Addiction Medicine

The majority of addiction specialists, including psychiatrists, believe psychedelics are promising for the treatment of substance use disorders (SUDs) and psychiatric illnesses and, with some caveats, support legalization of the substances for these indications, results of a new survey show.

This strong positive attitude is “a surprise” given previous wariness of addiction specialists regarding legalization of marijuana, noted study investigator Amanda Kim, MD, JD, of Brigham and Women’s Hospital and Harvard Medical School, Boston.

“We had hypothesized that addiction specialists would express more skepticism about psychedelics compared to nonaddiction specialists,” Dr. Kim said.

Instead, addiction experts who participated in the survey were very much in favor of psychedelics being legalized for therapeutic use, but only in a controlled setting.

The findings were presented at the annual meeting of the American Academy of Addiction Psychiatry.
 

Growing interest

In recent years, there has been increased interest in the scientific community and among the general public in the therapeutic potential of psychedelics, said Dr. Kim. Previous research has shown growing positivity about psychedelics and support for their legalization among psychiatrists, she added.

Psychedelics have been decriminalized and/or legalized in several jurisdictions. The Food and Drug Administration has granted breakthrough therapy designation for 3,4-methylenedioxymethamphetamine (MDMA) in the treatment of posttraumatic stress disorder (PTSD) and has granted the same designation to psilocybin in the treatment of major depressive disorder.

“Despite psychedelics increasingly entering the mainstream, we are unaware of any studies specifically assessing the current attitudes of physicians specializing in addictions regarding psychedelics,” Dr. Kim said.

For the study, investigators identified prospective survey participants from the AAAP directory. They also reached out to program directors of addiction medicine and addiction psychiatry fellowships.

In the anonymous online survey, respondents were asked to rate their level of agreement with 30 statements.

The analysis included 145 respondents (59% men; mean age, 46.2 years). Psychiatrists made up about two-thirds of the sample. The remainder specialized in internal and family medicine.

Most respondents had some clinical exposure to psychedelics. Almost 85% reported discussing a psychedelic experience with at least one patient.
 

Positive attitudes, concerns

Overall, participants expressed very positive attitudes regarding the therapeutic use of psychedelics. About 64% strongly agreed or agreed psychedelics show promise in treating SUDs, and 82% agreed they show promise in treating psychiatric disorders.

However, more than one-third of respondents (37.9%) expressed concern about the addictive potential of psychedelics. This is more than in previous research polling psychiatrists, possibly because the study’s “broad” definition of psychedelics included “nonclassic, nonserotonergic hallucinogens,” such as ketamine and MDMA, Dr. Kim noted.

Because ketamine and MDMA are both lumped into the hallucinogen category in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), “and both are known to have addictive potential, this may have obscured participant responses,” she added.

Some 28% of participants expressed concern about psychedelic use increasing the risk for subsequent psychiatric disorders and long-term cognitive impairment.

Almost three-quarters (74.5%) believe the therapeutic use of psychedelics should be legalized. However, most wanted legal therapeutic psychedelics to be highly regulated and administered only in controlled settings with specially trained providers.

Almost half of the sample believed therapeutic psychedelics should be legal in a variety of different contexts and by non-Western providers, in accordance with indigenous and/or spiritual traditions.

One surprising finding was that most respondents believed patients would be keen on using psychedelics to treat SUDs, said Dr. Kim.

“This may reflect evolving attitudes of both providers and patients about psychedelics, and it will be interesting to further study attitudes of patients toward the use of psychedelics to treat SUD in the future,” she added.

Attitudes toward psychedelics were generally similar for psychiatrists and nonpsychiatrists; but psychiatrists expressed greater comfort in discussing them with patients and were more likely to have observed complications of psychedelics use in their practice.

Dr. Kim said the study’s limitations included the small sample size and possible selection bias, as those with more favorable views of psychedelics may have been more likely to respond.

The study was supported by the Source Research Foundation.

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

The majority of addiction specialists, including psychiatrists, believe psychedelics are promising for the treatment of substance use disorders (SUDs) and psychiatric illnesses and, with some caveats, support legalization of the substances for these indications, results of a new survey show.

This strong positive attitude is “a surprise” given previous wariness of addiction specialists regarding legalization of marijuana, noted study investigator Amanda Kim, MD, JD, of Brigham and Women’s Hospital and Harvard Medical School, Boston.

“We had hypothesized that addiction specialists would express more skepticism about psychedelics compared to nonaddiction specialists,” Dr. Kim said.

Instead, addiction experts who participated in the survey were very much in favor of psychedelics being legalized for therapeutic use, but only in a controlled setting.

The findings were presented at the annual meeting of the American Academy of Addiction Psychiatry.
 

Growing interest

In recent years, there has been increased interest in the scientific community and among the general public in the therapeutic potential of psychedelics, said Dr. Kim. Previous research has shown growing positivity about psychedelics and support for their legalization among psychiatrists, she added.

Psychedelics have been decriminalized and/or legalized in several jurisdictions. The Food and Drug Administration has granted breakthrough therapy designation for 3,4-methylenedioxymethamphetamine (MDMA) in the treatment of posttraumatic stress disorder (PTSD) and has granted the same designation to psilocybin in the treatment of major depressive disorder.

“Despite psychedelics increasingly entering the mainstream, we are unaware of any studies specifically assessing the current attitudes of physicians specializing in addictions regarding psychedelics,” Dr. Kim said.

For the study, investigators identified prospective survey participants from the AAAP directory. They also reached out to program directors of addiction medicine and addiction psychiatry fellowships.

In the anonymous online survey, respondents were asked to rate their level of agreement with 30 statements.

The analysis included 145 respondents (59% men; mean age, 46.2 years). Psychiatrists made up about two-thirds of the sample. The remainder specialized in internal and family medicine.

Most respondents had some clinical exposure to psychedelics. Almost 85% reported discussing a psychedelic experience with at least one patient.
 

Positive attitudes, concerns

Overall, participants expressed very positive attitudes regarding the therapeutic use of psychedelics. About 64% strongly agreed or agreed psychedelics show promise in treating SUDs, and 82% agreed they show promise in treating psychiatric disorders.

However, more than one-third of respondents (37.9%) expressed concern about the addictive potential of psychedelics. This is more than in previous research polling psychiatrists, possibly because the study’s “broad” definition of psychedelics included “nonclassic, nonserotonergic hallucinogens,” such as ketamine and MDMA, Dr. Kim noted.

Because ketamine and MDMA are both lumped into the hallucinogen category in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), “and both are known to have addictive potential, this may have obscured participant responses,” she added.

Some 28% of participants expressed concern about psychedelic use increasing the risk for subsequent psychiatric disorders and long-term cognitive impairment.

Almost three-quarters (74.5%) believe the therapeutic use of psychedelics should be legalized. However, most wanted legal therapeutic psychedelics to be highly regulated and administered only in controlled settings with specially trained providers.

Almost half of the sample believed therapeutic psychedelics should be legal in a variety of different contexts and by non-Western providers, in accordance with indigenous and/or spiritual traditions.

One surprising finding was that most respondents believed patients would be keen on using psychedelics to treat SUDs, said Dr. Kim.

“This may reflect evolving attitudes of both providers and patients about psychedelics, and it will be interesting to further study attitudes of patients toward the use of psychedelics to treat SUD in the future,” she added.

Attitudes toward psychedelics were generally similar for psychiatrists and nonpsychiatrists; but psychiatrists expressed greater comfort in discussing them with patients and were more likely to have observed complications of psychedelics use in their practice.

Dr. Kim said the study’s limitations included the small sample size and possible selection bias, as those with more favorable views of psychedelics may have been more likely to respond.

The study was supported by the Source Research Foundation.

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

The majority of addiction specialists, including psychiatrists, believe psychedelics are promising for the treatment of substance use disorders (SUDs) and psychiatric illnesses and, with some caveats, support legalization of the substances for these indications, results of a new survey show.

This strong positive attitude is “a surprise” given previous wariness of addiction specialists regarding legalization of marijuana, noted study investigator Amanda Kim, MD, JD, of Brigham and Women’s Hospital and Harvard Medical School, Boston.

“We had hypothesized that addiction specialists would express more skepticism about psychedelics compared to nonaddiction specialists,” Dr. Kim said.

Instead, addiction experts who participated in the survey were very much in favor of psychedelics being legalized for therapeutic use, but only in a controlled setting.

The findings were presented at the annual meeting of the American Academy of Addiction Psychiatry.
 

Growing interest

In recent years, there has been increased interest in the scientific community and among the general public in the therapeutic potential of psychedelics, said Dr. Kim. Previous research has shown growing positivity about psychedelics and support for their legalization among psychiatrists, she added.

Psychedelics have been decriminalized and/or legalized in several jurisdictions. The Food and Drug Administration has granted breakthrough therapy designation for 3,4-methylenedioxymethamphetamine (MDMA) in the treatment of posttraumatic stress disorder (PTSD) and has granted the same designation to psilocybin in the treatment of major depressive disorder.

“Despite psychedelics increasingly entering the mainstream, we are unaware of any studies specifically assessing the current attitudes of physicians specializing in addictions regarding psychedelics,” Dr. Kim said.

For the study, investigators identified prospective survey participants from the AAAP directory. They also reached out to program directors of addiction medicine and addiction psychiatry fellowships.

In the anonymous online survey, respondents were asked to rate their level of agreement with 30 statements.

The analysis included 145 respondents (59% men; mean age, 46.2 years). Psychiatrists made up about two-thirds of the sample. The remainder specialized in internal and family medicine.

Most respondents had some clinical exposure to psychedelics. Almost 85% reported discussing a psychedelic experience with at least one patient.
 

Positive attitudes, concerns

Overall, participants expressed very positive attitudes regarding the therapeutic use of psychedelics. About 64% strongly agreed or agreed psychedelics show promise in treating SUDs, and 82% agreed they show promise in treating psychiatric disorders.

However, more than one-third of respondents (37.9%) expressed concern about the addictive potential of psychedelics. This is more than in previous research polling psychiatrists, possibly because the study’s “broad” definition of psychedelics included “nonclassic, nonserotonergic hallucinogens,” such as ketamine and MDMA, Dr. Kim noted.

Because ketamine and MDMA are both lumped into the hallucinogen category in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), “and both are known to have addictive potential, this may have obscured participant responses,” she added.

Some 28% of participants expressed concern about psychedelic use increasing the risk for subsequent psychiatric disorders and long-term cognitive impairment.

Almost three-quarters (74.5%) believe the therapeutic use of psychedelics should be legalized. However, most wanted legal therapeutic psychedelics to be highly regulated and administered only in controlled settings with specially trained providers.

Almost half of the sample believed therapeutic psychedelics should be legal in a variety of different contexts and by non-Western providers, in accordance with indigenous and/or spiritual traditions.

One surprising finding was that most respondents believed patients would be keen on using psychedelics to treat SUDs, said Dr. Kim.

“This may reflect evolving attitudes of both providers and patients about psychedelics, and it will be interesting to further study attitudes of patients toward the use of psychedelics to treat SUD in the future,” she added.

Attitudes toward psychedelics were generally similar for psychiatrists and nonpsychiatrists; but psychiatrists expressed greater comfort in discussing them with patients and were more likely to have observed complications of psychedelics use in their practice.

Dr. Kim said the study’s limitations included the small sample size and possible selection bias, as those with more favorable views of psychedelics may have been more likely to respond.

The study was supported by the Source Research Foundation.

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

A growing number of patients with opioid use disorder (OUD) have a diagnosis of comorbid attention-deficit/hyperactivity disorder (ADHD), raising issues about whether it’s appropriate to prescribe stimulants in this patient population.

One new study showed that from 2007-2017, there was a threefold increase in OUD and comorbid ADHD and that a significant number of these patients received prescription stimulants.

“This is the beginning stages of looking at whether or not there are risks of prescribing stimulants to patients who are on medications for opioid use disorder,” investigator Tae Woo (Ted) Park, MD, assistant professor, department of psychiatry, University of Pittsburgh School of Medicine, told this news organization.

“More and more people are being identified with ADHD, and we need to do more research on the best way to manage this patient group,” Dr. Park added.

The findings were presented at the annual meeting of the American Academy of Addiction Psychiatry.
 

Biological connection?

Dr. Park is not convinced there is “an actual biological connection” between ADHD and OUD, noting that there are many reasons why patients with ADHD may be more prone to developing such a disorder.

Perhaps they did not get an ADHD diagnosis as a child, “which led to impairment in their ability to be successful at school and then in a job,” which in turn predisposed them to having a substance use disorder, said Dr. Park.

From previous research and his own clinical experience, ADHD can significantly affect quality of life and “cause increased impairment” in patients with a substance use disorder, he added.

Interestingly, there’s evidence suggesting patients treated for ADHD early in life are less likely to develop a substance use disorder later on, he said.

The “gold standard” treatment for ADHD is a prescription stimulant, which carries its own addiction risks. “So the issue is about whether or not to prescribe risky medications and how to weigh the risks and benefits,” said Dr. Park.

From a private health insurance database, researchers examined records for patients aged 18-64 years who were receiving medication for OUD, including buprenorphine, methadone, or naltrexone, from 2007-2017.

In the study sample, about 17,000 individuals were receiving stimulants, and 156,000 were not receiving these drugs. The largest percentage of participants in both groups was in the age-18-to-25 category.

About 35% of those receiving stimulants had ADHD, and about the same percentage had a mood disorder diagnosis.

