a score of 7-12 is moderate, and a score of 13 or higher is severe.

Overall, 15.8% of participants reported moderate to severe nausea and 38.2% reported mild nausea. A total of 5.8% of participants tested positive for marijuana use based on THC levels in urine. Those with incrementally higher levels of THC, at least 500 ng/mg of creatinine, were 1.6 times more likely to report moderate to severe nausea after accounting for maternal age, body mass index, antiemetic drug use, and gestational age (adjusted odds ratio, 1.6; P < .001). An association did not exist, however, with any level of nausea overall. Those with higher creatinine levels were also 1.9 times more likely to report vomiting and 1.6 times more likely to report dry heaves or retching (P < .001).

About 1 in 10 participants (9.6%) overall had used a prescription antiemetic drug. Antiemetics were more common among those who had used marijuana: 18% of those with detectable THC had used antiemetics, compared with 12% of those without evidence of cannabis use (P < .001). However, most of those who used marijuana (83%) took only one antiemetic.

Among the study’s limitations were its lack of data on the reasons for cannabis use and the fact that it took place before widespread cannabidiol products became available, which meant most participants were using marijuana by smoking it.

Dr. Pluym also pointed out that the overall rate of marijuana use during pregnancy is likely higher today than it was in 2010-2013, before many states legalized its use. “But legalization shouldn’t equal normalization in pregnancy,” she added.

In addition, while the PUQE score assesses symptoms within the previous 12 hours, THC can remain in urine samples anywhere from several days to several weeks after marijuana is used.

”We’re unable to establish cause and effect,” Dr. Metz said, “but what we can conclude is that marijuana use was associated with early pregnancy nausea and vomiting.”

The findings emphasize the need for physicians to ask patients about their use of marijuana and seek to find out why they’re using it, Dr. Metz said. If it’s to treat nausea and vomiting of pregnancy, ob.gyns. should ensure patients are aware of the potential adverse effects of marijuana use in pregnancy and mention safe, effective alternatives. Research from the National Academy of Sciences has shown consistent evidence of decreased fetal growth with marijuana use in pregnancy, but there hasn’t been enough evidence to assess potential long-term neurological effects.

The research was funded by the National Institute on Drug Abuse and the National Institute of Child Health and Human Development. Dr. Metz and Dr. Pluym reported no disclosures.

Use of marijuana during pregnancy was associated with symptoms of nausea and vomiting and with use of prescribed antiemetics, according to a study presented Feb. 3 at the meeting sponsored by the Society for Maternal-Fetal Medicine. It’s unclear, however, whether the association suggests that pregnant individuals are using marijuana in an attempt to treat their symptoms or whether the marijuana use is contributing to nausea and vomiting – or neither, Torri D. Metz, MD, of the University of Utah Health in Salt Lake City, told attendees.

“Cannabis use has been increasing among pregnant individuals,” Dr. Metz said. “Reported reasons for use range from habit to perceived benefit for treatment of medical conditions, including nausea and vomiting.” She noted a previous study that found that dispensary employees in Colorado recommended cannabis to pregnant callers for treating of nausea despite no clinical evidence of it being an effective treatment.

”Anecdotally, I can say that many patients have told me that marijuana is the only thing that makes them feel better in the first trimester, but that could also be closely tied to marijuana alleviating their other symptoms, such as anxiety or sleep disturbances,” Ilina Pluym, MD, of the department of maternal-fetal medicine at the University of California, Los Angeles, said in an interview. ”In the brain, marijuana acts to alleviate nausea and vomiting, and it has been used successfully to treat nausea [caused by] chemotherapy,” said Dr. Pluym, who attended the abstract presentation but was not involved in the research. “But in the gut, with long-term marijuana use, it can have the opposite effect, which is what is seen in cannabinoid hyperemesis syndrome.”

Past research that has identified a link between cannabis use and nausea in pregnancy has typically relied on administrative data or self-reporting that are subject to recall and social desirability bias instead of a biomarker to assess cannabis use. This study therefore assessed marijuana use based on the presence of THC-COOH in urine samples and added the element of investigating antiemetic use in the population.

The study enrolled 10,038 nulliparous pregnant patients from eight U.S. centers from 2010 to 2013 who were an average 11 weeks pregnant. All participants completed the Pregnancy-Unique Quantification of Emesis (PUQE) tool at their first study visit and consented to testing of their previously frozen urine samples. The PUQE tool asks participants how often they have experienced nausea, vomiting, or retching or dry heaves within the previous 12 hours. A score of 1-6 is mild, a score of 7-12 is moderate, and a score of 13 or higher is severe.

Overall, 15.8% of participants reported moderate to severe nausea and 38.2% reported mild nausea. A total of 5.8% of participants tested positive for marijuana use based on THC levels in urine. Those with incrementally higher levels of THC, at least 500 ng/mg of creatinine, were 1.6 times more likely to report moderate to severe nausea after accounting for maternal age, body mass index, antiemetic drug use, and gestational age (adjusted odds ratio, 1.6; P < .001). An association did not exist, however, with any level of nausea overall. Those with higher creatinine levels were also 1.9 times more likely to report vomiting and 1.6 times more likely to report dry heaves or retching (P < .001).

About 1 in 10 participants (9.6%) overall had used a prescription antiemetic drug. Antiemetics were more common among those who had used marijuana: 18% of those with detectable THC had used antiemetics, compared with 12% of those without evidence of cannabis use (P < .001). However, most of those who used marijuana (83%) took only one antiemetic.

Among the study’s limitations were its lack of data on the reasons for cannabis use and the fact that it took place before widespread cannabidiol products became available, which meant most participants were using marijuana by smoking it.

Dr. Pluym also pointed out that the overall rate of marijuana use during pregnancy is likely higher today than it was in 2010-2013, before many states legalized its use. “But legalization shouldn’t equal normalization in pregnancy,” she added.

In addition, while the PUQE score assesses symptoms within the previous 12 hours, THC can remain in urine samples anywhere from several days to several weeks after marijuana is used.

”We’re unable to establish cause and effect,” Dr. Metz said, “but what we can conclude is that marijuana use was associated with early pregnancy nausea and vomiting.”

The findings emphasize the need for physicians to ask patients about their use of marijuana and seek to find out why they’re using it, Dr. Metz said. If it’s to treat nausea and vomiting of pregnancy, ob.gyns. should ensure patients are aware of the potential adverse effects of marijuana use in pregnancy and mention safe, effective alternatives. Research from the National Academy of Sciences has shown consistent evidence of decreased fetal growth with marijuana use in pregnancy, but there hasn’t been enough evidence to assess potential long-term neurological effects.

The research was funded by the National Institute on Drug Abuse and the National Institute of Child Health and Human Development. Dr. Metz and Dr. Pluym reported no disclosures.

Intranasal oxytocin (INOT) is showing early promise as a treatment for cocaine dependence, new research suggests.

Results of a small 6-week randomized, placebo-controlled trial in patients with cocaine use disorder showed a high level of abstinence in those who received INOT beginning 2 weeks after treatment initiation.

“In this population of cocaine-dependent individuals in a community clinic setting, we found the use of intranasal oxytocin to be safe and feasible, with no adverse events, and a high level of abstinence after 6 weeks, compared to placebo,” lead author Wilfrid Noel Raby, PhD, MD, a Teaneck, N.J.–based psychiatrist, said in an interview.

On the other hand, “the findings were paradoxical because there was a greater dropout rate in the intranasal oxytocin group after week 1, suggesting that oxytocin might have a biphasic effect, which should be addressed in future studies,” added Dr. Raby, who was an adjunct clinical professor of psychiatry, division on substance abuse, Montefiore Medical Center, Albert Einstein College of Medicine, New York, when the trial was conducted.

The study was published in the March issue of Drug and Alcohol Dependence Reports.
 

‘Crying need’

“Focus on stress reactivity in addiction and on the loss of social norms among drug users has generated interest in oxytocin, due to its purported role in these traits and regulation of stress,” the authors wrote.

Oxytocin is a neuropeptide that regulates autonomic functions. Previous research in cannabis users suggests it may have a role in treating addiction by reportedly reducing cravings. In addition, earlier research also suggests it cuts stress reactivity and state anger in cocaine users.

A previous trial of INOT showed it decreased cocaine craving, and additional research has revealed recurrent cocaine use results in lower endogenous oxytocin levels and depleted oxytocin in the hypothalamus and amygdala.

“The bias of my work is to look for simple, nonaddictive medicinal approaches that can be used in the community settings, because that’s where the greatest crying need lies and where most problems from drug addiction occur,” said Dr. Raby.

“There has been long-standing interest in how the brain adaptive systems, or so-called ‘stress systems,’ adjust in the face of drug dependence in general, and the main focus of the study has been to understand this response and use the insight from these adaptations to develop medicinal treatments for drug abuse, particularly cocaine dependence,” he added.

To investigate the potential for INOT to promote abstinence from cocaine, the researchers randomized 26 patients with cocaine use disorder (73% male, mean [SD] age, 50.2 [5.4] years). Most participants had been using cocaine on a regular basis for about 25 years, and baseline average days of cocaine use was 11.1 (5.7) during the 30 days prior to study entry.

At a baseline, the researchers collected participants’ medical history and conducted a physical examination, urine toxicology, electrocardiogram, comprehensive metabolic panel, and complete blood count. They used the MINI International Neuropsychiatric Interview to confirm the diagnosis of cocaine dependence.

The study began with a 7-day inpatient abstinence induction stage, after which participants were randomized to receive either INOT 24 IU or intranasal placebo (n = 15 and n = 11, respectively).

Patients attended the clinic three times per week. At each visit, they completed the cocaine craving scale, the Perceived Stress Scale, and the Clinician Global Inventory (all self-reports), as well as the Time Line Follow Back (TLFB) to document cocaine use.

Participants were trained to self-administer an intranasal solution at home, with compliance monitored in two ways – staff observed self-administration of the randomized medication at the time of clinic visits and weighed the “at home bottle.”

Cocaine use was determined via urine toxicology and TLFB self-report.
 

Threshold period

INOT did not induce ≥ 3 weeks of continuous abstinence. However, beginning with week 3, the odds of weekly abstinence increased dramatically in the INOT group, from 4.61 (95% confidence interval,1.05, 20.3) to 15.0 (1.18, 190.2) by week 6 (t = 2.12, P = .037).

The overall medication group by time interaction across all 6 weeks was not significant (F1,69 = 1.73, P = .19); but when the interaction was removed, the difference between the overall effect of medication (INOT vs. placebo) over all 6 weeks “reached trend-level significance” (F1,70) = 3.42, P = .07).

The subjective rating outcomes (cravings, perceived stress, cocaine dependence, and depression) “did not show a significant medication group by time interaction effect,” the authors reported, although stress-induced cravings did tend toward a significant difference between the groups.

Half of the patients did not complete the full 6 weeks. Of those who discontinued, 85% came from the INOT group and 15% from the placebo group. Of the 11 who dropped out from the treatment group, seven were abstinent at the time of discontinuation for ≥ 1 week.

There were no significant differences in rates of reported side effects between the two groups.

“This study highlights some promise that perhaps there is a threshold period of time you need to cross, after which time oxytocin could really be really helpful as acute or maintenance medication,” said Dr. Raby. The short study duration might have been a disadvantage. “We might have seen better results if the study had been 8 or 12 weeks in duration.”

Using motivational approaches during the early phase – e.g., psychotherapy or a voucher system – might increase adherence, and then “after this initial lag, we might see a more therapeutic effect,” he suggested.

Dr. Raby noted that his group studied stress hormone secretions in the cocaine-dependent study participants during the 7-day induction period and that the findings, when published, could shed light on this latency period. “Cocaine dependence creates adaptations in the stress system,” he said.
 

‘Nice first step’

Commenting on the study, Jane Joseph, PhD, professor in the department of neurosciences and director of the neuroimaging division at Medical University of South Carolina, Charleston, said it is “nice to see a clinical trial using oxytocin in cocaine dependence [because] preclinical research has shown fairly convincing effects of oxytocin in reducing craving or stress in the context of cocaine seeking, but findings are rather mixed in human studies.”

Dr. Joseph, who was not involved with the study, said her group’s research showed oxytocin to be the most helpful for men with cocaine use disorder who reported childhood trauma, while for women, oxytocin “seemed to worsen their reactivity to cocaine cues.”

She said the current study is a “nice first step” and suggested that future research should include larger sample sizes to “address some of the individual variability in the response to oxytocin by examining sex differences or trauma history.”

The study was supported by an award from the National Institute of Drug Abuse. Dr. Raby and coauthors and Dr. Joseph have disclosed no relevant financial relationships.

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

Intranasal oxytocin (INOT) is showing early promise as a treatment for cocaine dependence, new research suggests.

Results of a small 6-week randomized, placebo-controlled trial in patients with cocaine use disorder showed a high level of abstinence in those who received INOT beginning 2 weeks after treatment initiation.

“In this population of cocaine-dependent individuals in a community clinic setting, we found the use of intranasal oxytocin to be safe and feasible, with no adverse events, and a high level of abstinence after 6 weeks, compared to placebo,” lead author Wilfrid Noel Raby, PhD, MD, a Teaneck, N.J.–based psychiatrist, said in an interview.

On the other hand, “the findings were paradoxical because there was a greater dropout rate in the intranasal oxytocin group after week 1, suggesting that oxytocin might have a biphasic effect, which should be addressed in future studies,” added Dr. Raby, who was an adjunct clinical professor of psychiatry, division on substance abuse, Montefiore Medical Center, Albert Einstein College of Medicine, New York, when the trial was conducted.

The study was published in the March issue of Drug and Alcohol Dependence Reports.
 

‘Crying need’

“Focus on stress reactivity in addiction and on the loss of social norms among drug users has generated interest in oxytocin, due to its purported role in these traits and regulation of stress,” the authors wrote.

Oxytocin is a neuropeptide that regulates autonomic functions. Previous research in cannabis users suggests it may have a role in treating addiction by reportedly reducing cravings. In addition, earlier research also suggests it cuts stress reactivity and state anger in cocaine users.

A previous trial of INOT showed it decreased cocaine craving, and additional research has revealed recurrent cocaine use results in lower endogenous oxytocin levels and depleted oxytocin in the hypothalamus and amygdala.

“The bias of my work is to look for simple, nonaddictive medicinal approaches that can be used in the community settings, because that’s where the greatest crying need lies and where most problems from drug addiction occur,” said Dr. Raby.

“There has been long-standing interest in how the brain adaptive systems, or so-called ‘stress systems,’ adjust in the face of drug dependence in general, and the main focus of the study has been to understand this response and use the insight from these adaptations to develop medicinal treatments for drug abuse, particularly cocaine dependence,” he added.

To investigate the potential for INOT to promote abstinence from cocaine, the researchers randomized 26 patients with cocaine use disorder (73% male, mean [SD] age, 50.2 [5.4] years). Most participants had been using cocaine on a regular basis for about 25 years, and baseline average days of cocaine use was 11.1 (5.7) during the 30 days prior to study entry.

At a baseline, the researchers collected participants’ medical history and conducted a physical examination, urine toxicology, electrocardiogram, comprehensive metabolic panel, and complete blood count. They used the MINI International Neuropsychiatric Interview to confirm the diagnosis of cocaine dependence.

The study began with a 7-day inpatient abstinence induction stage, after which participants were randomized to receive either INOT 24 IU or intranasal placebo (n = 15 and n = 11, respectively).

Patients attended the clinic three times per week. At each visit, they completed the cocaine craving scale, the Perceived Stress Scale, and the Clinician Global Inventory (all self-reports), as well as the Time Line Follow Back (TLFB) to document cocaine use.

Participants were trained to self-administer an intranasal solution at home, with compliance monitored in two ways – staff observed self-administration of the randomized medication at the time of clinic visits and weighed the “at home bottle.”

Cocaine use was determined via urine toxicology and TLFB self-report.
 

Threshold period

INOT did not induce ≥ 3 weeks of continuous abstinence. However, beginning with week 3, the odds of weekly abstinence increased dramatically in the INOT group, from 4.61 (95% confidence interval,1.05, 20.3) to 15.0 (1.18, 190.2) by week 6 (t = 2.12, P = .037).

The overall medication group by time interaction across all 6 weeks was not significant (F1,69 = 1.73, P = .19); but when the interaction was removed, the difference between the overall effect of medication (INOT vs. placebo) over all 6 weeks “reached trend-level significance” (F1,70) = 3.42, P = .07).

The subjective rating outcomes (cravings, perceived stress, cocaine dependence, and depression) “did not show a significant medication group by time interaction effect,” the authors reported, although stress-induced cravings did tend toward a significant difference between the groups.

Half of the patients did not complete the full 6 weeks. Of those who discontinued, 85% came from the INOT group and 15% from the placebo group. Of the 11 who dropped out from the treatment group, seven were abstinent at the time of discontinuation for ≥ 1 week.

There were no significant differences in rates of reported side effects between the two groups.

“This study highlights some promise that perhaps there is a threshold period of time you need to cross, after which time oxytocin could really be really helpful as acute or maintenance medication,” said Dr. Raby. The short study duration might have been a disadvantage. “We might have seen better results if the study had been 8 or 12 weeks in duration.”