Percentage of co-occurring ADHD and OUD increased from more than 4% in 2007 to more than 14% in 2017. The prevalence of stimulant use plus medication for OUD also increased during that time.

The increase in ADHD diagnoses may reflect growing identification of the condition, Dr. Park noted. As the opioid problem became more apparent and additional treatments made available, “there were more health care contacts, more assessments, and more diagnoses, including of ADHD,” he said.
 

Risks versus benefits

Stimulants may also be risky in patients with OUD. Results from another study presented at the AAAP meeting showed these drugs were associated with an increased chance of poisoning in patients receiving buprenorphine.

However, Dr. Park is skeptical the combination of stimulants and buprenorphine “leads to a biological risk of overdose.” He used a hypothetical scenario where other factors play into the connection: A patient gets a prescription stimulant, becomes addicted, then starts using street or illicit stimulants, which leads to a relapse on opioids, and then to an overdose.

Dr. Park noted that the same study that found an increased poisoning risk in stimulant users also found that patients tend to stay on buprenorphine treatment, providing protection against overdose.

“So there are risks and benefits of prescribing these medications, and it becomes tricky to know whether to prescribe them or not,” he said.

While stimulants are by far the best treatment for ADHD, atomoxetine (Strattera), a nonstimulant medication with antidepressant effects is another option, Dr. Park said.

He added that a limitation of his study was that very few individuals in the database received methadone.

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

A growing number of patients with opioid use disorder (OUD) have a diagnosis of comorbid attention-deficit/hyperactivity disorder (ADHD), raising issues about whether it’s appropriate to prescribe stimulants in this patient population.

One new study showed that from 2007-2017, there was a threefold increase in OUD and comorbid ADHD and that a significant number of these patients received prescription stimulants.

“This is the beginning stages of looking at whether or not there are risks of prescribing stimulants to patients who are on medications for opioid use disorder,” investigator Tae Woo (Ted) Park, MD, assistant professor, department of psychiatry, University of Pittsburgh School of Medicine, told this news organization.

“More and more people are being identified with ADHD, and we need to do more research on the best way to manage this patient group,” Dr. Park added.

The findings were presented at the annual meeting of the American Academy of Addiction Psychiatry.
 

Biological connection?

Dr. Park is not convinced there is “an actual biological connection” between ADHD and OUD, noting that there are many reasons why patients with ADHD may be more prone to developing such a disorder.

Perhaps they did not get an ADHD diagnosis as a child, “which led to impairment in their ability to be successful at school and then in a job,” which in turn predisposed them to having a substance use disorder, said Dr. Park.

From previous research and his own clinical experience, ADHD can significantly affect quality of life and “cause increased impairment” in patients with a substance use disorder, he added.

Interestingly, there’s evidence suggesting patients treated for ADHD early in life are less likely to develop a substance use disorder later on, he said.

The “gold standard” treatment for ADHD is a prescription stimulant, which carries its own addiction risks. “So the issue is about whether or not to prescribe risky medications and how to weigh the risks and benefits,” said Dr. Park.

From a private health insurance database, researchers examined records for patients aged 18-64 years who were receiving medication for OUD, including buprenorphine, methadone, or naltrexone, from 2007-2017.

In the study sample, about 17,000 individuals were receiving stimulants, and 156,000 were not receiving these drugs. The largest percentage of participants in both groups was in the age-18-to-25 category.

About 35% of those receiving stimulants had ADHD, and about the same percentage had a mood disorder diagnosis.

Percentage of co-occurring ADHD and OUD increased from more than 4% in 2007 to more than 14% in 2017. The prevalence of stimulant use plus medication for OUD also increased during that time.

The increase in ADHD diagnoses may reflect growing identification of the condition, Dr. Park noted. As the opioid problem became more apparent and additional treatments made available, “there were more health care contacts, more assessments, and more diagnoses, including of ADHD,” he said.
 

Risks versus benefits

Stimulants may also be risky in patients with OUD. Results from another study presented at the AAAP meeting showed these drugs were associated with an increased chance of poisoning in patients receiving buprenorphine.

However, Dr. Park is skeptical the combination of stimulants and buprenorphine “leads to a biological risk of overdose.” He used a hypothetical scenario where other factors play into the connection: A patient gets a prescription stimulant, becomes addicted, then starts using street or illicit stimulants, which leads to a relapse on opioids, and then to an overdose.

Dr. Park noted that the same study that found an increased poisoning risk in stimulant users also found that patients tend to stay on buprenorphine treatment, providing protection against overdose.

“So there are risks and benefits of prescribing these medications, and it becomes tricky to know whether to prescribe them or not,” he said.

While stimulants are by far the best treatment for ADHD, atomoxetine (Strattera), a nonstimulant medication with antidepressant effects is another option, Dr. Park said.

He added that a limitation of his study was that very few individuals in the database received methadone.

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

A growing number of patients with opioid use disorder (OUD) have a diagnosis of comorbid attention-deficit/hyperactivity disorder (ADHD), raising issues about whether it’s appropriate to prescribe stimulants in this patient population.

One new study showed that from 2007-2017, there was a threefold increase in OUD and comorbid ADHD and that a significant number of these patients received prescription stimulants.

“This is the beginning stages of looking at whether or not there are risks of prescribing stimulants to patients who are on medications for opioid use disorder,” investigator Tae Woo (Ted) Park, MD, assistant professor, department of psychiatry, University of Pittsburgh School of Medicine, told this news organization.

“More and more people are being identified with ADHD, and we need to do more research on the best way to manage this patient group,” Dr. Park added.

The findings were presented at the annual meeting of the American Academy of Addiction Psychiatry.
 

Biological connection?

Dr. Park is not convinced there is “an actual biological connection” between ADHD and OUD, noting that there are many reasons why patients with ADHD may be more prone to developing such a disorder.

Perhaps they did not get an ADHD diagnosis as a child, “which led to impairment in their ability to be successful at school and then in a job,” which in turn predisposed them to having a substance use disorder, said Dr. Park.

From previous research and his own clinical experience, ADHD can significantly affect quality of life and “cause increased impairment” in patients with a substance use disorder, he added.

Interestingly, there’s evidence suggesting patients treated for ADHD early in life are less likely to develop a substance use disorder later on, he said.

The “gold standard” treatment for ADHD is a prescription stimulant, which carries its own addiction risks. “So the issue is about whether or not to prescribe risky medications and how to weigh the risks and benefits,” said Dr. Park.

From a private health insurance database, researchers examined records for patients aged 18-64 years who were receiving medication for OUD, including buprenorphine, methadone, or naltrexone, from 2007-2017.

In the study sample, about 17,000 individuals were receiving stimulants, and 156,000 were not receiving these drugs. The largest percentage of participants in both groups was in the age-18-to-25 category.

About 35% of those receiving stimulants had ADHD, and about the same percentage had a mood disorder diagnosis.

Percentage of co-occurring ADHD and OUD increased from more than 4% in 2007 to more than 14% in 2017. The prevalence of stimulant use plus medication for OUD also increased during that time.

The increase in ADHD diagnoses may reflect growing identification of the condition, Dr. Park noted. As the opioid problem became more apparent and additional treatments made available, “there were more health care contacts, more assessments, and more diagnoses, including of ADHD,” he said.
 

Risks versus benefits

Stimulants may also be risky in patients with OUD. Results from another study presented at the AAAP meeting showed these drugs were associated with an increased chance of poisoning in patients receiving buprenorphine.

However, Dr. Park is skeptical the combination of stimulants and buprenorphine “leads to a biological risk of overdose.” He used a hypothetical scenario where other factors play into the connection: A patient gets a prescription stimulant, becomes addicted, then starts using street or illicit stimulants, which leads to a relapse on opioids, and then to an overdose.

Dr. Park noted that the same study that found an increased poisoning risk in stimulant users also found that patients tend to stay on buprenorphine treatment, providing protection against overdose.

“So there are risks and benefits of prescribing these medications, and it becomes tricky to know whether to prescribe them or not,” he said.

While stimulants are by far the best treatment for ADHD, atomoxetine (Strattera), a nonstimulant medication with antidepressant effects is another option, Dr. Park said.

He added that a limitation of his study was that very few individuals in the database received methadone.

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

Illicit drug use among U.S. teenagers dropped sharply in 2021, likely because of stay-at-home orders and other restrictions on social activities due to the COVID-19 pandemic.

The latest findings, from the Monitoring the Future survey, represent the largest 1-year decrease in overall illicit drug use reported since the survey began in 1975.

“We have never seen such dramatic decreases in drug use among teens in just a 1-year period,” Nora Volkow, MD, director of the National Institute on Drug Abuse (NIDA), said in a news release. 

“These data are unprecedented and highlight one unexpected potential consequence of the COVID-19 pandemic, which caused seismic shifts in the day-to-day lives of adolescents,” said Dr. Volkow.

The annual Monitoring the Future survey is conducted by researchers at the University of Michigan, Ann Arbor, and funded by NIDA, to assess drug and alcohol use and related attitudes among adolescent students across the United States.

This year’s self-reported survey included 32,260 students in grades 8, 10, and 12 across 319 public and private schools.

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

Illicit drug use among U.S. teenagers dropped sharply in 2021, likely because of stay-at-home orders and other restrictions on social activities due to the COVID-19 pandemic.

The latest findings, from the Monitoring the Future survey, represent the largest 1-year decrease in overall illicit drug use reported since the survey began in 1975.

“We have never seen such dramatic decreases in drug use among teens in just a 1-year period,” Nora Volkow, MD, director of the National Institute on Drug Abuse (NIDA), said in a news release. 

“These data are unprecedented and highlight one unexpected potential consequence of the COVID-19 pandemic, which caused seismic shifts in the day-to-day lives of adolescents,” said Dr. Volkow.

The annual Monitoring the Future survey is conducted by researchers at the University of Michigan, Ann Arbor, and funded by NIDA, to assess drug and alcohol use and related attitudes among adolescent students across the United States.

This year’s self-reported survey included 32,260 students in grades 8, 10, and 12 across 319 public and private schools.

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

Illicit drug use among U.S. teenagers dropped sharply in 2021, likely because of stay-at-home orders and other restrictions on social activities due to the COVID-19 pandemic.

The latest findings, from the Monitoring the Future survey, represent the largest 1-year decrease in overall illicit drug use reported since the survey began in 1975.

“We have never seen such dramatic decreases in drug use among teens in just a 1-year period,” Nora Volkow, MD, director of the National Institute on Drug Abuse (NIDA), said in a news release. 

“These data are unprecedented and highlight one unexpected potential consequence of the COVID-19 pandemic, which caused seismic shifts in the day-to-day lives of adolescents,” said Dr. Volkow.

The annual Monitoring the Future survey is conducted by researchers at the University of Michigan, Ann Arbor, and funded by NIDA, to assess drug and alcohol use and related attitudes among adolescent students across the United States.

This year’s self-reported survey included 32,260 students in grades 8, 10, and 12 across 319 public and private schools.

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

SAN ANTONIO – Sedative-hypnotic medications, such as benzodiazepines and nonbenzodiazepine sedative-hypnotics commonly used to treat chemotherapy-related nausea, anxiety, and insomnia in women being treated for breast cancer, put women at high risk of dependency after chemotherapy treatment, shows a new study.

While benzodiazepines and nonbenzodiazepine sedative-hypnotics are effective for these indications, misuse and increased health care utilization can ensue from their prolonged use, said Jacob C. Cogan, MD, a fellow in oncology/hematology at the Herbert Irving Comprehensive Cancer Center, Columbia University, New York. Dr. Cogan recently presented the results of the study at the San Antonio Breast Cancer Symposium.

The study included patients with breast cancer who received adjuvant chemotherapy between 2008 and 2017. Prescriptions for sedatives were divided into three periods: 365 days prior to chemotherapy to the start of chemotherapy (period one); start of chemotherapy to 90 days after the end of chemotherapy (period two); and 90-365 days after chemotherapy (period three). Patients who filled at least one benzodiazepine prescription in period two and patients who filled at least two benzodiazepine in period three were classified as new persistent benzodiazepine users. The same definitions were then used for nonbenzodiazepine sedative-hypnotics.

Among 17,532 benzodiazepine-naive patients (mean age, 57 years) and 21,863 nonbenzodiazepine sedative-hypnotic drug–naive patients (mean age, 56 years) who received adjuvant chemotherapy for breast cancer, lumpectomies were performed for a small majority (56.6% benzodiazepine naive, 55.1% nonbenzodiazepine sedative-hypnotics naive) versus mastectomy, and about half of patients received less than 4 months of chemotherapy (48.0% benzodiazepine naive, 48.6% nonbenzodiazepine sedative-hypnotics naive). Among benzodiazepine-naive patients, 4,447 (25.4%) filled at least one benzodiazepine prescription during chemotherapy, and 2,160 (9.9%) filled at least one nonbenzodiazepine sedative-hypnotic prescription during chemotherapy. The rate of new persistent benzodiazepine use after initial exposure during chemotherapy was 26.8% (n = 1,192). Similarly, 33.8% (n = 730) of nonbenzodiazepine sedative-hypnotics users became new persistent users. In addition, 115 patients became new persistent users of both types of sedative-hypnotics.

New persistent benzodiazepine use was associated with several characteristics: age 50-65 (odds ratio, 1.23; P = .01) and age greater than 65 (OR, 1.38, P = .005) relative to age less than 49; as well as Medicaid insurance, relative to commercial and Medicare insurance (OR, 1.68; P < .0001). Both new persistent benzodiazepine and nonbenzodiazepine sedative-hypnotics use was associated with chemotherapy duration of less than 4 months relative to 4 or more months of chemotherapy (OR, 1.17; P = .03 for benzodiazepines; OR, 1.58; P < .0001 for nonbenzodiazepine sedative-hypnotics).