Using motivational approaches during the early phase – e.g., psychotherapy or a voucher system – might increase adherence, and then “after this initial lag, we might see a more therapeutic effect,” he suggested.

Dr. Raby noted that his group studied stress hormone secretions in the cocaine-dependent study participants during the 7-day induction period and that the findings, when published, could shed light on this latency period. “Cocaine dependence creates adaptations in the stress system,” he said.
 

‘Nice first step’

Commenting on the study, Jane Joseph, PhD, professor in the department of neurosciences and director of the neuroimaging division at Medical University of South Carolina, Charleston, said it is “nice to see a clinical trial using oxytocin in cocaine dependence [because] preclinical research has shown fairly convincing effects of oxytocin in reducing craving or stress in the context of cocaine seeking, but findings are rather mixed in human studies.”

Dr. Joseph, who was not involved with the study, said her group’s research showed oxytocin to be the most helpful for men with cocaine use disorder who reported childhood trauma, while for women, oxytocin “seemed to worsen their reactivity to cocaine cues.”

She said the current study is a “nice first step” and suggested that future research should include larger sample sizes to “address some of the individual variability in the response to oxytocin by examining sex differences or trauma history.”

The study was supported by an award from the National Institute of Drug Abuse. Dr. Raby and coauthors and Dr. Joseph have disclosed no relevant financial relationships.

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

Intranasal oxytocin (INOT) is showing early promise as a treatment for cocaine dependence, new research suggests.

Results of a small 6-week randomized, placebo-controlled trial in patients with cocaine use disorder showed a high level of abstinence in those who received INOT beginning 2 weeks after treatment initiation.

“In this population of cocaine-dependent individuals in a community clinic setting, we found the use of intranasal oxytocin to be safe and feasible, with no adverse events, and a high level of abstinence after 6 weeks, compared to placebo,” lead author Wilfrid Noel Raby, PhD, MD, a Teaneck, N.J.–based psychiatrist, said in an interview.

On the other hand, “the findings were paradoxical because there was a greater dropout rate in the intranasal oxytocin group after week 1, suggesting that oxytocin might have a biphasic effect, which should be addressed in future studies,” added Dr. Raby, who was an adjunct clinical professor of psychiatry, division on substance abuse, Montefiore Medical Center, Albert Einstein College of Medicine, New York, when the trial was conducted.

The study was published in the March issue of Drug and Alcohol Dependence Reports.
 

‘Crying need’

“Focus on stress reactivity in addiction and on the loss of social norms among drug users has generated interest in oxytocin, due to its purported role in these traits and regulation of stress,” the authors wrote.

Oxytocin is a neuropeptide that regulates autonomic functions. Previous research in cannabis users suggests it may have a role in treating addiction by reportedly reducing cravings. In addition, earlier research also suggests it cuts stress reactivity and state anger in cocaine users.

A previous trial of INOT showed it decreased cocaine craving, and additional research has revealed recurrent cocaine use results in lower endogenous oxytocin levels and depleted oxytocin in the hypothalamus and amygdala.

“The bias of my work is to look for simple, nonaddictive medicinal approaches that can be used in the community settings, because that’s where the greatest crying need lies and where most problems from drug addiction occur,” said Dr. Raby.

“There has been long-standing interest in how the brain adaptive systems, or so-called ‘stress systems,’ adjust in the face of drug dependence in general, and the main focus of the study has been to understand this response and use the insight from these adaptations to develop medicinal treatments for drug abuse, particularly cocaine dependence,” he added.

To investigate the potential for INOT to promote abstinence from cocaine, the researchers randomized 26 patients with cocaine use disorder (73% male, mean [SD] age, 50.2 [5.4] years). Most participants had been using cocaine on a regular basis for about 25 years, and baseline average days of cocaine use was 11.1 (5.7) during the 30 days prior to study entry.

At a baseline, the researchers collected participants’ medical history and conducted a physical examination, urine toxicology, electrocardiogram, comprehensive metabolic panel, and complete blood count. They used the MINI International Neuropsychiatric Interview to confirm the diagnosis of cocaine dependence.

The study began with a 7-day inpatient abstinence induction stage, after which participants were randomized to receive either INOT 24 IU or intranasal placebo (n = 15 and n = 11, respectively).

Patients attended the clinic three times per week. At each visit, they completed the cocaine craving scale, the Perceived Stress Scale, and the Clinician Global Inventory (all self-reports), as well as the Time Line Follow Back (TLFB) to document cocaine use.

Participants were trained to self-administer an intranasal solution at home, with compliance monitored in two ways – staff observed self-administration of the randomized medication at the time of clinic visits and weighed the “at home bottle.”

Cocaine use was determined via urine toxicology and TLFB self-report.
 

Threshold period

INOT did not induce ≥ 3 weeks of continuous abstinence. However, beginning with week 3, the odds of weekly abstinence increased dramatically in the INOT group, from 4.61 (95% confidence interval,1.05, 20.3) to 15.0 (1.18, 190.2) by week 6 (t = 2.12, P = .037).

The overall medication group by time interaction across all 6 weeks was not significant (F1,69 = 1.73, P = .19); but when the interaction was removed, the difference between the overall effect of medication (INOT vs. placebo) over all 6 weeks “reached trend-level significance” (F1,70) = 3.42, P = .07).

The subjective rating outcomes (cravings, perceived stress, cocaine dependence, and depression) “did not show a significant medication group by time interaction effect,” the authors reported, although stress-induced cravings did tend toward a significant difference between the groups.

Half of the patients did not complete the full 6 weeks. Of those who discontinued, 85% came from the INOT group and 15% from the placebo group. Of the 11 who dropped out from the treatment group, seven were abstinent at the time of discontinuation for ≥ 1 week.

There were no significant differences in rates of reported side effects between the two groups.

“This study highlights some promise that perhaps there is a threshold period of time you need to cross, after which time oxytocin could really be really helpful as acute or maintenance medication,” said Dr. Raby. The short study duration might have been a disadvantage. “We might have seen better results if the study had been 8 or 12 weeks in duration.”

Using motivational approaches during the early phase – e.g., psychotherapy or a voucher system – might increase adherence, and then “after this initial lag, we might see a more therapeutic effect,” he suggested.

Dr. Raby noted that his group studied stress hormone secretions in the cocaine-dependent study participants during the 7-day induction period and that the findings, when published, could shed light on this latency period. “Cocaine dependence creates adaptations in the stress system,” he said.
 

‘Nice first step’

Commenting on the study, Jane Joseph, PhD, professor in the department of neurosciences and director of the neuroimaging division at Medical University of South Carolina, Charleston, said it is “nice to see a clinical trial using oxytocin in cocaine dependence [because] preclinical research has shown fairly convincing effects of oxytocin in reducing craving or stress in the context of cocaine seeking, but findings are rather mixed in human studies.”

Dr. Joseph, who was not involved with the study, said her group’s research showed oxytocin to be the most helpful for men with cocaine use disorder who reported childhood trauma, while for women, oxytocin “seemed to worsen their reactivity to cocaine cues.”

She said the current study is a “nice first step” and suggested that future research should include larger sample sizes to “address some of the individual variability in the response to oxytocin by examining sex differences or trauma history.”

The study was supported by an award from the National Institute of Drug Abuse. Dr. Raby and coauthors and Dr. Joseph have disclosed no relevant financial relationships.

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

Opioid overdose is a major public health challenge, with recent reports estimating 41 deaths per day in the United States from prescription opioid overdose.^1,2 Prescribing naloxone has increasingly been advocated to reduce the risk of opioid overdose for patients identified as high risk. Naloxone distribution has been shown to decrease the incidence of opioid overdoses in the general population.^3,4 The Centers for Disease Control and Prevention (CDC) Guideline for Prescribing Opioids for Chronic Pain recommends considering naloxone prescription for patients with a history of overdose or substance use disorder, opioid dosages ≥ 50 morphine equivalent daily dose (MEDD), and concurrent use of benzodiazepines.⁵

Although the CDC guidelines are intended for primary care clinicians in outpatient settings, naloxone prescribing is also relevant in the postsurgical setting.⁵ Many surgical patients are at risk for opioid overdose and data from the Veterans Health Administration (VHA) has shown that risk of opioid overdose is 11-fold higher in the 30 days following discharge from a surgical admission, when compared with the subsequent calendar year.^6,7 This likely occurs due to new prescriptions or escalated doses of opioids following surgery. Overdose risk may be particularly relevant to orthopedic surgery as postoperative opioids are commonly prescribed.⁸ Patients undergoing total knee arthroplasty (TKA) may represent a vulnerable population to overdose as it is one of the most commonly performed surgeries for the treatment of chronic pain, and is frequently performed in older adults with medical comorbidities.^9,10

Identifying patients at high risk for opioid overdose is important for targeted naloxone dispensing.⁵ A risk index for overdose or serious opioid-induced respiratory depression (RIOSORD) tool has been developed and validated in veteran and other populations to identify such patients.¹¹ The RIOSORD tool classifies patients by risk level (1-10) and predicts probability of overdose or serious opioid-induced respiratory depression (OSORD). A patient’s level of risk is based on a weighted combination of the 15 independent risk factors most highly associated with OSORD, including comorbid conditions, prescription drug use, and health care utilization.¹² Using the RIOSORD tool, the VHA Opioid Education and Naloxone Distribution (OEND) program is a risk mitigation initiative that aims to decrease opioid-related overdose morbidity and mortality. This is achieved via opioid overdose education for prevention, recognition, and response and includes outpatient naloxone prescription.^13,14

Despite the comprehensive OEND program, there exists very little data to guide postsurgical naloxone prescribing. The prevalence of known risk factors for overdose in surgical patients remains unknown, as does the prevalence of perioperative naloxone distribution. Understanding overdose risk factors and naloxone prescribing patterns in surgical patients may identify potential targets for OEND efforts. This study retrospectively estimated RIOSORD scores for TKA patients between 2013 to 2016 and described naloxone distribution based on RIOSORD scores and risk factors.

Methods

We identified patients who had undergone primary TKA at VHA hospitals using Current Procedural Terminology (CPT), International Classification of Diseases, Ninth Revision (ICD-9) procedure codes, and data extracted from the VHA Corporate Data Warehouse (CDW) of electronic health records (EHRs). Our study was granted approval with exemption from informed consent by the Durham Veteran Affairs Healthcare System Institutional Review Board.

This retrospective cohort study included all veterans who underwent elective primary TKA from January 1, 2013 through December 31, 2016. We excluded patients who died before discharge.

Outcomes

Our primary outcome was being dispensed an outpatient naloxone prescription following TKA. Naloxone dispensing was identified by examining CDW outpatient pharmacy records with a final dispense date from 1 year before surgery through 7 days after discharge following TKA. To exclude naloxone administration that may have been given in a clinic, prescription data included only records with an outpatient prescription copay. Naloxone dispensing in the year before surgery was chosen to estimate likely preoperative possession of naloxone which could be available in the postoperative period. Naloxone dispensing until 7 days after discharge was chosen to identify any new dispensing that would be available in the postoperative period. These outcomes were examined over the study time frame on an annual basis.

Patient Factors

Demographic variables included age, sex, and race/ethnicity. Independent risk factors for overdose from RIOSORD were identified for each patient.¹⁵ These risk factors included comorbidities (opioid use disorder, schizophrenia, bipolar disorder, liver disease, chronic kidney disease, sleep apnea, or lung disease) and prescription drug use (use of opioids, benzodiazepines, long-acting opioids, ≥ 50 MEDD or ≥ 100 MEDD). ICD-9 and ICD-10 diagnosis codes were used to identify comorbidities. Risk classes on day of surgery were identified using a RIOSORD algorithm code. Consistent with the display of RIOSORD risk classes on the VHA Academic Detailing Service OEND risk report, patients were grouped into 3 groups based on their RIOSORD score: classes 1 to 4 (low risk), 5 to 7 (moderate risk), and 8 to 10 (high risk).

Descriptive statistics were used to summarize data on patient demographics, RIOSORD risk factors, overdose events, and naloxone dispensing over time.

Results

The study cohort included 38,011 veterans who underwent primary TKA in the VHA between January 1, 2013 and December 30, 2016. In this cohort, the mean age was 65 years, 93% were male, and 77% were White patients (Table 1). The most common comorbidities were lung disease in 9170 (24.1%) patients, sleep apnea in 6630 (17.4%) patients, chronic kidney disease in 4036 (10.6%) patients, liver disease in 2822 (7.4%) patients, and bipolar disorder in 1748 (4.6%) patients.

In 2013, 63.1% of patients presenting for surgery were actively prescribed opioids. By 2016, this decreased to 50.5%. Benzodiazepine use decreased from 13.2 to 8.8% and long-acting opioid use decreased from 8.5 to 5.8% over the same period. Patients taking ≥ 50 MEDD decreased from 8.0 to 5.3% and patients taking ≥ 100 MEDD decreased from 3.3 to 2.2%. The prevalence of moderate-risk patients decreased from 2.5 to 1.6% and high-risk patients decreased from 0.8 to 0.6% (Figure 1). Cumulatively, the prevalence of presenting with either moderate or high risk of overdose decreased from 3.3 to 2.2% between 2013 to 2016.

Naloxone Dispensing

In 2013, naloxone was not dispensed to any patients at moderate or high risk for overdose between 365 days prior to surgery until 7 days after discharge (Table 2 and Figure 2). Low-risk group naloxone dispensing increased to 2 (0.0%) in 2014, to 13 (0.1%), in 2015, and to 86 (0.9%) in 2016. Moderate-risk group naloxone dispensing remained at 0 (0.0%) in 2014, but increased to 8 (3.5%) in 2015, and to 18 (10.9%) in 2016. High-risk group naloxone dispensing remained at 0 (0.0%) in 2014, but increased to 5 (5.8%) in 2015, and to 8 (12.7%) in 2016 (Figure 3).

Discussion

Our data demonstrate that patients presenting for TKA between 2013 and 2016 routinely had individual risk factors for overdose related to either prescription drug use or comorbidities. We also show that, although the number of patients at moderate and high risk for opioid overdose is decreasing, 2.2% of TKA patients remain at moderate or high risk for opioid overdose based on a weighted combination of these individual risk factors using RIOSORD. As demand for primary TKA is projected to grow to 3.5 million procedures by 2030, using prevalence from 2016, we estimate that 76,560 patients may present for TKA across the US with moderate or high risk for opioid overdose.⁹ Following discharge, this risk may be even higher as this estimate does not yet account for postoperative opioid use. We demonstrate that through a VHA OEND initiative, naloxone distribution increased and appeared to be targeted to those most at risk using a simple validated tool like RIOSORD.

Presence of an individual risk factor for overdose was present in as many as 63.1% of patients presenting for TKA, as was seen in 2013 with preoperative opioid use. The 3 highest scoring prescription use–related risk factors in RIOSORD are use of opioids ≥ 100 MEDD (16 points), ≥ 50 MEDD (9 points), and long-acting formulations (9 points). All 3 decreased in prevalence over the study period but by 2016 were still seen in 2.2% for ≥ 100 MEDD, 5.3% for ≥ 50 MEDD, and 5.8% for long-acting opioids. This decrease was not surprising given implementation of a VHA-wide opioid safety initiative and the OEND program, but this could also be related to changes in patient selection for surgery in the context of increased awareness of the opioid epidemic. Despite the trend toward safer opioid prescribing, by 2016 over half of patients (50.5%) who presented for TKA were already taking opioids, with 10.6% (543 of 5127) on doses ≥ 50 MEDD.

We observed a decrease in RIOSORD risk each year, consistent with decreasing prescription-related risk factors over time. This was most obvious in the moderate-risk group. It is unclear why a similar decrease was not as obvious in the high-risk group, but this in part may be due to the already low numbers of patients in the high-risk group. This may also represent the high-risk group being somewhat resistant to the initiatives that shifted moderate-risk patients to the low-risk group. There were proportionately more patients in the moderate- and high-risk groups in the original RIOSORD population than in our surgical population, which may be attributed to the fewer comorbidities seen in our surgical population, as well as the higher opioid-prescribing patterns seen prior to the VA OEND initiative.¹²

Naloxone prescribing was rare prior to the OEND initiative and increased from 2013 to 2016. Increases were most marked in those in moderate- and high-risk groups, although naloxone prescribing also increased among the low-risk group. Integration of RIOSORD stratification into the OEND initiative likely played a role in targeting increased access to naloxone among those at highest risk of overdose. Naloxone dispensing increased for every group, although a significant proportion of moderate- and high-risk patients, 89.1% and 87.3%, respectively, were still not dispensed naloxone by 2016. Moreover, our estimates of perioperative naloxone access were likely an overestimate by including patients dispensed naloxone up to 1 year before surgery until 7 days after surgery. The aim was to include patients who may not have been prescribed naloxone postoperatively because of an existing naloxone prescription at home. Perioperative naloxone access estimates would have been even lower if a narrower window had been used to approximate perioperative access. This identifies an important gap between those who may benefit from naloxone dispensing and those who received naloxone. This in part may be because OEND has not been implemented as routinely in surgical settings as other settings (eg, primary care). OEND efforts may more effectively increase naloxone prescribing among surgical patients if these efforts were targeted at surgical and anesthesia departments. Given that the Comprehensive Addiction and Recovery Act of 2016 requires an assessment of patient risk prior to opioid prescribing and VHA efforts to increase utilization of tools like the Stratification Tool for Opioid Risk Mitigation (STORM), which estimates patient risk when initiating an opioid prescription and includes naloxone as one of many risk mitigation strategies, we anticipate that rates of naloxone prescribing will increase over time.