It is not clear why shorter chemotherapy duration is associated with more new persistent use, Dr. Cogan said. “It may be that, paradoxically, a shorter duration of treatment could lead to more anxiety about recurrence. These patients may need closer monitoring of mental health symptoms and earlier referral for psychological services.”

Dr. Cogan said that providers should take steps to ensure that benzodiazepines and nonbenzodiazepine sedatives are used appropriately, which includes tapering dosages and, when appropriate, encouraging nonpharmacologic strategies.

There were no funding or other conflicts of interest associated with this study.

SAN ANTONIO – Sedative-hypnotic medications, such as benzodiazepines and nonbenzodiazepine sedative-hypnotics commonly used to treat chemotherapy-related nausea, anxiety, and insomnia in women being treated for breast cancer, put women at high risk of dependency after chemotherapy treatment, shows a new study.

While benzodiazepines and nonbenzodiazepine sedative-hypnotics are effective for these indications, misuse and increased health care utilization can ensue from their prolonged use, said Jacob C. Cogan, MD, a fellow in oncology/hematology at the Herbert Irving Comprehensive Cancer Center, Columbia University, New York. Dr. Cogan recently presented the results of the study at the San Antonio Breast Cancer Symposium.

The study included patients with breast cancer who received adjuvant chemotherapy between 2008 and 2017. Prescriptions for sedatives were divided into three periods: 365 days prior to chemotherapy to the start of chemotherapy (period one); start of chemotherapy to 90 days after the end of chemotherapy (period two); and 90-365 days after chemotherapy (period three). Patients who filled at least one benzodiazepine prescription in period two and patients who filled at least two benzodiazepine in period three were classified as new persistent benzodiazepine users. The same definitions were then used for nonbenzodiazepine sedative-hypnotics.

Among 17,532 benzodiazepine-naive patients (mean age, 57 years) and 21,863 nonbenzodiazepine sedative-hypnotic drug–naive patients (mean age, 56 years) who received adjuvant chemotherapy for breast cancer, lumpectomies were performed for a small majority (56.6% benzodiazepine naive, 55.1% nonbenzodiazepine sedative-hypnotics naive) versus mastectomy, and about half of patients received less than 4 months of chemotherapy (48.0% benzodiazepine naive, 48.6% nonbenzodiazepine sedative-hypnotics naive). Among benzodiazepine-naive patients, 4,447 (25.4%) filled at least one benzodiazepine prescription during chemotherapy, and 2,160 (9.9%) filled at least one nonbenzodiazepine sedative-hypnotic prescription during chemotherapy. The rate of new persistent benzodiazepine use after initial exposure during chemotherapy was 26.8% (n = 1,192). Similarly, 33.8% (n = 730) of nonbenzodiazepine sedative-hypnotics users became new persistent users. In addition, 115 patients became new persistent users of both types of sedative-hypnotics.

New persistent benzodiazepine use was associated with several characteristics: age 50-65 (odds ratio, 1.23; P = .01) and age greater than 65 (OR, 1.38, P = .005) relative to age less than 49; as well as Medicaid insurance, relative to commercial and Medicare insurance (OR, 1.68; P < .0001). Both new persistent benzodiazepine and nonbenzodiazepine sedative-hypnotics use was associated with chemotherapy duration of less than 4 months relative to 4 or more months of chemotherapy (OR, 1.17; P = .03 for benzodiazepines; OR, 1.58; P < .0001 for nonbenzodiazepine sedative-hypnotics).

It is not clear why shorter chemotherapy duration is associated with more new persistent use, Dr. Cogan said. “It may be that, paradoxically, a shorter duration of treatment could lead to more anxiety about recurrence. These patients may need closer monitoring of mental health symptoms and earlier referral for psychological services.”

Dr. Cogan said that providers should take steps to ensure that benzodiazepines and nonbenzodiazepine sedatives are used appropriately, which includes tapering dosages and, when appropriate, encouraging nonpharmacologic strategies.

There were no funding or other conflicts of interest associated with this study.

SAN ANTONIO – Sedative-hypnotic medications, such as benzodiazepines and nonbenzodiazepine sedative-hypnotics commonly used to treat chemotherapy-related nausea, anxiety, and insomnia in women being treated for breast cancer, put women at high risk of dependency after chemotherapy treatment, shows a new study.

While benzodiazepines and nonbenzodiazepine sedative-hypnotics are effective for these indications, misuse and increased health care utilization can ensue from their prolonged use, said Jacob C. Cogan, MD, a fellow in oncology/hematology at the Herbert Irving Comprehensive Cancer Center, Columbia University, New York. Dr. Cogan recently presented the results of the study at the San Antonio Breast Cancer Symposium.

The study included patients with breast cancer who received adjuvant chemotherapy between 2008 and 2017. Prescriptions for sedatives were divided into three periods: 365 days prior to chemotherapy to the start of chemotherapy (period one); start of chemotherapy to 90 days after the end of chemotherapy (period two); and 90-365 days after chemotherapy (period three). Patients who filled at least one benzodiazepine prescription in period two and patients who filled at least two benzodiazepine in period three were classified as new persistent benzodiazepine users. The same definitions were then used for nonbenzodiazepine sedative-hypnotics.

Among 17,532 benzodiazepine-naive patients (mean age, 57 years) and 21,863 nonbenzodiazepine sedative-hypnotic drug–naive patients (mean age, 56 years) who received adjuvant chemotherapy for breast cancer, lumpectomies were performed for a small majority (56.6% benzodiazepine naive, 55.1% nonbenzodiazepine sedative-hypnotics naive) versus mastectomy, and about half of patients received less than 4 months of chemotherapy (48.0% benzodiazepine naive, 48.6% nonbenzodiazepine sedative-hypnotics naive). Among benzodiazepine-naive patients, 4,447 (25.4%) filled at least one benzodiazepine prescription during chemotherapy, and 2,160 (9.9%) filled at least one nonbenzodiazepine sedative-hypnotic prescription during chemotherapy. The rate of new persistent benzodiazepine use after initial exposure during chemotherapy was 26.8% (n = 1,192). Similarly, 33.8% (n = 730) of nonbenzodiazepine sedative-hypnotics users became new persistent users. In addition, 115 patients became new persistent users of both types of sedative-hypnotics.

New persistent benzodiazepine use was associated with several characteristics: age 50-65 (odds ratio, 1.23; P = .01) and age greater than 65 (OR, 1.38, P = .005) relative to age less than 49; as well as Medicaid insurance, relative to commercial and Medicare insurance (OR, 1.68; P < .0001). Both new persistent benzodiazepine and nonbenzodiazepine sedative-hypnotics use was associated with chemotherapy duration of less than 4 months relative to 4 or more months of chemotherapy (OR, 1.17; P = .03 for benzodiazepines; OR, 1.58; P < .0001 for nonbenzodiazepine sedative-hypnotics).

It is not clear why shorter chemotherapy duration is associated with more new persistent use, Dr. Cogan said. “It may be that, paradoxically, a shorter duration of treatment could lead to more anxiety about recurrence. These patients may need closer monitoring of mental health symptoms and earlier referral for psychological services.”

Dr. Cogan said that providers should take steps to ensure that benzodiazepines and nonbenzodiazepine sedatives are used appropriately, which includes tapering dosages and, when appropriate, encouraging nonpharmacologic strategies.

There were no funding or other conflicts of interest associated with this study.

Ease of access to opioids in the perioperative period is a risk factor for opioid misuse and has been identified as a strong risk factor for heroin use.^1,2 Three-quarters of today’s heroin users were introduced to opioids through prescription medications.² The United States accounts for about 80% of the global opioid supply consumption, and deaths from opioid overdose are increasing: 70,630 deaths in 2019 alone.^3,4

The Centers for Disease Control and Prevention (CDC) has called for changes in opioid prescribing. The American Academy of Orthopaedic Surgeons (AAOS) also has published an information statement with strategies to decrease opioid misuse and abuse.^5,6 Arthroplasty surgeons have recently focused on decreasing use of opioids in total knee arthroplasty (TKA), a procedure traditionally associated with high levels of opioid consumption and historical reliance on opioid monotherapy for postoperative analgesia.^7,8 From a clinical perspective, prolonged postoperative opioid use contributes to poorer surgical outcomes due to increased risk of complications, including stiffness, infection, and revision TKA.⁹

Multimodal pain regimens are increasingly being used to control postoperative pain as data supports their efficacy.^10,11 Previous studies have found that simultaneous modulation of multiple pain pathways decreases narcotics consumption and improves patient outcomes.^12,13 Along with other adjuvant therapies, peripheral nerve blocks, such as adductor canal block (ACB) and femoral nerve block (FNB), have been used to decrease postoperative pain.¹⁴ Studies have shown that ACB has fewer complications and shorter functional recovery times compared with FNB.^15,16 The distribution of the ACB excludes the femoral nerve, thus preserving greater quadriceps strength while providing equivalent levels of analgesia compared with FNB.^15,17,18 The ACB has shown decreased near-fall events and improved balance scores in the immediate postoperative period.¹⁹

Our study analyzed opioid consumption patterns of TKA patients from a US Department of Veterans Affairs (VA) medical center before and after the institution of a multimodal analgesic protocol using ACB. The primary purpose of this study was to determine whether a protocol that included intraoperative spinal anesthesia with a postoperative multimodal analgesic regimen and ACB was associated with a decreased postoperative opioid requirement when compared with patients who received intraoperative general anesthesia and a traditional opioid regimen. Secondary outcomes included the effect of opioid consumption on range of motion on postoperative day (POD) 1 and number of opioid prescriptions written at the first postoperative clinic visit.

Methods

Approval for the study was obtained from the institutional review board at the Dayton Veterans Affairs Medical Center (DVAMC) in Ohio. A retrospective chart review was performed to collect data from all patients undergoing TKA at DVAMC from June 1, 2011, through December 31, 2015. Exclusion criteria included multiple surgeries in the study time frame, documented chronic pain, allergy to local anesthetics, daily preoperative use of opioids, and incomplete data in the health record.

All surgeries were performed by 2 staff arthroplasty surgeons at a single VAMC. All patients attended a preoperative visit where a history, physical, and anesthesia evaluation were performed, and watched an educational video detailing surgical indications and postoperative rehabilitation. All surgeries were performed with tourniquets and a periarticular injection was performed at the conclusion of each case. Surgeon 1 treatment of choice was 10 mL 0.5% bupivacaine, whereas surgeon 2 performed a posterior capsular injection of 30 mL 0.25% bupivacaine and a periarticular injection of 30 mg ketorolac in 10 mL 0.25% bupivacaine with epinephrine.

Prior to August 2014, general endotracheal anesthesia was used intraoperatively. A patient-controlled analgesia (PCA) pump of morphine or hydromorphone and additional oral oxycodone or hydrocodone was used for postoperative pain. PCA pumps were patient dependent. In the control group, 245 patients received the morphine PCA while 61 received the hydromorphone PCA. Morphine PCA dosing consisted of 1-mg doses every 10 minutes with potential baseline infusion rates of 0.5 to 1.0 mg/h and a 4-hour limit of 20 mg. Hydromorphone PCA dosing consisted of 0.2 to 0.4-mg doses with a potential continuous dose of 0.2 to 0.4 mg/h and a 4-hour limit of 4 mg.

Results

During the study period from June 1, 2011, through December 31, 2015, 533 eligible TKAs were performed, 306 in the control group and 227 in the protocol group. The groups had similar sex distribution; body mass index; knee range of motion; diagnoses of diabetes mellitus, coronary artery disease, and chronic kidney disease; and history of deep vein thrombosis (DVT) or pulmonary embolism (P ≥ .05). The protocol group was significantly older (P = .04) and had a significantly higher rate of chronic obstructive pulmonary disease (COPD) (P = .002). There were no significant differences between number of procedures performed by surgeon (P = .48) or total tourniquet time (P = .13) (Table 2). Mean (SD) length of stay was significantly greater in the control group compared with the protocol group (2.5 [1.3] vs 1.4 [0.7] days, P < .001).

Figure 1 shows the distributions of each type of opioid used. Compared with the control group, the protocol group had a significantly lower mean (SD) IV opioid use: 178.2 (98.0) MED vs 12.0 (24.6) MED (P < .001; d = 2.19; Δ = 0.94) and mean (SD) total opioid use: 241.7 (120.1) MED vs 74.8 (42.7) MED (P < .001; d = 1.76; Δ = 0.89). Mean (SD) oral opioid use did not differ between groups (control, 63.6 [45.4] MED; protocol, 62.9 [31.4] MED; P = .85; d = 0.02; Δ = 0.51). A significantly lower percentage of patients in the protocol group received additional opioids at the 3-week follow-up when compared to the control group: 46.7% vs 61.3%, respectively (P < .001; RR, 0.76; 95% CI, 0.65-0.90).

Discussion

Coordinated efforts with major medical organizations are being made to decrease opioid prescriptions and exposure.^5,6 To our knowledge, no study has quantified a decrease in opioid requirement in a VA population after implementation of a protocol that includes intraoperative spinal anesthesia and a postoperative multimodal analgesic regimen including ACB after TKA. The analgesic protocol described in this study aligns with recommendations from both the CDC and the AAOS to decrease opioid use and misuse by maximizing nonopioid medications and limiting the size and number of opioid prescriptions. However, public and medical opinion of opioids as well as prescribing practices have changed over time with a trend toward lower opioid use. The interventions, as part of the described protocol, are a result of these changes and attempt to minimize opioid use while maximizing postoperative analgesia.