Limitations

Our study captures a large number of patients across VHA hospitals of varying size nationwide, including a mix of those with and without academic medical center affiliations. This veteran population may not represent the US commercially insured population (CIP). Zedler and colleagues highlighted the differences in prevalence of individual risk factors: notably, the CIP had a substantially higher proportion of females and younger patients.¹¹ VHA had a greater prevalence of common chronic conditions associated with older age. The frequency of opioid dependence was similar among CIP and VHA. However, substance abuse and nonopioid substance dependence diagnoses were 4-fold more frequent among VHA controls as CIP controls. Prescribing of all opioids, except morphine and methadone, was substantially greater in CIP than in VHA.¹¹ Despite a difference in individual risk factors, a CIP-specific RIOSORD has been validated and can be used outside of the VHA to obviate the limitations of the VHA-specific RIOSORD.¹¹

Other limitations include our estimation of naloxone access. We do not know whether naloxone was administered or have a reliable estimate of overdose incidence in this postoperative TKA population. Also, it is important to note that RIOSORD was not developed for surgical patients. The use of RIOSORD in a postoperative population likely underestimates risk of opioid overdose due to the frequent prescriptions of new opioids or escalation of existing MEDD to the postoperative patient. Our study was also retrospective in nature and reliant on accurate coding of patient risk factors. It is possible that comorbidities were not accurately identified by EHR and therefore subject to inconsistency.

Conclusions

Veterans presenting for TKA routinely have risk factors for opioid overdose. We observed a trend toward decreasing overdose risk which coincided with the Opioid Safety and OEND initiatives within the VHA. We also observed an increase in naloxone prescription for moderate- and high-risk patients undergoing TKA, although most of these patients still did not receive naloxone as of 2016. More research is needed to refine and validate the RIOSORD score for surgical populations. Expanding initiatives such as OEND to include surgical patients presents an opportunity to improve access to naloxone for postoperative patients that may help reduce opioid overdose in this population.

Opioid overdose is a major public health challenge, with recent reports estimating 41 deaths per day in the United States from prescription opioid overdose.^1,2 Prescribing naloxone has increasingly been advocated to reduce the risk of opioid overdose for patients identified as high risk. Naloxone distribution has been shown to decrease the incidence of opioid overdoses in the general population.^3,4 The Centers for Disease Control and Prevention (CDC) Guideline for Prescribing Opioids for Chronic Pain recommends considering naloxone prescription for patients with a history of overdose or substance use disorder, opioid dosages ≥ 50 morphine equivalent daily dose (MEDD), and concurrent use of benzodiazepines.⁵

Although the CDC guidelines are intended for primary care clinicians in outpatient settings, naloxone prescribing is also relevant in the postsurgical setting.⁵ Many surgical patients are at risk for opioid overdose and data from the Veterans Health Administration (VHA) has shown that risk of opioid overdose is 11-fold higher in the 30 days following discharge from a surgical admission, when compared with the subsequent calendar year.^6,7 This likely occurs due to new prescriptions or escalated doses of opioids following surgery. Overdose risk may be particularly relevant to orthopedic surgery as postoperative opioids are commonly prescribed.⁸ Patients undergoing total knee arthroplasty (TKA) may represent a vulnerable population to overdose as it is one of the most commonly performed surgeries for the treatment of chronic pain, and is frequently performed in older adults with medical comorbidities.^9,10

Identifying patients at high risk for opioid overdose is important for targeted naloxone dispensing.⁵ A risk index for overdose or serious opioid-induced respiratory depression (RIOSORD) tool has been developed and validated in veteran and other populations to identify such patients.¹¹ The RIOSORD tool classifies patients by risk level (1-10) and predicts probability of overdose or serious opioid-induced respiratory depression (OSORD). A patient’s level of risk is based on a weighted combination of the 15 independent risk factors most highly associated with OSORD, including comorbid conditions, prescription drug use, and health care utilization.¹² Using the RIOSORD tool, the VHA Opioid Education and Naloxone Distribution (OEND) program is a risk mitigation initiative that aims to decrease opioid-related overdose morbidity and mortality. This is achieved via opioid overdose education for prevention, recognition, and response and includes outpatient naloxone prescription.^13,14

Despite the comprehensive OEND program, there exists very little data to guide postsurgical naloxone prescribing. The prevalence of known risk factors for overdose in surgical patients remains unknown, as does the prevalence of perioperative naloxone distribution. Understanding overdose risk factors and naloxone prescribing patterns in surgical patients may identify potential targets for OEND efforts. This study retrospectively estimated RIOSORD scores for TKA patients between 2013 to 2016 and described naloxone distribution based on RIOSORD scores and risk factors.

Methods

We identified patients who had undergone primary TKA at VHA hospitals using Current Procedural Terminology (CPT), International Classification of Diseases, Ninth Revision (ICD-9) procedure codes, and data extracted from the VHA Corporate Data Warehouse (CDW) of electronic health records (EHRs). Our study was granted approval with exemption from informed consent by the Durham Veteran Affairs Healthcare System Institutional Review Board.

This retrospective cohort study included all veterans who underwent elective primary TKA from January 1, 2013 through December 31, 2016. We excluded patients who died before discharge.

Outcomes

Our primary outcome was being dispensed an outpatient naloxone prescription following TKA. Naloxone dispensing was identified by examining CDW outpatient pharmacy records with a final dispense date from 1 year before surgery through 7 days after discharge following TKA. To exclude naloxone administration that may have been given in a clinic, prescription data included only records with an outpatient prescription copay. Naloxone dispensing in the year before surgery was chosen to estimate likely preoperative possession of naloxone which could be available in the postoperative period. Naloxone dispensing until 7 days after discharge was chosen to identify any new dispensing that would be available in the postoperative period. These outcomes were examined over the study time frame on an annual basis.

Patient Factors

Demographic variables included age, sex, and race/ethnicity. Independent risk factors for overdose from RIOSORD were identified for each patient.¹⁵ These risk factors included comorbidities (opioid use disorder, schizophrenia, bipolar disorder, liver disease, chronic kidney disease, sleep apnea, or lung disease) and prescription drug use (use of opioids, benzodiazepines, long-acting opioids, ≥ 50 MEDD or ≥ 100 MEDD). ICD-9 and ICD-10 diagnosis codes were used to identify comorbidities. Risk classes on day of surgery were identified using a RIOSORD algorithm code. Consistent with the display of RIOSORD risk classes on the VHA Academic Detailing Service OEND risk report, patients were grouped into 3 groups based on their RIOSORD score: classes 1 to 4 (low risk), 5 to 7 (moderate risk), and 8 to 10 (high risk).

Descriptive statistics were used to summarize data on patient demographics, RIOSORD risk factors, overdose events, and naloxone dispensing over time.

Results

The study cohort included 38,011 veterans who underwent primary TKA in the VHA between January 1, 2013 and December 30, 2016. In this cohort, the mean age was 65 years, 93% were male, and 77% were White patients (Table 1). The most common comorbidities were lung disease in 9170 (24.1%) patients, sleep apnea in 6630 (17.4%) patients, chronic kidney disease in 4036 (10.6%) patients, liver disease in 2822 (7.4%) patients, and bipolar disorder in 1748 (4.6%) patients.

In 2013, 63.1% of patients presenting for surgery were actively prescribed opioids. By 2016, this decreased to 50.5%. Benzodiazepine use decreased from 13.2 to 8.8% and long-acting opioid use decreased from 8.5 to 5.8% over the same period. Patients taking ≥ 50 MEDD decreased from 8.0 to 5.3% and patients taking ≥ 100 MEDD decreased from 3.3 to 2.2%. The prevalence of moderate-risk patients decreased from 2.5 to 1.6% and high-risk patients decreased from 0.8 to 0.6% (Figure 1). Cumulatively, the prevalence of presenting with either moderate or high risk of overdose decreased from 3.3 to 2.2% between 2013 to 2016.

Naloxone Dispensing

In 2013, naloxone was not dispensed to any patients at moderate or high risk for overdose between 365 days prior to surgery until 7 days after discharge (Table 2 and Figure 2). Low-risk group naloxone dispensing increased to 2 (0.0%) in 2014, to 13 (0.1%), in 2015, and to 86 (0.9%) in 2016. Moderate-risk group naloxone dispensing remained at 0 (0.0%) in 2014, but increased to 8 (3.5%) in 2015, and to 18 (10.9%) in 2016. High-risk group naloxone dispensing remained at 0 (0.0%) in 2014, but increased to 5 (5.8%) in 2015, and to 8 (12.7%) in 2016 (Figure 3).

Discussion

Our data demonstrate that patients presenting for TKA between 2013 and 2016 routinely had individual risk factors for overdose related to either prescription drug use or comorbidities. We also show that, although the number of patients at moderate and high risk for opioid overdose is decreasing, 2.2% of TKA patients remain at moderate or high risk for opioid overdose based on a weighted combination of these individual risk factors using RIOSORD. As demand for primary TKA is projected to grow to 3.5 million procedures by 2030, using prevalence from 2016, we estimate that 76,560 patients may present for TKA across the US with moderate or high risk for opioid overdose.⁹ Following discharge, this risk may be even higher as this estimate does not yet account for postoperative opioid use. We demonstrate that through a VHA OEND initiative, naloxone distribution increased and appeared to be targeted to those most at risk using a simple validated tool like RIOSORD.

Presence of an individual risk factor for overdose was present in as many as 63.1% of patients presenting for TKA, as was seen in 2013 with preoperative opioid use. The 3 highest scoring prescription use–related risk factors in RIOSORD are use of opioids ≥ 100 MEDD (16 points), ≥ 50 MEDD (9 points), and long-acting formulations (9 points). All 3 decreased in prevalence over the study period but by 2016 were still seen in 2.2% for ≥ 100 MEDD, 5.3% for ≥ 50 MEDD, and 5.8% for long-acting opioids. This decrease was not surprising given implementation of a VHA-wide opioid safety initiative and the OEND program, but this could also be related to changes in patient selection for surgery in the context of increased awareness of the opioid epidemic. Despite the trend toward safer opioid prescribing, by 2016 over half of patients (50.5%) who presented for TKA were already taking opioids, with 10.6% (543 of 5127) on doses ≥ 50 MEDD.

We observed a decrease in RIOSORD risk each year, consistent with decreasing prescription-related risk factors over time. This was most obvious in the moderate-risk group. It is unclear why a similar decrease was not as obvious in the high-risk group, but this in part may be due to the already low numbers of patients in the high-risk group. This may also represent the high-risk group being somewhat resistant to the initiatives that shifted moderate-risk patients to the low-risk group. There were proportionately more patients in the moderate- and high-risk groups in the original RIOSORD population than in our surgical population, which may be attributed to the fewer comorbidities seen in our surgical population, as well as the higher opioid-prescribing patterns seen prior to the VA OEND initiative.¹²

Naloxone prescribing was rare prior to the OEND initiative and increased from 2013 to 2016. Increases were most marked in those in moderate- and high-risk groups, although naloxone prescribing also increased among the low-risk group. Integration of RIOSORD stratification into the OEND initiative likely played a role in targeting increased access to naloxone among those at highest risk of overdose. Naloxone dispensing increased for every group, although a significant proportion of moderate- and high-risk patients, 89.1% and 87.3%, respectively, were still not dispensed naloxone by 2016. Moreover, our estimates of perioperative naloxone access were likely an overestimate by including patients dispensed naloxone up to 1 year before surgery until 7 days after surgery. The aim was to include patients who may not have been prescribed naloxone postoperatively because of an existing naloxone prescription at home. Perioperative naloxone access estimates would have been even lower if a narrower window had been used to approximate perioperative access. This identifies an important gap between those who may benefit from naloxone dispensing and those who received naloxone. This in part may be because OEND has not been implemented as routinely in surgical settings as other settings (eg, primary care). OEND efforts may more effectively increase naloxone prescribing among surgical patients if these efforts were targeted at surgical and anesthesia departments. Given that the Comprehensive Addiction and Recovery Act of 2016 requires an assessment of patient risk prior to opioid prescribing and VHA efforts to increase utilization of tools like the Stratification Tool for Opioid Risk Mitigation (STORM), which estimates patient risk when initiating an opioid prescription and includes naloxone as one of many risk mitigation strategies, we anticipate that rates of naloxone prescribing will increase over time.

Limitations

Our study captures a large number of patients across VHA hospitals of varying size nationwide, including a mix of those with and without academic medical center affiliations. This veteran population may not represent the US commercially insured population (CIP). Zedler and colleagues highlighted the differences in prevalence of individual risk factors: notably, the CIP had a substantially higher proportion of females and younger patients.¹¹ VHA had a greater prevalence of common chronic conditions associated with older age. The frequency of opioid dependence was similar among CIP and VHA. However, substance abuse and nonopioid substance dependence diagnoses were 4-fold more frequent among VHA controls as CIP controls. Prescribing of all opioids, except morphine and methadone, was substantially greater in CIP than in VHA.¹¹ Despite a difference in individual risk factors, a CIP-specific RIOSORD has been validated and can be used outside of the VHA to obviate the limitations of the VHA-specific RIOSORD.¹¹

Other limitations include our estimation of naloxone access. We do not know whether naloxone was administered or have a reliable estimate of overdose incidence in this postoperative TKA population. Also, it is important to note that RIOSORD was not developed for surgical patients. The use of RIOSORD in a postoperative population likely underestimates risk of opioid overdose due to the frequent prescriptions of new opioids or escalation of existing MEDD to the postoperative patient. Our study was also retrospective in nature and reliant on accurate coding of patient risk factors. It is possible that comorbidities were not accurately identified by EHR and therefore subject to inconsistency.

Conclusions

Veterans presenting for TKA routinely have risk factors for opioid overdose. We observed a trend toward decreasing overdose risk which coincided with the Opioid Safety and OEND initiatives within the VHA. We also observed an increase in naloxone prescription for moderate- and high-risk patients undergoing TKA, although most of these patients still did not receive naloxone as of 2016. More research is needed to refine and validate the RIOSORD score for surgical populations. Expanding initiatives such as OEND to include surgical patients presents an opportunity to improve access to naloxone for postoperative patients that may help reduce opioid overdose in this population.

Opioid overdose is a major public health challenge, with recent reports estimating 41 deaths per day in the United States from prescription opioid overdose.^1,2 Prescribing naloxone has increasingly been advocated to reduce the risk of opioid overdose for patients identified as high risk. Naloxone distribution has been shown to decrease the incidence of opioid overdoses in the general population.^3,4 The Centers for Disease Control and Prevention (CDC) Guideline for Prescribing Opioids for Chronic Pain recommends considering naloxone prescription for patients with a history of overdose or substance use disorder, opioid dosages ≥ 50 morphine equivalent daily dose (MEDD), and concurrent use of benzodiazepines.⁵

Although the CDC guidelines are intended for primary care clinicians in outpatient settings, naloxone prescribing is also relevant in the postsurgical setting.⁵ Many surgical patients are at risk for opioid overdose and data from the Veterans Health Administration (VHA) has shown that risk of opioid overdose is 11-fold higher in the 30 days following discharge from a surgical admission, when compared with the subsequent calendar year.^6,7 This likely occurs due to new prescriptions or escalated doses of opioids following surgery. Overdose risk may be particularly relevant to orthopedic surgery as postoperative opioids are commonly prescribed.⁸ Patients undergoing total knee arthroplasty (TKA) may represent a vulnerable population to overdose as it is one of the most commonly performed surgeries for the treatment of chronic pain, and is frequently performed in older adults with medical comorbidities.^9,10

Identifying patients at high risk for opioid overdose is important for targeted naloxone dispensing.⁵ A risk index for overdose or serious opioid-induced respiratory depression (RIOSORD) tool has been developed and validated in veteran and other populations to identify such patients.¹¹ The RIOSORD tool classifies patients by risk level (1-10) and predicts probability of overdose or serious opioid-induced respiratory depression (OSORD). A patient’s level of risk is based on a weighted combination of the 15 independent risk factors most highly associated with OSORD, including comorbid conditions, prescription drug use, and health care utilization.¹² Using the RIOSORD tool, the VHA Opioid Education and Naloxone Distribution (OEND) program is a risk mitigation initiative that aims to decrease opioid-related overdose morbidity and mortality. This is achieved via opioid overdose education for prevention, recognition, and response and includes outpatient naloxone prescription.^13,14

Despite the comprehensive OEND program, there exists very little data to guide postsurgical naloxone prescribing. The prevalence of known risk factors for overdose in surgical patients remains unknown, as does the prevalence of perioperative naloxone distribution. Understanding overdose risk factors and naloxone prescribing patterns in surgical patients may identify potential targets for OEND efforts. This study retrospectively estimated RIOSORD scores for TKA patients between 2013 to 2016 and described naloxone distribution based on RIOSORD scores and risk factors.