Our data showed a significant decrease in total opioid use through POD 1, IV opioid use, and opioid prescriptions provided at the first postoperative visit. The protocol group used only 6.7% of the IV opioids and 30.9% of the total opioids that were used by the control group. The substantial difference in IV opioid requirement, 166.2 MED, is equivalent to 8 mg of IV hydromorphone or 55 mg of IV morphine. The difference in total opioid requirement was similar at 166.9 MED, equivalent to 111 mg of oral oxycodone.

Decreasing opioid use has the additional benefit of improving outcomes, as higher doses of opioids have been associated with increased length of stay, greater rates of DVT, and postoperative infection.²³ These complications occurred in a stepwise manner, suggesting a dose-response gradient that makes the sizable decrease noted in our data of greater relevance.²³ While the adverse effects (AEs) of opioids are well known, there are limited data on opioid dosing and its effect on perioperative outcomes.²³

A significant decrease in the percentage of patients receiving an opioid prescription at the first postoperative visit suggests a decrease in the number of patients on prolonged opioids after TKA with implementation of modern analgesic modalities. The duration of postoperative opioid use has been found to be the strongest predictor of misuse, and each postoperative refill increases the probability of misuse by 44%.²⁴ In addition, opioid use for > 3 months after TKA is associated with increased risk of periprosthetic infection, increased overall revision rate, and stiffness at 1 year postoperatively.⁹ While not entirely under the control of the surgeon, measures to decrease the number of postoperative opioid refills may lead to a decrease in opioid misuse.

Limitations

A number of limitations of this study should be noted. One was a protocol change regarding length of stay, which occurred during the study period and resulted in a significantly shorter length of stay in the protocol group. As a result, opioid use data were analyzed only through midnight at the end of POD 1. Patients who were discharged on POD 1 did not have opioid use data available for the full duration of the first POD, which may exaggerate the decrease in opioid requirements, as opioids used after discharge but prior to midnight on POD 1 were not recorded. However, opioids taken at home are oral with a low MME compared with IV opioids received by hospitalized patients in the control group. In addition, if taken as prescribed, patients at home would only have enough time to take a few doses of opioids prior to the midnight cutoff. We do not believe this difference in time of opioid use meaningfully affected the data. An additional limitation includes the variability between periarticular injections between surgeons. While the percentage of patients that received injections from surgeon 1 vs surgeon 2 were similar, it cannot be ruled out as a potential confounding factor. Other limitations include a lack of pain scores to compare subjective pain ratings, the retrospective nature of the study, and a largely homogenous male VA population.

Conclusions

Ease of access to opioids is a risk factor for opioid abuse, which itself is a risk factor for subsequent heroin use.^1,2 The CDC and AAOS have thus published recommendations regarding opioid prescribing practices to decrease opioid use and abuse.^5,6 Our described protocol, which aligns with these recommendations, resulted in a significant decrease in IV opioid requirement, total opioid requirement, and lower rates of opioid prescriptions provided at the first postoperative visit. These promising findings demonstrate a lower percentage of patients on long-term opioids after TKA and a significantly decreased cumulative opioid exposure.

Ease of access to opioids in the perioperative period is a risk factor for opioid misuse and has been identified as a strong risk factor for heroin use.^1,2 Three-quarters of today’s heroin users were introduced to opioids through prescription medications.² The United States accounts for about 80% of the global opioid supply consumption, and deaths from opioid overdose are increasing: 70,630 deaths in 2019 alone.^3,4

The Centers for Disease Control and Prevention (CDC) has called for changes in opioid prescribing. The American Academy of Orthopaedic Surgeons (AAOS) also has published an information statement with strategies to decrease opioid misuse and abuse.^5,6 Arthroplasty surgeons have recently focused on decreasing use of opioids in total knee arthroplasty (TKA), a procedure traditionally associated with high levels of opioid consumption and historical reliance on opioid monotherapy for postoperative analgesia.^7,8 From a clinical perspective, prolonged postoperative opioid use contributes to poorer surgical outcomes due to increased risk of complications, including stiffness, infection, and revision TKA.⁹

Multimodal pain regimens are increasingly being used to control postoperative pain as data supports their efficacy.^10,11 Previous studies have found that simultaneous modulation of multiple pain pathways decreases narcotics consumption and improves patient outcomes.^12,13 Along with other adjuvant therapies, peripheral nerve blocks, such as adductor canal block (ACB) and femoral nerve block (FNB), have been used to decrease postoperative pain.¹⁴ Studies have shown that ACB has fewer complications and shorter functional recovery times compared with FNB.^15,16 The distribution of the ACB excludes the femoral nerve, thus preserving greater quadriceps strength while providing equivalent levels of analgesia compared with FNB.^15,17,18 The ACB has shown decreased near-fall events and improved balance scores in the immediate postoperative period.¹⁹

Our study analyzed opioid consumption patterns of TKA patients from a US Department of Veterans Affairs (VA) medical center before and after the institution of a multimodal analgesic protocol using ACB. The primary purpose of this study was to determine whether a protocol that included intraoperative spinal anesthesia with a postoperative multimodal analgesic regimen and ACB was associated with a decreased postoperative opioid requirement when compared with patients who received intraoperative general anesthesia and a traditional opioid regimen. Secondary outcomes included the effect of opioid consumption on range of motion on postoperative day (POD) 1 and number of opioid prescriptions written at the first postoperative clinic visit.

Methods

Approval for the study was obtained from the institutional review board at the Dayton Veterans Affairs Medical Center (DVAMC) in Ohio. A retrospective chart review was performed to collect data from all patients undergoing TKA at DVAMC from June 1, 2011, through December 31, 2015. Exclusion criteria included multiple surgeries in the study time frame, documented chronic pain, allergy to local anesthetics, daily preoperative use of opioids, and incomplete data in the health record.

All surgeries were performed by 2 staff arthroplasty surgeons at a single VAMC. All patients attended a preoperative visit where a history, physical, and anesthesia evaluation were performed, and watched an educational video detailing surgical indications and postoperative rehabilitation. All surgeries were performed with tourniquets and a periarticular injection was performed at the conclusion of each case. Surgeon 1 treatment of choice was 10 mL 0.5% bupivacaine, whereas surgeon 2 performed a posterior capsular injection of 30 mL 0.25% bupivacaine and a periarticular injection of 30 mg ketorolac in 10 mL 0.25% bupivacaine with epinephrine.

Prior to August 2014, general endotracheal anesthesia was used intraoperatively. A patient-controlled analgesia (PCA) pump of morphine or hydromorphone and additional oral oxycodone or hydrocodone was used for postoperative pain. PCA pumps were patient dependent. In the control group, 245 patients received the morphine PCA while 61 received the hydromorphone PCA. Morphine PCA dosing consisted of 1-mg doses every 10 minutes with potential baseline infusion rates of 0.5 to 1.0 mg/h and a 4-hour limit of 20 mg. Hydromorphone PCA dosing consisted of 0.2 to 0.4-mg doses with a potential continuous dose of 0.2 to 0.4 mg/h and a 4-hour limit of 4 mg.

Results

During the study period from June 1, 2011, through December 31, 2015, 533 eligible TKAs were performed, 306 in the control group and 227 in the protocol group. The groups had similar sex distribution; body mass index; knee range of motion; diagnoses of diabetes mellitus, coronary artery disease, and chronic kidney disease; and history of deep vein thrombosis (DVT) or pulmonary embolism (P ≥ .05). The protocol group was significantly older (P = .04) and had a significantly higher rate of chronic obstructive pulmonary disease (COPD) (P = .002). There were no significant differences between number of procedures performed by surgeon (P = .48) or total tourniquet time (P = .13) (Table 2). Mean (SD) length of stay was significantly greater in the control group compared with the protocol group (2.5 [1.3] vs 1.4 [0.7] days, P < .001).

Figure 1 shows the distributions of each type of opioid used. Compared with the control group, the protocol group had a significantly lower mean (SD) IV opioid use: 178.2 (98.0) MED vs 12.0 (24.6) MED (P < .001; d = 2.19; Δ = 0.94) and mean (SD) total opioid use: 241.7 (120.1) MED vs 74.8 (42.7) MED (P < .001; d = 1.76; Δ = 0.89). Mean (SD) oral opioid use did not differ between groups (control, 63.6 [45.4] MED; protocol, 62.9 [31.4] MED; P = .85; d = 0.02; Δ = 0.51). A significantly lower percentage of patients in the protocol group received additional opioids at the 3-week follow-up when compared to the control group: 46.7% vs 61.3%, respectively (P < .001; RR, 0.76; 95% CI, 0.65-0.90).

Discussion

Coordinated efforts with major medical organizations are being made to decrease opioid prescriptions and exposure.^5,6 To our knowledge, no study has quantified a decrease in opioid requirement in a VA population after implementation of a protocol that includes intraoperative spinal anesthesia and a postoperative multimodal analgesic regimen including ACB after TKA. The analgesic protocol described in this study aligns with recommendations from both the CDC and the AAOS to decrease opioid use and misuse by maximizing nonopioid medications and limiting the size and number of opioid prescriptions. However, public and medical opinion of opioids as well as prescribing practices have changed over time with a trend toward lower opioid use. The interventions, as part of the described protocol, are a result of these changes and attempt to minimize opioid use while maximizing postoperative analgesia.

Our data showed a significant decrease in total opioid use through POD 1, IV opioid use, and opioid prescriptions provided at the first postoperative visit. The protocol group used only 6.7% of the IV opioids and 30.9% of the total opioids that were used by the control group. The substantial difference in IV opioid requirement, 166.2 MED, is equivalent to 8 mg of IV hydromorphone or 55 mg of IV morphine. The difference in total opioid requirement was similar at 166.9 MED, equivalent to 111 mg of oral oxycodone.

Decreasing opioid use has the additional benefit of improving outcomes, as higher doses of opioids have been associated with increased length of stay, greater rates of DVT, and postoperative infection.²³ These complications occurred in a stepwise manner, suggesting a dose-response gradient that makes the sizable decrease noted in our data of greater relevance.²³ While the adverse effects (AEs) of opioids are well known, there are limited data on opioid dosing and its effect on perioperative outcomes.²³

A significant decrease in the percentage of patients receiving an opioid prescription at the first postoperative visit suggests a decrease in the number of patients on prolonged opioids after TKA with implementation of modern analgesic modalities. The duration of postoperative opioid use has been found to be the strongest predictor of misuse, and each postoperative refill increases the probability of misuse by 44%.²⁴ In addition, opioid use for > 3 months after TKA is associated with increased risk of periprosthetic infection, increased overall revision rate, and stiffness at 1 year postoperatively.⁹ While not entirely under the control of the surgeon, measures to decrease the number of postoperative opioid refills may lead to a decrease in opioid misuse.

Limitations

A number of limitations of this study should be noted. One was a protocol change regarding length of stay, which occurred during the study period and resulted in a significantly shorter length of stay in the protocol group. As a result, opioid use data were analyzed only through midnight at the end of POD 1. Patients who were discharged on POD 1 did not have opioid use data available for the full duration of the first POD, which may exaggerate the decrease in opioid requirements, as opioids used after discharge but prior to midnight on POD 1 were not recorded. However, opioids taken at home are oral with a low MME compared with IV opioids received by hospitalized patients in the control group. In addition, if taken as prescribed, patients at home would only have enough time to take a few doses of opioids prior to the midnight cutoff. We do not believe this difference in time of opioid use meaningfully affected the data. An additional limitation includes the variability between periarticular injections between surgeons. While the percentage of patients that received injections from surgeon 1 vs surgeon 2 were similar, it cannot be ruled out as a potential confounding factor. Other limitations include a lack of pain scores to compare subjective pain ratings, the retrospective nature of the study, and a largely homogenous male VA population.

Conclusions

Ease of access to opioids is a risk factor for opioid abuse, which itself is a risk factor for subsequent heroin use.^1,2 The CDC and AAOS have thus published recommendations regarding opioid prescribing practices to decrease opioid use and abuse.^5,6 Our described protocol, which aligns with these recommendations, resulted in a significant decrease in IV opioid requirement, total opioid requirement, and lower rates of opioid prescriptions provided at the first postoperative visit. These promising findings demonstrate a lower percentage of patients on long-term opioids after TKA and a significantly decreased cumulative opioid exposure.

Ease of access to opioids in the perioperative period is a risk factor for opioid misuse and has been identified as a strong risk factor for heroin use.^1,2 Three-quarters of today’s heroin users were introduced to opioids through prescription medications.² The United States accounts for about 80% of the global opioid supply consumption, and deaths from opioid overdose are increasing: 70,630 deaths in 2019 alone.^3,4

The Centers for Disease Control and Prevention (CDC) has called for changes in opioid prescribing. The American Academy of Orthopaedic Surgeons (AAOS) also has published an information statement with strategies to decrease opioid misuse and abuse.^5,6 Arthroplasty surgeons have recently focused on decreasing use of opioids in total knee arthroplasty (TKA), a procedure traditionally associated with high levels of opioid consumption and historical reliance on opioid monotherapy for postoperative analgesia.^7,8 From a clinical perspective, prolonged postoperative opioid use contributes to poorer surgical outcomes due to increased risk of complications, including stiffness, infection, and revision TKA.⁹

Multimodal pain regimens are increasingly being used to control postoperative pain as data supports their efficacy.^10,11 Previous studies have found that simultaneous modulation of multiple pain pathways decreases narcotics consumption and improves patient outcomes.^12,13 Along with other adjuvant therapies, peripheral nerve blocks, such as adductor canal block (ACB) and femoral nerve block (FNB), have been used to decrease postoperative pain.¹⁴ Studies have shown that ACB has fewer complications and shorter functional recovery times compared with FNB.^15,16 The distribution of the ACB excludes the femoral nerve, thus preserving greater quadriceps strength while providing equivalent levels of analgesia compared with FNB.^15,17,18 The ACB has shown decreased near-fall events and improved balance scores in the immediate postoperative period.¹⁹

Our study analyzed opioid consumption patterns of TKA patients from a US Department of Veterans Affairs (VA) medical center before and after the institution of a multimodal analgesic protocol using ACB. The primary purpose of this study was to determine whether a protocol that included intraoperative spinal anesthesia with a postoperative multimodal analgesic regimen and ACB was associated with a decreased postoperative opioid requirement when compared with patients who received intraoperative general anesthesia and a traditional opioid regimen. Secondary outcomes included the effect of opioid consumption on range of motion on postoperative day (POD) 1 and number of opioid prescriptions written at the first postoperative clinic visit.

Methods

Approval for the study was obtained from the institutional review board at the Dayton Veterans Affairs Medical Center (DVAMC) in Ohio. A retrospective chart review was performed to collect data from all patients undergoing TKA at DVAMC from June 1, 2011, through December 31, 2015. Exclusion criteria included multiple surgeries in the study time frame, documented chronic pain, allergy to local anesthetics, daily preoperative use of opioids, and incomplete data in the health record.

All surgeries were performed by 2 staff arthroplasty surgeons at a single VAMC. All patients attended a preoperative visit where a history, physical, and anesthesia evaluation were performed, and watched an educational video detailing surgical indications and postoperative rehabilitation. All surgeries were performed with tourniquets and a periarticular injection was performed at the conclusion of each case. Surgeon 1 treatment of choice was 10 mL 0.5% bupivacaine, whereas surgeon 2 performed a posterior capsular injection of 30 mL 0.25% bupivacaine and a periarticular injection of 30 mg ketorolac in 10 mL 0.25% bupivacaine with epinephrine.

Prior to August 2014, general endotracheal anesthesia was used intraoperatively. A patient-controlled analgesia (PCA) pump of morphine or hydromorphone and additional oral oxycodone or hydrocodone was used for postoperative pain. PCA pumps were patient dependent. In the control group, 245 patients received the morphine PCA while 61 received the hydromorphone PCA. Morphine PCA dosing consisted of 1-mg doses every 10 minutes with potential baseline infusion rates of 0.5 to 1.0 mg/h and a 4-hour limit of 20 mg. Hydromorphone PCA dosing consisted of 0.2 to 0.4-mg doses with a potential continuous dose of 0.2 to 0.4 mg/h and a 4-hour limit of 4 mg.

Results

During the study period from June 1, 2011, through December 31, 2015, 533 eligible TKAs were performed, 306 in the control group and 227 in the protocol group. The groups had similar sex distribution; body mass index; knee range of motion; diagnoses of diabetes mellitus, coronary artery disease, and chronic kidney disease; and history of deep vein thrombosis (DVT) or pulmonary embolism (P ≥ .05). The protocol group was significantly older (P = .04) and had a significantly higher rate of chronic obstructive pulmonary disease (COPD) (P = .002). There were no significant differences between number of procedures performed by surgeon (P = .48) or total tourniquet time (P = .13) (Table 2). Mean (SD) length of stay was significantly greater in the control group compared with the protocol group (2.5 [1.3] vs 1.4 [0.7] days, P < .001).

Figure 1 shows the distributions of each type of opioid used. Compared with the control group, the protocol group had a significantly lower mean (SD) IV opioid use: 178.2 (98.0) MED vs 12.0 (24.6) MED (P < .001; d = 2.19; Δ = 0.94) and mean (SD) total opioid use: 241.7 (120.1) MED vs 74.8 (42.7) MED (P < .001; d = 1.76; Δ = 0.89). Mean (SD) oral opioid use did not differ between groups (control, 63.6 [45.4] MED; protocol, 62.9 [31.4] MED; P = .85; d = 0.02; Δ = 0.51). A significantly lower percentage of patients in the protocol group received additional opioids at the 3-week follow-up when compared to the control group: 46.7% vs 61.3%, respectively (P < .001; RR, 0.76; 95% CI, 0.65-0.90).

Discussion

Coordinated efforts with major medical organizations are being made to decrease opioid prescriptions and exposure.^5,6 To our knowledge, no study has quantified a decrease in opioid requirement in a VA population after implementation of a protocol that includes intraoperative spinal anesthesia and a postoperative multimodal analgesic regimen including ACB after TKA. The analgesic protocol described in this study aligns with recommendations from both the CDC and the AAOS to decrease opioid use and misuse by maximizing nonopioid medications and limiting the size and number of opioid prescriptions. However, public and medical opinion of opioids as well as prescribing practices have changed over time with a trend toward lower opioid use. The interventions, as part of the described protocol, are a result of these changes and attempt to minimize opioid use while maximizing postoperative analgesia.

Our data showed a significant decrease in total opioid use through POD 1, IV opioid use, and opioid prescriptions provided at the first postoperative visit. The protocol group used only 6.7% of the IV opioids and 30.9% of the total opioids that were used by the control group. The substantial difference in IV opioid requirement, 166.2 MED, is equivalent to 8 mg of IV hydromorphone or 55 mg of IV morphine. The difference in total opioid requirement was similar at 166.9 MED, equivalent to 111 mg of oral oxycodone.

Decreasing opioid use has the additional benefit of improving outcomes, as higher doses of opioids have been associated with increased length of stay, greater rates of DVT, and postoperative infection.²³ These complications occurred in a stepwise manner, suggesting a dose-response gradient that makes the sizable decrease noted in our data of greater relevance.²³ While the adverse effects (AEs) of opioids are well known, there are limited data on opioid dosing and its effect on perioperative outcomes.²³

A significant decrease in the percentage of patients receiving an opioid prescription at the first postoperative visit suggests a decrease in the number of patients on prolonged opioids after TKA with implementation of modern analgesic modalities. The duration of postoperative opioid use has been found to be the strongest predictor of misuse, and each postoperative refill increases the probability of misuse by 44%.²⁴ In addition, opioid use for > 3 months after TKA is associated with increased risk of periprosthetic infection, increased overall revision rate, and stiffness at 1 year postoperatively.⁹ While not entirely under the control of the surgeon, measures to decrease the number of postoperative opioid refills may lead to a decrease in opioid misuse.

Limitations

A number of limitations of this study should be noted. One was a protocol change regarding length of stay, which occurred during the study period and resulted in a significantly shorter length of stay in the protocol group. As a result, opioid use data were analyzed only through midnight at the end of POD 1. Patients who were discharged on POD 1 did not have opioid use data available for the full duration of the first POD, which may exaggerate the decrease in opioid requirements, as opioids used after discharge but prior to midnight on POD 1 were not recorded. However, opioids taken at home are oral with a low MME compared with IV opioids received by hospitalized patients in the control group. In addition, if taken as prescribed, patients at home would only have enough time to take a few doses of opioids prior to the midnight cutoff. We do not believe this difference in time of opioid use meaningfully affected the data. An additional limitation includes the variability between periarticular injections between surgeons. While the percentage of patients that received injections from surgeon 1 vs surgeon 2 were similar, it cannot be ruled out as a potential confounding factor. Other limitations include a lack of pain scores to compare subjective pain ratings, the retrospective nature of the study, and a largely homogenous male VA population.

Conclusions

Ease of access to opioids is a risk factor for opioid abuse, which itself is a risk factor for subsequent heroin use.^1,2 The CDC and AAOS have thus published recommendations regarding opioid prescribing practices to decrease opioid use and abuse.^5,6 Our described protocol, which aligns with these recommendations, resulted in a significant decrease in IV opioid requirement, total opioid requirement, and lower rates of opioid prescriptions provided at the first postoperative visit. These promising findings demonstrate a lower percentage of patients on long-term opioids after TKA and a significantly decreased cumulative opioid exposure.

CASE A 34-year-old woman presents with fatigue. She appears defensive when asked about her alcohol use. She answers No to all questions on the CAGE (cut down, annoyed, guilty, eye-opener) screening tool, but acknowledges drinking excessively on rare occasions. Her physician has a high suspicion for alcohol use disorder (AUD) and recommends further testing. The patient agrees but denies having used alcohol over the past several days. Which of the following is most likely to help support the suspicion of a heavy drinking pattern?

1. Routine lab tests (liver panel and complete blood count).
2. Blood or urine alcohol level.
3. Phosphatidylethanol (PEth) level in the blood.
4. Ethyl glucuronide (EtG) in the urine.
5. Carbohydrate-deficient transferrin (CDT) in the blood.

(See "Case answer.").

About 1 in 12 Americans have AUD,¹ and 1 in 10 children live in a home with a parent who has a drinking problem.² While the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) succinctly defines AUD with specific criteria,¹ the term generally refers to an inability to control or stop drinking despite adverse social or health consequences. AUD is regarded as > 4 drinks per day for men and > 3 drinks per day for women.³ A “standard drink” would be a 12-oz bottle of beer, a 5-oz glass of wine, or 1.5 oz of distilled spirits. Effects of chronic alcohol use are vast and include malnutrition, alcohol withdrawal syndrome, alcoholic liver disease, pancreatitis/pancreatic cancer, cardiomyopathy, and stroke.^4-6 Alcohol use by a pregnant woman can lead to fetal alcohol syndrome in her child.⁷

AUD may be more prevalent in the wake of COVID-19. Primary care practitioners tend to miss a large fraction of patients with AUD in their practice, especially younger patients and those without somatic comorbidities.⁸ Systematic screening for AUD can identify many of these people.⁸ Particularly as the COVID-19 pandemic continues to unfold and increases stress for everyone, risk of worsening drinking increases both in individuals with current AUD and for those in remission.⁹ Contrary to common belief, patients visiting primary care favor screening for at-risk drinking.¹⁰ Thus, awareness of the prevalence of AUD and patient acceptance of screening should encourage wider testing.

Screening tools. The 2014 guidelines published by the Centers for Disease Control and Prevention recommend using quick screening tools—ie, single question or ­AUDIT 1-3 (TABLE 1^11-18)—as an objective means of determining whether patients’ drinking creates a risk for themselves or others.¹¹ Excessive drinking identified using alcohol questionnaires can help reduce medical complications and health care costs.¹⁹ The questionnaires we review do not provide a diagnosis but help identify individuals who might benefit from more thorough assessment.²⁰ Following up, as needed, by testing for alcohol biomarkers can provide quantitative insight into problematic alcohol use.²

Primary care practitioners tend to miss a large fraction of patients with alcohol use disorder in their practice. Systematic screening for AUD can identify many of these patients.

But before we discuss the utility of biomarkers, it’s important to quickly review how alcohol is eliminated from the body.

Alcohol elimination

The stomach and small intestine are the primary sites for alcohol absorption. Alcohol elimination from the body occurs through 3 pathways. The first involves oxidative metabolism, which eliminates most ethanol (95%) through the actions of alcohol dehydrogenase, cytochrome P4502E1, or catalase. A lesser amount of alcohol (2%-5%) is eliminated, unchanged, via the second pathway, which includes urine, sweat, and breath. Nonoxidative metabolism makes up the third pathway. Nonoxidative metabolism removes a very small amount (0.1%) of alcohol and involves the direct ethanol biomarkers PEth, EtG, ethyl sulfate (EtS), and fatty acid ethyl esters (FAEEs).²¹ Our emphasis in this article is on assays of direct metabolites of alcohol—particularly PEth.

Continue to: To understand the utility...

To understand the utility of these direct biomarkers, it is helpful to look at the indirect biomarkers first.

Indirect biomarkers have limited sensitivity and specificity

When alcohol is consumed in large enough quantities over time, indirect biomarkers of alcohol can become abnormal.²² The major indirect biomarkers are the liver enzymes aspartate and alanine aminotransferase (AST and ALT), gamma-glutamyl transferase (GGT), mean corpuscular volume (MCV) of red blood cells, and carbohydrate-deficient transferrin (CDT). Indirect biomarkers have limited sensitivity and specificity for AUD. (For specifics on sensitivity and specificity of indirect and direct biomarkers, see TABLE 2.^23-31)

Liver enzymes. AST and ALT are also present in the heart, muscle, and kidneys. Elevated levels usually imply injury to hepatocytes, with ALT being more reflective of liver involvement than AST. Both AST and ALT are elevated in other common liver conditions including hepatitis C virus infection and fatty liver disease. In alcoholic liver disease (ALD), AST is elevated more than ALT; an AST-to-ALT ratio > 3 suggests ALD. An elevated GGT often indicates hepatic injury and is used to confirm that elevated alkaline phosphatase is of hepatic origin.³²

MCV is the average volume of erythrocytes,³³ and an elevated MCV is a potential indicator of excessive alcohol intake. Macrocytosis requires sustained alcohol use, and the test has low sensitivity. Other diseases such as vitamin B12 or folic acid deficiency, hypothyroidism, hematologic diseases (eg, cold agglutinin disease, multiple myeloma, amyloidosis), and certain medications can also increase MCV.³⁴ Moreover, MCV responds slowly to alcohol use, abstinence, and relapse because red cells have a life span of 120 days.³⁵

CDT. Transferrin is a glycoprotein produced in the liver. The level of transferrin with sialic acid chains increases with alcohol consumption as well as in the carbohydrate deficient glycoprotein syndrome, leading to so-called carbohydrate deficient transferrin.³⁶ It is a sensitive marker for detecting alcohol relapse and monitoring sobriety. Moderate-to-heavy alcohol use, averaging ≥ 40 g of alcohol per day for 2 weeks,³⁶ can decrease the amount of carbohydrate attached to transferrin. Two weeks after complete alcohol cessation, CDT levels will return to normal.³⁷

Continue to: CDT is approved...