Methods

We identified patients who had undergone primary TKA at VHA hospitals using Current Procedural Terminology (CPT), International Classification of Diseases, Ninth Revision (ICD-9) procedure codes, and data extracted from the VHA Corporate Data Warehouse (CDW) of electronic health records (EHRs). Our study was granted approval with exemption from informed consent by the Durham Veteran Affairs Healthcare System Institutional Review Board.

This retrospective cohort study included all veterans who underwent elective primary TKA from January 1, 2013 through December 31, 2016. We excluded patients who died before discharge.

Outcomes

Our primary outcome was being dispensed an outpatient naloxone prescription following TKA. Naloxone dispensing was identified by examining CDW outpatient pharmacy records with a final dispense date from 1 year before surgery through 7 days after discharge following TKA. To exclude naloxone administration that may have been given in a clinic, prescription data included only records with an outpatient prescription copay. Naloxone dispensing in the year before surgery was chosen to estimate likely preoperative possession of naloxone which could be available in the postoperative period. Naloxone dispensing until 7 days after discharge was chosen to identify any new dispensing that would be available in the postoperative period. These outcomes were examined over the study time frame on an annual basis.

Patient Factors

Demographic variables included age, sex, and race/ethnicity. Independent risk factors for overdose from RIOSORD were identified for each patient.¹⁵ These risk factors included comorbidities (opioid use disorder, schizophrenia, bipolar disorder, liver disease, chronic kidney disease, sleep apnea, or lung disease) and prescription drug use (use of opioids, benzodiazepines, long-acting opioids, ≥ 50 MEDD or ≥ 100 MEDD). ICD-9 and ICD-10 diagnosis codes were used to identify comorbidities. Risk classes on day of surgery were identified using a RIOSORD algorithm code. Consistent with the display of RIOSORD risk classes on the VHA Academic Detailing Service OEND risk report, patients were grouped into 3 groups based on their RIOSORD score: classes 1 to 4 (low risk), 5 to 7 (moderate risk), and 8 to 10 (high risk).

Descriptive statistics were used to summarize data on patient demographics, RIOSORD risk factors, overdose events, and naloxone dispensing over time.

Results

The study cohort included 38,011 veterans who underwent primary TKA in the VHA between January 1, 2013 and December 30, 2016. In this cohort, the mean age was 65 years, 93% were male, and 77% were White patients (Table 1). The most common comorbidities were lung disease in 9170 (24.1%) patients, sleep apnea in 6630 (17.4%) patients, chronic kidney disease in 4036 (10.6%) patients, liver disease in 2822 (7.4%) patients, and bipolar disorder in 1748 (4.6%) patients.

In 2013, 63.1% of patients presenting for surgery were actively prescribed opioids. By 2016, this decreased to 50.5%. Benzodiazepine use decreased from 13.2 to 8.8% and long-acting opioid use decreased from 8.5 to 5.8% over the same period. Patients taking ≥ 50 MEDD decreased from 8.0 to 5.3% and patients taking ≥ 100 MEDD decreased from 3.3 to 2.2%. The prevalence of moderate-risk patients decreased from 2.5 to 1.6% and high-risk patients decreased from 0.8 to 0.6% (Figure 1). Cumulatively, the prevalence of presenting with either moderate or high risk of overdose decreased from 3.3 to 2.2% between 2013 to 2016.

Naloxone Dispensing

In 2013, naloxone was not dispensed to any patients at moderate or high risk for overdose between 365 days prior to surgery until 7 days after discharge (Table 2 and Figure 2). Low-risk group naloxone dispensing increased to 2 (0.0%) in 2014, to 13 (0.1%), in 2015, and to 86 (0.9%) in 2016. Moderate-risk group naloxone dispensing remained at 0 (0.0%) in 2014, but increased to 8 (3.5%) in 2015, and to 18 (10.9%) in 2016. High-risk group naloxone dispensing remained at 0 (0.0%) in 2014, but increased to 5 (5.8%) in 2015, and to 8 (12.7%) in 2016 (Figure 3).

Discussion

Our data demonstrate that patients presenting for TKA between 2013 and 2016 routinely had individual risk factors for overdose related to either prescription drug use or comorbidities. We also show that, although the number of patients at moderate and high risk for opioid overdose is decreasing, 2.2% of TKA patients remain at moderate or high risk for opioid overdose based on a weighted combination of these individual risk factors using RIOSORD. As demand for primary TKA is projected to grow to 3.5 million procedures by 2030, using prevalence from 2016, we estimate that 76,560 patients may present for TKA across the US with moderate or high risk for opioid overdose.⁹ Following discharge, this risk may be even higher as this estimate does not yet account for postoperative opioid use. We demonstrate that through a VHA OEND initiative, naloxone distribution increased and appeared to be targeted to those most at risk using a simple validated tool like RIOSORD.

Presence of an individual risk factor for overdose was present in as many as 63.1% of patients presenting for TKA, as was seen in 2013 with preoperative opioid use. The 3 highest scoring prescription use–related risk factors in RIOSORD are use of opioids ≥ 100 MEDD (16 points), ≥ 50 MEDD (9 points), and long-acting formulations (9 points). All 3 decreased in prevalence over the study period but by 2016 were still seen in 2.2% for ≥ 100 MEDD, 5.3% for ≥ 50 MEDD, and 5.8% for long-acting opioids. This decrease was not surprising given implementation of a VHA-wide opioid safety initiative and the OEND program, but this could also be related to changes in patient selection for surgery in the context of increased awareness of the opioid epidemic. Despite the trend toward safer opioid prescribing, by 2016 over half of patients (50.5%) who presented for TKA were already taking opioids, with 10.6% (543 of 5127) on doses ≥ 50 MEDD.

We observed a decrease in RIOSORD risk each year, consistent with decreasing prescription-related risk factors over time. This was most obvious in the moderate-risk group. It is unclear why a similar decrease was not as obvious in the high-risk group, but this in part may be due to the already low numbers of patients in the high-risk group. This may also represent the high-risk group being somewhat resistant to the initiatives that shifted moderate-risk patients to the low-risk group. There were proportionately more patients in the moderate- and high-risk groups in the original RIOSORD population than in our surgical population, which may be attributed to the fewer comorbidities seen in our surgical population, as well as the higher opioid-prescribing patterns seen prior to the VA OEND initiative.¹²

Naloxone prescribing was rare prior to the OEND initiative and increased from 2013 to 2016. Increases were most marked in those in moderate- and high-risk groups, although naloxone prescribing also increased among the low-risk group. Integration of RIOSORD stratification into the OEND initiative likely played a role in targeting increased access to naloxone among those at highest risk of overdose. Naloxone dispensing increased for every group, although a significant proportion of moderate- and high-risk patients, 89.1% and 87.3%, respectively, were still not dispensed naloxone by 2016. Moreover, our estimates of perioperative naloxone access were likely an overestimate by including patients dispensed naloxone up to 1 year before surgery until 7 days after surgery. The aim was to include patients who may not have been prescribed naloxone postoperatively because of an existing naloxone prescription at home. Perioperative naloxone access estimates would have been even lower if a narrower window had been used to approximate perioperative access. This identifies an important gap between those who may benefit from naloxone dispensing and those who received naloxone. This in part may be because OEND has not been implemented as routinely in surgical settings as other settings (eg, primary care). OEND efforts may more effectively increase naloxone prescribing among surgical patients if these efforts were targeted at surgical and anesthesia departments. Given that the Comprehensive Addiction and Recovery Act of 2016 requires an assessment of patient risk prior to opioid prescribing and VHA efforts to increase utilization of tools like the Stratification Tool for Opioid Risk Mitigation (STORM), which estimates patient risk when initiating an opioid prescription and includes naloxone as one of many risk mitigation strategies, we anticipate that rates of naloxone prescribing will increase over time.