CDT is approved by the FDA as an assay for alcohol consumption.³⁷ While CDT is felt to be one of the better indirect markers of AUD and can extend the window of detection, there are still issues with its sensitivity and specificity.³⁸ This biomarker can be elevated with other liver diseases and can be affected by the patient’s age, body mass index, gender, and tobacco use.^39,40 Testing for CDT has never achieved widespread clinical use and has been largely supplanted by the more accurate PEth test (described in a bit).

Direct biomarkers offer insight into recent alcohol use

Other than ethanol itself, direct biomarkers of alcohol use are minor ethanol metabolites created through biochemical reactions when ethanol is coupled to endogenous compounds. Hence, the presence of these metabolites is usually directly related to ethanol consumption.⁴¹ Direct alcohol biomarkers are EtG, EtS, FAEEs, and PEth (TABLE 2^23-31). They reflect alcohol consumption over a period of several days, making them useful when paired with questionnaire data, especially for identifying young adults who engage in binge drinking.⁴²

Ethanol can be measured in blood, urine, and breath and is detectable a bit longer in urine than in blood. However, alcohol is detectable in the blood only for 6 to 12 hours after drinking. After alcohol consumption, concentrations peak in the blood within 2 hours. The window for detecting ethanol in the blood depends on the amount of alcohol consumed and the elimination rate of alcohol, which is about 12 mg/dL/h (or 0.012%)—approximately the same amount of alcohol contained in a standard drink (14 g).

EtG can be detected in urine for ≥ 24 hours after just 1 or 2 drinks, and for up to 4 days after heavy consumption.

Checking the blood alcohol level might be helpful in the office if a patient appears intoxicated but denies alcohol use. A blood alcohol level > 300 mg/dL, or > 150 mg/dL without gross evidence of intoxication, or > 100 mg/dL upon routine examination indicates AUD with a high degree of reliability.^33,43 But the short half-life of ethanol in blood limits its use as a biomarker,³³ and it is not a good indicator of chronic drinking.⁴⁴

EtG and EtS. Less than 0.1% of ethanol is secreted as the metabolites EtG and EtS, which are generated, respectively, by the enzymes uridine diphosphate glucuronosyltransferase and sulfotransferase.⁴⁵ They have value in the diagnosis of AUD because of the length of time in which they can be detected. Urinary EtG and EtS have been especially important biomarkers for monitoring relapse in outpatients treated for alcohol-­related problems.⁴⁶ Generally, EtG and EtS can be detected in urine for 13 to 20 hours after a single drink (0.1 g/kg), and for up to 4 to 5 days following ingestion of large amounts of alcohol.⁴⁷

Continue to: EtG has been detectable...

EtG has been detectable in urine for ≥ 24 hours following only 1 or 2 drinks, and for up to 4 days following heavy consumption.⁴⁸ Shortly after alcohol intake, even in small amounts, EtG is detectable. Analysis of EtG in urine is helpful in monitoring alcohol consumption during withdrawal treatment, for workplace testing, and to check for abstinence in legal matters. The EtG urine test is useful in detecting alcohol consumption in a person who claims to be abstinent but who drank 2 or 3 days before the evaluation. Although accurate, EtG’s window for detection is narrower than that of the PEth assay.

EtS is a good marker of acute short-term alcohol use, up to 12 hours in the blood (or longer in heavier drinkers) and up to 5 days in urine.⁴⁹ Its sensitivity is highest in heavy drinkers. Post-sampling formation and degradation of EtS have not been known to occur in urine samples. Testing for this second metabolite of ethanol can slightly improve the sensitivity and specificity of the EtG test. A urine test for EtS has a wider detection window. But it has little practical advantage compared with EtG.⁵⁰

For better clinical specificity, a combination of both EtG and EtS testing has been recommended. However, the EtS assay is more cumbersome and provides little advantage over EtG. EtG values do not correlate precisely with the amount or frequency of ethanol use, but the magnitude of the EtG finding roughly corresponds to the amount of alcohol recently consumed.

False-positive and false-negative results for EtG and EtS are uncommon in practice. However, false-positive results are possible with the EtG test in certain circumstances: presence of Escherichia coli in the specimen, use of ethanol-based hand sanitizers (> 20 times a day) or mouthwashes, and the consumption of substances like pralines, nonalcoholic beer, pharmaceutical products, and fruit juice. Similarly, false-negative results of EtG can occur from degradation if the samples are contaminated with other bacteria, transported without cooling, or stored improperly.⁵¹ In practice, this is uncommon, and the test is believed to be specific with few false-positive results. Commercially available EtG colorimetric test strips permit on-site analysis of urine samples.

FAEEs are a combination of different esters and products of alcohol metabolism through a nonoxidative pathway. They are formed by esterification of endogenous free fatty acids and ethanol in blood and several tissues.²⁹ These are sensitive and specific markers of alcohol ingestion and can differentiate chronic alcohol consumption from binge drinking.²⁹ It is elevated for up to 99 hours in heavy alcohol drinkers.³⁰ It can be detected in hair for a longer period than in blood.⁵² Detection of FAEEs in meconium can help establish fetal alcohol exposure.⁵³

Continue to: PEth

PEth. Use of the PEth assay has increased in recent years and its accuracy has had a transformative effect on the diagnosis of AUD.⁵⁴ PEth is a phospholipid found in erythrocyte membranes, formed by an interaction between ethanol and phosphatidylcholine, catalyzed by phospholipase D.^55,56 Major advantages of PEth include an unusually long half-life and specificity. Red cells lack enzymes to degrade PEth, therefore PEth accumulates in red cells and has a half-life of 4 to 10 days^57,58 allowing for detection of significant ethanol consumption extending back 3 to 4 weeks.⁵⁹ There is no evidence that PEth is formed in the absence of ethanol, making the test essentially 100% specific, particularly at higher cutoff values of ≥ 150 ng/mL.^31,60

PEth is known to be formed only in the presence of ethanol, making the test virtually 100% specific.

PEth levels are not affected by age, gender, or underlying liver or renal disease.⁶¹ PEth can differentiate between heavy alcohol use and social drinking and can therefore identify chronic excessive use.⁶² With chronic excessive alcohol consumption, PEth is detectable in blood up to 28 days after sobriety.⁶³ A correlation exists between PEth concentrations in blood and the amount of consumed ethanol. PEth has increased specificity and sensitivity for the detection of latent ethanol use compared with other direct biomarkers.²¹ It can identify recent heavy drinking earlier than indirect biomarkers, as it does not rely on hepatic injury.

Using a cutoff level of 20 ng/mL, PEth assays have a sensitivity of 73% for any alcohol use in the past month; at 80 ng/mL, the sensitivity is 91% for > 4 drinks/d.⁶¹ PEth is considered semi-quantitative. The World Health Organization defines acceptable social alcohol use at a PEth value < 40 ng/dL for men and < 20 ng/dL for women. Chronic excessive use is defined by a level > 60 ng/dL.⁵⁵ The cutoff levels tend to be arbitrary and vary with different guidelines.

PEth may be a useful marker in difficult-toassess settings, or in confirming or invalidating self-reported alcohol consumption.

Although false-positive PEth test results may be possible, most experts believe that dishonesty in self-reporting by test subjects is more likely. That said, the true specificity of PEth remains unknown; a lower value detected should not be regarded as absolute proof of relapse or chronic alcoholism.

Studies have shown a positive correlation between the AUDIT-C score and PEth values combined with self-reported alcohol consumption, indicating that PEth may be a useful marker in difficult-to-assess settings, or in confirming or invalidating self-reported alcohol consumption.^61,64,65 The PEth test is now widely available and, in the authors’ experience, usually costs $100 to $200. Analysis typically costs $40 to $100,⁶⁶ and costs could decrease as the test becomes more widely used. Turnaround time for PEth is 5 to 10 days. It is now the recommended assay by transplant hepatologists for detecting alcohol use.⁶⁷TABLE 3^22,68 explains the currently accepted ranges for various PEth results.

Continue to: CASE ANSWER

CASE ANSWER While every test mentioned can aid in detecting alcohol consumption, the PEth assay in this scenario would be the most clinically useful.

CORRESPONDENCE
Frederick Nunes, MD, Pennsylvania Hospital of University of Pennsylvania, 230 West Washington Square, 4th Floor, Philadelphia, PA 19104; [email protected]

CASE A 34-year-old woman presents with fatigue. She appears defensive when asked about her alcohol use. She answers No to all questions on the CAGE (cut down, annoyed, guilty, eye-opener) screening tool, but acknowledges drinking excessively on rare occasions. Her physician has a high suspicion for alcohol use disorder (AUD) and recommends further testing. The patient agrees but denies having used alcohol over the past several days. Which of the following is most likely to help support the suspicion of a heavy drinking pattern?

1. Routine lab tests (liver panel and complete blood count).
2. Blood or urine alcohol level.
3. Phosphatidylethanol (PEth) level in the blood.
4. Ethyl glucuronide (EtG) in the urine.
5. Carbohydrate-deficient transferrin (CDT) in the blood.

(See "Case answer.").

About 1 in 12 Americans have AUD,¹ and 1 in 10 children live in a home with a parent who has a drinking problem.² While the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) succinctly defines AUD with specific criteria,¹ the term generally refers to an inability to control or stop drinking despite adverse social or health consequences. AUD is regarded as > 4 drinks per day for men and > 3 drinks per day for women.³ A “standard drink” would be a 12-oz bottle of beer, a 5-oz glass of wine, or 1.5 oz of distilled spirits. Effects of chronic alcohol use are vast and include malnutrition, alcohol withdrawal syndrome, alcoholic liver disease, pancreatitis/pancreatic cancer, cardiomyopathy, and stroke.^4-6 Alcohol use by a pregnant woman can lead to fetal alcohol syndrome in her child.⁷

AUD may be more prevalent in the wake of COVID-19. Primary care practitioners tend to miss a large fraction of patients with AUD in their practice, especially younger patients and those without somatic comorbidities.⁸ Systematic screening for AUD can identify many of these people.⁸ Particularly as the COVID-19 pandemic continues to unfold and increases stress for everyone, risk of worsening drinking increases both in individuals with current AUD and for those in remission.⁹ Contrary to common belief, patients visiting primary care favor screening for at-risk drinking.¹⁰ Thus, awareness of the prevalence of AUD and patient acceptance of screening should encourage wider testing.

Screening tools. The 2014 guidelines published by the Centers for Disease Control and Prevention recommend using quick screening tools—ie, single question or ­AUDIT 1-3 (TABLE 1^11-18)—as an objective means of determining whether patients’ drinking creates a risk for themselves or others.¹¹ Excessive drinking identified using alcohol questionnaires can help reduce medical complications and health care costs.¹⁹ The questionnaires we review do not provide a diagnosis but help identify individuals who might benefit from more thorough assessment.²⁰ Following up, as needed, by testing for alcohol biomarkers can provide quantitative insight into problematic alcohol use.²

Primary care practitioners tend to miss a large fraction of patients with alcohol use disorder in their practice. Systematic screening for AUD can identify many of these patients.

But before we discuss the utility of biomarkers, it’s important to quickly review how alcohol is eliminated from the body.

Alcohol elimination

The stomach and small intestine are the primary sites for alcohol absorption. Alcohol elimination from the body occurs through 3 pathways. The first involves oxidative metabolism, which eliminates most ethanol (95%) through the actions of alcohol dehydrogenase, cytochrome P4502E1, or catalase. A lesser amount of alcohol (2%-5%) is eliminated, unchanged, via the second pathway, which includes urine, sweat, and breath. Nonoxidative metabolism makes up the third pathway. Nonoxidative metabolism removes a very small amount (0.1%) of alcohol and involves the direct ethanol biomarkers PEth, EtG, ethyl sulfate (EtS), and fatty acid ethyl esters (FAEEs).²¹ Our emphasis in this article is on assays of direct metabolites of alcohol—particularly PEth.

Continue to: To understand the utility...

To understand the utility of these direct biomarkers, it is helpful to look at the indirect biomarkers first.

Indirect biomarkers have limited sensitivity and specificity

When alcohol is consumed in large enough quantities over time, indirect biomarkers of alcohol can become abnormal.²² The major indirect biomarkers are the liver enzymes aspartate and alanine aminotransferase (AST and ALT), gamma-glutamyl transferase (GGT), mean corpuscular volume (MCV) of red blood cells, and carbohydrate-deficient transferrin (CDT). Indirect biomarkers have limited sensitivity and specificity for AUD. (For specifics on sensitivity and specificity of indirect and direct biomarkers, see TABLE 2.^23-31)

Liver enzymes. AST and ALT are also present in the heart, muscle, and kidneys. Elevated levels usually imply injury to hepatocytes, with ALT being more reflective of liver involvement than AST. Both AST and ALT are elevated in other common liver conditions including hepatitis C virus infection and fatty liver disease. In alcoholic liver disease (ALD), AST is elevated more than ALT; an AST-to-ALT ratio > 3 suggests ALD. An elevated GGT often indicates hepatic injury and is used to confirm that elevated alkaline phosphatase is of hepatic origin.³²

MCV is the average volume of erythrocytes,³³ and an elevated MCV is a potential indicator of excessive alcohol intake. Macrocytosis requires sustained alcohol use, and the test has low sensitivity. Other diseases such as vitamin B12 or folic acid deficiency, hypothyroidism, hematologic diseases (eg, cold agglutinin disease, multiple myeloma, amyloidosis), and certain medications can also increase MCV.³⁴ Moreover, MCV responds slowly to alcohol use, abstinence, and relapse because red cells have a life span of 120 days.³⁵

CDT. Transferrin is a glycoprotein produced in the liver. The level of transferrin with sialic acid chains increases with alcohol consumption as well as in the carbohydrate deficient glycoprotein syndrome, leading to so-called carbohydrate deficient transferrin.³⁶ It is a sensitive marker for detecting alcohol relapse and monitoring sobriety. Moderate-to-heavy alcohol use, averaging ≥ 40 g of alcohol per day for 2 weeks,³⁶ can decrease the amount of carbohydrate attached to transferrin. Two weeks after complete alcohol cessation, CDT levels will return to normal.³⁷

Continue to: CDT is approved...

CDT is approved by the FDA as an assay for alcohol consumption.³⁷ While CDT is felt to be one of the better indirect markers of AUD and can extend the window of detection, there are still issues with its sensitivity and specificity.³⁸ This biomarker can be elevated with other liver diseases and can be affected by the patient’s age, body mass index, gender, and tobacco use.^39,40 Testing for CDT has never achieved widespread clinical use and has been largely supplanted by the more accurate PEth test (described in a bit).

Direct biomarkers offer insight into recent alcohol use

Other than ethanol itself, direct biomarkers of alcohol use are minor ethanol metabolites created through biochemical reactions when ethanol is coupled to endogenous compounds. Hence, the presence of these metabolites is usually directly related to ethanol consumption.⁴¹ Direct alcohol biomarkers are EtG, EtS, FAEEs, and PEth (TABLE 2^23-31). They reflect alcohol consumption over a period of several days, making them useful when paired with questionnaire data, especially for identifying young adults who engage in binge drinking.⁴²

Ethanol can be measured in blood, urine, and breath and is detectable a bit longer in urine than in blood. However, alcohol is detectable in the blood only for 6 to 12 hours after drinking. After alcohol consumption, concentrations peak in the blood within 2 hours. The window for detecting ethanol in the blood depends on the amount of alcohol consumed and the elimination rate of alcohol, which is about 12 mg/dL/h (or 0.012%)—approximately the same amount of alcohol contained in a standard drink (14 g).

EtG can be detected in urine for ≥ 24 hours after just 1 or 2 drinks, and for up to 4 days after heavy consumption.

Checking the blood alcohol level might be helpful in the office if a patient appears intoxicated but denies alcohol use. A blood alcohol level > 300 mg/dL, or > 150 mg/dL without gross evidence of intoxication, or > 100 mg/dL upon routine examination indicates AUD with a high degree of reliability.^33,43 But the short half-life of ethanol in blood limits its use as a biomarker,³³ and it is not a good indicator of chronic drinking.⁴⁴

EtG and EtS. Less than 0.1% of ethanol is secreted as the metabolites EtG and EtS, which are generated, respectively, by the enzymes uridine diphosphate glucuronosyltransferase and sulfotransferase.⁴⁵ They have value in the diagnosis of AUD because of the length of time in which they can be detected. Urinary EtG and EtS have been especially important biomarkers for monitoring relapse in outpatients treated for alcohol-­related problems.⁴⁶ Generally, EtG and EtS can be detected in urine for 13 to 20 hours after a single drink (0.1 g/kg), and for up to 4 to 5 days following ingestion of large amounts of alcohol.⁴⁷

Continue to: EtG has been detectable...

EtG has been detectable in urine for ≥ 24 hours following only 1 or 2 drinks, and for up to 4 days following heavy consumption.⁴⁸ Shortly after alcohol intake, even in small amounts, EtG is detectable. Analysis of EtG in urine is helpful in monitoring alcohol consumption during withdrawal treatment, for workplace testing, and to check for abstinence in legal matters. The EtG urine test is useful in detecting alcohol consumption in a person who claims to be abstinent but who drank 2 or 3 days before the evaluation. Although accurate, EtG’s window for detection is narrower than that of the PEth assay.

EtS is a good marker of acute short-term alcohol use, up to 12 hours in the blood (or longer in heavier drinkers) and up to 5 days in urine.⁴⁹ Its sensitivity is highest in heavy drinkers. Post-sampling formation and degradation of EtS have not been known to occur in urine samples. Testing for this second metabolite of ethanol can slightly improve the sensitivity and specificity of the EtG test. A urine test for EtS has a wider detection window. But it has little practical advantage compared with EtG.⁵⁰

For better clinical specificity, a combination of both EtG and EtS testing has been recommended. However, the EtS assay is more cumbersome and provides little advantage over EtG. EtG values do not correlate precisely with the amount or frequency of ethanol use, but the magnitude of the EtG finding roughly corresponds to the amount of alcohol recently consumed.

False-positive and false-negative results for EtG and EtS are uncommon in practice. However, false-positive results are possible with the EtG test in certain circumstances: presence of Escherichia coli in the specimen, use of ethanol-based hand sanitizers (> 20 times a day) or mouthwashes, and the consumption of substances like pralines, nonalcoholic beer, pharmaceutical products, and fruit juice. Similarly, false-negative results of EtG can occur from degradation if the samples are contaminated with other bacteria, transported without cooling, or stored improperly.⁵¹ In practice, this is uncommon, and the test is believed to be specific with few false-positive results. Commercially available EtG colorimetric test strips permit on-site analysis of urine samples.

FAEEs are a combination of different esters and products of alcohol metabolism through a nonoxidative pathway. They are formed by esterification of endogenous free fatty acids and ethanol in blood and several tissues.²⁹ These are sensitive and specific markers of alcohol ingestion and can differentiate chronic alcohol consumption from binge drinking.²⁹ It is elevated for up to 99 hours in heavy alcohol drinkers.³⁰ It can be detected in hair for a longer period than in blood.⁵² Detection of FAEEs in meconium can help establish fetal alcohol exposure.⁵³

Continue to: PEth

PEth. Use of the PEth assay has increased in recent years and its accuracy has had a transformative effect on the diagnosis of AUD.⁵⁴ PEth is a phospholipid found in erythrocyte membranes, formed by an interaction between ethanol and phosphatidylcholine, catalyzed by phospholipase D.^55,56 Major advantages of PEth include an unusually long half-life and specificity. Red cells lack enzymes to degrade PEth, therefore PEth accumulates in red cells and has a half-life of 4 to 10 days^57,58 allowing for detection of significant ethanol consumption extending back 3 to 4 weeks.⁵⁹ There is no evidence that PEth is formed in the absence of ethanol, making the test essentially 100% specific, particularly at higher cutoff values of ≥ 150 ng/mL.^31,60

PEth is known to be formed only in the presence of ethanol, making the test virtually 100% specific.

PEth levels are not affected by age, gender, or underlying liver or renal disease.⁶¹ PEth can differentiate between heavy alcohol use and social drinking and can therefore identify chronic excessive use.⁶² With chronic excessive alcohol consumption, PEth is detectable in blood up to 28 days after sobriety.⁶³ A correlation exists between PEth concentrations in blood and the amount of consumed ethanol. PEth has increased specificity and sensitivity for the detection of latent ethanol use compared with other direct biomarkers.²¹ It can identify recent heavy drinking earlier than indirect biomarkers, as it does not rely on hepatic injury.

Using a cutoff level of 20 ng/mL, PEth assays have a sensitivity of 73% for any alcohol use in the past month; at 80 ng/mL, the sensitivity is 91% for > 4 drinks/d.⁶¹ PEth is considered semi-quantitative. The World Health Organization defines acceptable social alcohol use at a PEth value < 40 ng/dL for men and < 20 ng/dL for women. Chronic excessive use is defined by a level > 60 ng/dL.⁵⁵ The cutoff levels tend to be arbitrary and vary with different guidelines.

PEth may be a useful marker in difficult-toassess settings, or in confirming or invalidating self-reported alcohol consumption.

Although false-positive PEth test results may be possible, most experts believe that dishonesty in self-reporting by test subjects is more likely. That said, the true specificity of PEth remains unknown; a lower value detected should not be regarded as absolute proof of relapse or chronic alcoholism.

Studies have shown a positive correlation between the AUDIT-C score and PEth values combined with self-reported alcohol consumption, indicating that PEth may be a useful marker in difficult-to-assess settings, or in confirming or invalidating self-reported alcohol consumption.^61,64,65 The PEth test is now widely available and, in the authors’ experience, usually costs $100 to $200. Analysis typically costs $40 to $100,⁶⁶ and costs could decrease as the test becomes more widely used. Turnaround time for PEth is 5 to 10 days. It is now the recommended assay by transplant hepatologists for detecting alcohol use.⁶⁷TABLE 3^22,68 explains the currently accepted ranges for various PEth results.

Continue to: CASE ANSWER

CASE ANSWER While every test mentioned can aid in detecting alcohol consumption, the PEth assay in this scenario would be the most clinically useful.

CORRESPONDENCE
Frederick Nunes, MD, Pennsylvania Hospital of University of Pennsylvania, 230 West Washington Square, 4th Floor, Philadelphia, PA 19104; [email protected]

CASE A 34-year-old woman presents with fatigue. She appears defensive when asked about her alcohol use. She answers No to all questions on the CAGE (cut down, annoyed, guilty, eye-opener) screening tool, but acknowledges drinking excessively on rare occasions. Her physician has a high suspicion for alcohol use disorder (AUD) and recommends further testing. The patient agrees but denies having used alcohol over the past several days. Which of the following is most likely to help support the suspicion of a heavy drinking pattern?

1. Routine lab tests (liver panel and complete blood count).
2. Blood or urine alcohol level.
3. Phosphatidylethanol (PEth) level in the blood.
4. Ethyl glucuronide (EtG) in the urine.
5. Carbohydrate-deficient transferrin (CDT) in the blood.

(See "Case answer.").

About 1 in 12 Americans have AUD,¹ and 1 in 10 children live in a home with a parent who has a drinking problem.² While the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) succinctly defines AUD with specific criteria,¹ the term generally refers to an inability to control or stop drinking despite adverse social or health consequences. AUD is regarded as > 4 drinks per day for men and > 3 drinks per day for women.³ A “standard drink” would be a 12-oz bottle of beer, a 5-oz glass of wine, or 1.5 oz of distilled spirits. Effects of chronic alcohol use are vast and include malnutrition, alcohol withdrawal syndrome, alcoholic liver disease, pancreatitis/pancreatic cancer, cardiomyopathy, and stroke.^4-6 Alcohol use by a pregnant woman can lead to fetal alcohol syndrome in her child.⁷

AUD may be more prevalent in the wake of COVID-19. Primary care practitioners tend to miss a large fraction of patients with AUD in their practice, especially younger patients and those without somatic comorbidities.⁸ Systematic screening for AUD can identify many of these people.⁸ Particularly as the COVID-19 pandemic continues to unfold and increases stress for everyone, risk of worsening drinking increases both in individuals with current AUD and for those in remission.⁹ Contrary to common belief, patients visiting primary care favor screening for at-risk drinking.¹⁰ Thus, awareness of the prevalence of AUD and patient acceptance of screening should encourage wider testing.

Screening tools. The 2014 guidelines published by the Centers for Disease Control and Prevention recommend using quick screening tools—ie, single question or ­AUDIT 1-3 (TABLE 1^11-18)—as an objective means of determining whether patients’ drinking creates a risk for themselves or others.¹¹ Excessive drinking identified using alcohol questionnaires can help reduce medical complications and health care costs.¹⁹ The questionnaires we review do not provide a diagnosis but help identify individuals who might benefit from more thorough assessment.²⁰ Following up, as needed, by testing for alcohol biomarkers can provide quantitative insight into problematic alcohol use.²

Primary care practitioners tend to miss a large fraction of patients with alcohol use disorder in their practice. Systematic screening for AUD can identify many of these patients.

But before we discuss the utility of biomarkers, it’s important to quickly review how alcohol is eliminated from the body.

Alcohol elimination

The stomach and small intestine are the primary sites for alcohol absorption. Alcohol elimination from the body occurs through 3 pathways. The first involves oxidative metabolism, which eliminates most ethanol (95%) through the actions of alcohol dehydrogenase, cytochrome P4502E1, or catalase. A lesser amount of alcohol (2%-5%) is eliminated, unchanged, via the second pathway, which includes urine, sweat, and breath. Nonoxidative metabolism makes up the third pathway. Nonoxidative metabolism removes a very small amount (0.1%) of alcohol and involves the direct ethanol biomarkers PEth, EtG, ethyl sulfate (EtS), and fatty acid ethyl esters (FAEEs).²¹ Our emphasis in this article is on assays of direct metabolites of alcohol—particularly PEth.

Continue to: To understand the utility...

To understand the utility of these direct biomarkers, it is helpful to look at the indirect biomarkers first.