Limitations

Our study captures a large number of patients across VHA hospitals of varying size nationwide, including a mix of those with and without academic medical center affiliations. This veteran population may not represent the US commercially insured population (CIP). Zedler and colleagues highlighted the differences in prevalence of individual risk factors: notably, the CIP had a substantially higher proportion of females and younger patients.¹¹ VHA had a greater prevalence of common chronic conditions associated with older age. The frequency of opioid dependence was similar among CIP and VHA. However, substance abuse and nonopioid substance dependence diagnoses were 4-fold more frequent among VHA controls as CIP controls. Prescribing of all opioids, except morphine and methadone, was substantially greater in CIP than in VHA.¹¹ Despite a difference in individual risk factors, a CIP-specific RIOSORD has been validated and can be used outside of the VHA to obviate the limitations of the VHA-specific RIOSORD.¹¹

Other limitations include our estimation of naloxone access. We do not know whether naloxone was administered or have a reliable estimate of overdose incidence in this postoperative TKA population. Also, it is important to note that RIOSORD was not developed for surgical patients. The use of RIOSORD in a postoperative population likely underestimates risk of opioid overdose due to the frequent prescriptions of new opioids or escalation of existing MEDD to the postoperative patient. Our study was also retrospective in nature and reliant on accurate coding of patient risk factors. It is possible that comorbidities were not accurately identified by EHR and therefore subject to inconsistency.

Conclusions

Veterans presenting for TKA routinely have risk factors for opioid overdose. We observed a trend toward decreasing overdose risk which coincided with the Opioid Safety and OEND initiatives within the VHA. We also observed an increase in naloxone prescription for moderate- and high-risk patients undergoing TKA, although most of these patients still did not receive naloxone as of 2016. More research is needed to refine and validate the RIOSORD score for surgical populations. Expanding initiatives such as OEND to include surgical patients presents an opportunity to improve access to naloxone for postoperative patients that may help reduce opioid overdose in this population.

You have a 16-year-old patient who has been doing poorly in school. He has withdrawn from his social group and quit the sports in which he excelled. He admits to using marijuana “maybe once or twice a week.” But you and his parents suspect that it is much more often and contributing to the change in his behavior and school performance.

They would prefer he not use marijuana at all but could maybe be comfortable with some arrangement in which their son could demonstrate that his usage was indeed limited to once or twice on the weekends. They ask for your help with crafting a contract that might include “some urine or blood test” that would allow them to be sure their son was adhering to the contract.

You explain to them that there are hazards associated with setting up contracts such as the one they are proposing. One revolving around the issue of trust. Another being that he may be addicted to the point that a compromise that includes scaling back his usage is unlikely to succeed. And, finally, you tell them that because of marijuana’s pharmacokinetics, their son’s urine tests will always be positive and not reflective of the how much he is using or whether he is intoxicated.

Scenarios similar to this are increasingly common for those of us living in states that have legalized recreational cannabis use. The absence of a laboratory test that can determine when a person is impaired by marijuana has made life difficult for law enforcement officers accustomed to relying on breath and blood tests for alcohol to confirm their suspicion that a driver is under the influence.

In addition, because marijuana is still detectable days after it is used, many well-paying jobs go unfilled when potential applicants are hesitant to submit to a required drug test. The quirky pharmacokinetics of cannabis are well-known to the recreational users and they see no reason to risk failing a urine test regardless of how good the job may be.

This lack of a reliable indicator of cannabis intoxication has not gone unnoticed, and in a recent study published in the journal Neuropharmacology, researchers at Massachusetts General Hospital in Boston report some hopeful results using fNIRS brain scanning. The investigators observed an increase in the level of oxygenated hemoglobin concentration (HbO), which is a type of neural activity signature, in the prefrontal cortex region of the volunteers who reported being impaired.

While a brain scan may sound like an unwieldy tool to use on roadside sobriety stops, the researchers report that portable scanners – some using skull cap sensors – could be easily adapted for use by law enforcement in the field. This technology also could be used by employers on the job site to test truck drivers and heavy machine operators at the beginning of each shift, thereby allaying the fears of responsible cannabis users.

This technology might be helpful to you in advising the parents of the 16-year-old you suspect of heavy usage. It would certainly help in confirming the suspicion that he is using more often than he claims. However, the contract the parents propose still may not work. If this young man demonstrates on multiple attempts that his word can’t be trusted, technology isn’t going to be the answer.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

You have a 16-year-old patient who has been doing poorly in school. He has withdrawn from his social group and quit the sports in which he excelled. He admits to using marijuana “maybe once or twice a week.” But you and his parents suspect that it is much more often and contributing to the change in his behavior and school performance.

They would prefer he not use marijuana at all but could maybe be comfortable with some arrangement in which their son could demonstrate that his usage was indeed limited to once or twice on the weekends. They ask for your help with crafting a contract that might include “some urine or blood test” that would allow them to be sure their son was adhering to the contract.

You explain to them that there are hazards associated with setting up contracts such as the one they are proposing. One revolving around the issue of trust. Another being that he may be addicted to the point that a compromise that includes scaling back his usage is unlikely to succeed. And, finally, you tell them that because of marijuana’s pharmacokinetics, their son’s urine tests will always be positive and not reflective of the how much he is using or whether he is intoxicated.

Scenarios similar to this are increasingly common for those of us living in states that have legalized recreational cannabis use. The absence of a laboratory test that can determine when a person is impaired by marijuana has made life difficult for law enforcement officers accustomed to relying on breath and blood tests for alcohol to confirm their suspicion that a driver is under the influence.

In addition, because marijuana is still detectable days after it is used, many well-paying jobs go unfilled when potential applicants are hesitant to submit to a required drug test. The quirky pharmacokinetics of cannabis are well-known to the recreational users and they see no reason to risk failing a urine test regardless of how good the job may be.

This lack of a reliable indicator of cannabis intoxication has not gone unnoticed, and in a recent study published in the journal Neuropharmacology, researchers at Massachusetts General Hospital in Boston report some hopeful results using fNIRS brain scanning. The investigators observed an increase in the level of oxygenated hemoglobin concentration (HbO), which is a type of neural activity signature, in the prefrontal cortex region of the volunteers who reported being impaired.

While a brain scan may sound like an unwieldy tool to use on roadside sobriety stops, the researchers report that portable scanners – some using skull cap sensors – could be easily adapted for use by law enforcement in the field. This technology also could be used by employers on the job site to test truck drivers and heavy machine operators at the beginning of each shift, thereby allaying the fears of responsible cannabis users.

This technology might be helpful to you in advising the parents of the 16-year-old you suspect of heavy usage. It would certainly help in confirming the suspicion that he is using more often than he claims. However, the contract the parents propose still may not work. If this young man demonstrates on multiple attempts that his word can’t be trusted, technology isn’t going to be the answer.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

You have a 16-year-old patient who has been doing poorly in school. He has withdrawn from his social group and quit the sports in which he excelled. He admits to using marijuana “maybe once or twice a week.” But you and his parents suspect that it is much more often and contributing to the change in his behavior and school performance.

They would prefer he not use marijuana at all but could maybe be comfortable with some arrangement in which their son could demonstrate that his usage was indeed limited to once or twice on the weekends. They ask for your help with crafting a contract that might include “some urine or blood test” that would allow them to be sure their son was adhering to the contract.

You explain to them that there are hazards associated with setting up contracts such as the one they are proposing. One revolving around the issue of trust. Another being that he may be addicted to the point that a compromise that includes scaling back his usage is unlikely to succeed. And, finally, you tell them that because of marijuana’s pharmacokinetics, their son’s urine tests will always be positive and not reflective of the how much he is using or whether he is intoxicated.

Scenarios similar to this are increasingly common for those of us living in states that have legalized recreational cannabis use. The absence of a laboratory test that can determine when a person is impaired by marijuana has made life difficult for law enforcement officers accustomed to relying on breath and blood tests for alcohol to confirm their suspicion that a driver is under the influence.

In addition, because marijuana is still detectable days after it is used, many well-paying jobs go unfilled when potential applicants are hesitant to submit to a required drug test. The quirky pharmacokinetics of cannabis are well-known to the recreational users and they see no reason to risk failing a urine test regardless of how good the job may be.

This lack of a reliable indicator of cannabis intoxication has not gone unnoticed, and in a recent study published in the journal Neuropharmacology, researchers at Massachusetts General Hospital in Boston report some hopeful results using fNIRS brain scanning. The investigators observed an increase in the level of oxygenated hemoglobin concentration (HbO), which is a type of neural activity signature, in the prefrontal cortex region of the volunteers who reported being impaired.

While a brain scan may sound like an unwieldy tool to use on roadside sobriety stops, the researchers report that portable scanners – some using skull cap sensors – could be easily adapted for use by law enforcement in the field. This technology also could be used by employers on the job site to test truck drivers and heavy machine operators at the beginning of each shift, thereby allaying the fears of responsible cannabis users.

This technology might be helpful to you in advising the parents of the 16-year-old you suspect of heavy usage. It would certainly help in confirming the suspicion that he is using more often than he claims. However, the contract the parents propose still may not work. If this young man demonstrates on multiple attempts that his word can’t be trusted, technology isn’t going to be the answer.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].