Indirect biomarkers have limited sensitivity and specificity

When alcohol is consumed in large enough quantities over time, indirect biomarkers of alcohol can become abnormal.²² The major indirect biomarkers are the liver enzymes aspartate and alanine aminotransferase (AST and ALT), gamma-glutamyl transferase (GGT), mean corpuscular volume (MCV) of red blood cells, and carbohydrate-deficient transferrin (CDT). Indirect biomarkers have limited sensitivity and specificity for AUD. (For specifics on sensitivity and specificity of indirect and direct biomarkers, see TABLE 2.^23-31)

Liver enzymes. AST and ALT are also present in the heart, muscle, and kidneys. Elevated levels usually imply injury to hepatocytes, with ALT being more reflective of liver involvement than AST. Both AST and ALT are elevated in other common liver conditions including hepatitis C virus infection and fatty liver disease. In alcoholic liver disease (ALD), AST is elevated more than ALT; an AST-to-ALT ratio > 3 suggests ALD. An elevated GGT often indicates hepatic injury and is used to confirm that elevated alkaline phosphatase is of hepatic origin.³²

MCV is the average volume of erythrocytes,³³ and an elevated MCV is a potential indicator of excessive alcohol intake. Macrocytosis requires sustained alcohol use, and the test has low sensitivity. Other diseases such as vitamin B12 or folic acid deficiency, hypothyroidism, hematologic diseases (eg, cold agglutinin disease, multiple myeloma, amyloidosis), and certain medications can also increase MCV.³⁴ Moreover, MCV responds slowly to alcohol use, abstinence, and relapse because red cells have a life span of 120 days.³⁵

CDT. Transferrin is a glycoprotein produced in the liver. The level of transferrin with sialic acid chains increases with alcohol consumption as well as in the carbohydrate deficient glycoprotein syndrome, leading to so-called carbohydrate deficient transferrin.³⁶ It is a sensitive marker for detecting alcohol relapse and monitoring sobriety. Moderate-to-heavy alcohol use, averaging ≥ 40 g of alcohol per day for 2 weeks,³⁶ can decrease the amount of carbohydrate attached to transferrin. Two weeks after complete alcohol cessation, CDT levels will return to normal.³⁷

Continue to: CDT is approved...

CDT is approved by the FDA as an assay for alcohol consumption.³⁷ While CDT is felt to be one of the better indirect markers of AUD and can extend the window of detection, there are still issues with its sensitivity and specificity.³⁸ This biomarker can be elevated with other liver diseases and can be affected by the patient’s age, body mass index, gender, and tobacco use.^39,40 Testing for CDT has never achieved widespread clinical use and has been largely supplanted by the more accurate PEth test (described in a bit).

Direct biomarkers offer insight into recent alcohol use

Other than ethanol itself, direct biomarkers of alcohol use are minor ethanol metabolites created through biochemical reactions when ethanol is coupled to endogenous compounds. Hence, the presence of these metabolites is usually directly related to ethanol consumption.⁴¹ Direct alcohol biomarkers are EtG, EtS, FAEEs, and PEth (TABLE 2^23-31). They reflect alcohol consumption over a period of several days, making them useful when paired with questionnaire data, especially for identifying young adults who engage in binge drinking.⁴²

Ethanol can be measured in blood, urine, and breath and is detectable a bit longer in urine than in blood. However, alcohol is detectable in the blood only for 6 to 12 hours after drinking. After alcohol consumption, concentrations peak in the blood within 2 hours. The window for detecting ethanol in the blood depends on the amount of alcohol consumed and the elimination rate of alcohol, which is about 12 mg/dL/h (or 0.012%)—approximately the same amount of alcohol contained in a standard drink (14 g).

EtG can be detected in urine for ≥ 24 hours after just 1 or 2 drinks, and for up to 4 days after heavy consumption.

Checking the blood alcohol level might be helpful in the office if a patient appears intoxicated but denies alcohol use. A blood alcohol level > 300 mg/dL, or > 150 mg/dL without gross evidence of intoxication, or > 100 mg/dL upon routine examination indicates AUD with a high degree of reliability.^33,43 But the short half-life of ethanol in blood limits its use as a biomarker,³³ and it is not a good indicator of chronic drinking.⁴⁴

EtG and EtS. Less than 0.1% of ethanol is secreted as the metabolites EtG and EtS, which are generated, respectively, by the enzymes uridine diphosphate glucuronosyltransferase and sulfotransferase.⁴⁵ They have value in the diagnosis of AUD because of the length of time in which they can be detected. Urinary EtG and EtS have been especially important biomarkers for monitoring relapse in outpatients treated for alcohol-­related problems.⁴⁶ Generally, EtG and EtS can be detected in urine for 13 to 20 hours after a single drink (0.1 g/kg), and for up to 4 to 5 days following ingestion of large amounts of alcohol.⁴⁷

Continue to: EtG has been detectable...

EtG has been detectable in urine for ≥ 24 hours following only 1 or 2 drinks, and for up to 4 days following heavy consumption.⁴⁸ Shortly after alcohol intake, even in small amounts, EtG is detectable. Analysis of EtG in urine is helpful in monitoring alcohol consumption during withdrawal treatment, for workplace testing, and to check for abstinence in legal matters. The EtG urine test is useful in detecting alcohol consumption in a person who claims to be abstinent but who drank 2 or 3 days before the evaluation. Although accurate, EtG’s window for detection is narrower than that of the PEth assay.

EtS is a good marker of acute short-term alcohol use, up to 12 hours in the blood (or longer in heavier drinkers) and up to 5 days in urine.⁴⁹ Its sensitivity is highest in heavy drinkers. Post-sampling formation and degradation of EtS have not been known to occur in urine samples. Testing for this second metabolite of ethanol can slightly improve the sensitivity and specificity of the EtG test. A urine test for EtS has a wider detection window. But it has little practical advantage compared with EtG.⁵⁰

For better clinical specificity, a combination of both EtG and EtS testing has been recommended. However, the EtS assay is more cumbersome and provides little advantage over EtG. EtG values do not correlate precisely with the amount or frequency of ethanol use, but the magnitude of the EtG finding roughly corresponds to the amount of alcohol recently consumed.

False-positive and false-negative results for EtG and EtS are uncommon in practice. However, false-positive results are possible with the EtG test in certain circumstances: presence of Escherichia coli in the specimen, use of ethanol-based hand sanitizers (> 20 times a day) or mouthwashes, and the consumption of substances like pralines, nonalcoholic beer, pharmaceutical products, and fruit juice. Similarly, false-negative results of EtG can occur from degradation if the samples are contaminated with other bacteria, transported without cooling, or stored improperly.⁵¹ In practice, this is uncommon, and the test is believed to be specific with few false-positive results. Commercially available EtG colorimetric test strips permit on-site analysis of urine samples.

FAEEs are a combination of different esters and products of alcohol metabolism through a nonoxidative pathway. They are formed by esterification of endogenous free fatty acids and ethanol in blood and several tissues.²⁹ These are sensitive and specific markers of alcohol ingestion and can differentiate chronic alcohol consumption from binge drinking.²⁹ It is elevated for up to 99 hours in heavy alcohol drinkers.³⁰ It can be detected in hair for a longer period than in blood.⁵² Detection of FAEEs in meconium can help establish fetal alcohol exposure.⁵³

Continue to: PEth

PEth. Use of the PEth assay has increased in recent years and its accuracy has had a transformative effect on the diagnosis of AUD.⁵⁴ PEth is a phospholipid found in erythrocyte membranes, formed by an interaction between ethanol and phosphatidylcholine, catalyzed by phospholipase D.^55,56 Major advantages of PEth include an unusually long half-life and specificity. Red cells lack enzymes to degrade PEth, therefore PEth accumulates in red cells and has a half-life of 4 to 10 days^57,58 allowing for detection of significant ethanol consumption extending back 3 to 4 weeks.⁵⁹ There is no evidence that PEth is formed in the absence of ethanol, making the test essentially 100% specific, particularly at higher cutoff values of ≥ 150 ng/mL.^31,60

PEth is known to be formed only in the presence of ethanol, making the test virtually 100% specific.

PEth levels are not affected by age, gender, or underlying liver or renal disease.⁶¹ PEth can differentiate between heavy alcohol use and social drinking and can therefore identify chronic excessive use.⁶² With chronic excessive alcohol consumption, PEth is detectable in blood up to 28 days after sobriety.⁶³ A correlation exists between PEth concentrations in blood and the amount of consumed ethanol. PEth has increased specificity and sensitivity for the detection of latent ethanol use compared with other direct biomarkers.²¹ It can identify recent heavy drinking earlier than indirect biomarkers, as it does not rely on hepatic injury.

Using a cutoff level of 20 ng/mL, PEth assays have a sensitivity of 73% for any alcohol use in the past month; at 80 ng/mL, the sensitivity is 91% for > 4 drinks/d.⁶¹ PEth is considered semi-quantitative. The World Health Organization defines acceptable social alcohol use at a PEth value < 40 ng/dL for men and < 20 ng/dL for women. Chronic excessive use is defined by a level > 60 ng/dL.⁵⁵ The cutoff levels tend to be arbitrary and vary with different guidelines.

PEth may be a useful marker in difficult-toassess settings, or in confirming or invalidating self-reported alcohol consumption.

Although false-positive PEth test results may be possible, most experts believe that dishonesty in self-reporting by test subjects is more likely. That said, the true specificity of PEth remains unknown; a lower value detected should not be regarded as absolute proof of relapse or chronic alcoholism.

Studies have shown a positive correlation between the AUDIT-C score and PEth values combined with self-reported alcohol consumption, indicating that PEth may be a useful marker in difficult-to-assess settings, or in confirming or invalidating self-reported alcohol consumption.^61,64,65 The PEth test is now widely available and, in the authors’ experience, usually costs $100 to $200. Analysis typically costs $40 to $100,⁶⁶ and costs could decrease as the test becomes more widely used. Turnaround time for PEth is 5 to 10 days. It is now the recommended assay by transplant hepatologists for detecting alcohol use.⁶⁷TABLE 3^22,68 explains the currently accepted ranges for various PEth results.

Continue to: CASE ANSWER

CASE ANSWER While every test mentioned can aid in detecting alcohol consumption, the PEth assay in this scenario would be the most clinically useful.

CORRESPONDENCE
Frederick Nunes, MD, Pennsylvania Hospital of University of Pennsylvania, 230 West Washington Square, 4th Floor, Philadelphia, PA 19104; [email protected]

Amid growing concerns about the impact of increased legalized online sports gambling, the American Psychiatric Association has issued an updated guide on gambling disorder.

The guide provides expert guidance based on current research and provides information on the etiology, psychopathology, neurobiology, and treatment of the disorder.

“For doctors who might think of gambling as either innocuous behavior or simply equivalent to, say, an alcohol problem, this guide not only shows the complexity and seriousness of gambling disorder but also evidence-based treatments that may help people actually get better,” the guide’s coeditor, Jon E. Grant, MD, MPH, JD, professor of psychiatry at the University of Chicago, said in an interview.

Online sports betting is booming. “It has really taken off” in recent years and is now a multibillion dollar industry worldwide, Dr. Grant added.

A recent CBS News report highlights a record volume of legally placed online sports bets during the first week of this year’s NFL season. All told, 26 states now have legalized sports betting.

The COVID-19 pandemic has played a large role in boosting online gambling; as in-person casinos shut down, customers shifted to online betting, said Dr. Grant. “They realized they could stay home, stay safe, and still gamble, so there was an uptick in that movement.”

However, the popularity of online gambling is also a sign of the times. “A whole generation of young adults have been raised on the Internet. A lot of companies realize this is not a market that would ever go to a land-based casino, so they essentially took their product to the young people,” said Dr. Grant.
 

Gambling meets technology

In addition to football, online gamblers can bet on other sports, including horse racing, or participate in “fantasy” sports where users assemble virtual teams of stand-ins for real professional players. There are also online casinos where users can play such things as blackjack and roulette.

The new guide devotes a chapter to online gambling and the complex interplay between gambling and technology. It highlights the growth of interactive platforms, the role of new player experiences and reward structures, and the integration into other online activities, such as social media.

Other chapters explore the interface between gambling and the legal system and differences in gender and between age groups.

There is also information on advances in treatments. Although there are no Food and Drug Administration–approved drugs for gambling disorder, new evidence supports the use of certain agents for this disorder, said Dr. Grant.

These include naltrexone, which has long been used for alcohol and drug addiction, and over-the-counter N-acetylcysteine (NAC), an amino acid that affects the reward system in the brain and has been used for cocaine and marijuana addiction.

Research also suggests that brief-format cognitive-behavioral therapy may be effective for gambling disorder, said Dr. Grant.

An estimated 1% of the population has such a disorder, which involves repeated, problem gambling with sufferers struggling to control their gambling behavior. Gambling disorder is associated with decreased self-esteem, comorbid substance abuse disorders, financial and legal difficulties, relationship and family stress, and suicidality.
 

Early intervention is key

Most gamblers don’t have a diagnosable disorder and can participate in the pastime without any long-term harm. However, some will show signs of problem gambling, Dr. Grant noted.

“We believe that’s where interventions may have an even bigger impact,” said Dr. Grant. “We want to get people early on in the illness.” He added that gambling “runs along a continuum” from simply dabbling to serious addiction.

Whereas previous versions of the DSM put gambling in an impulse control category, the latest version – DSM-5 – recognizes gambling as an addiction alongside substances.

“That shows greater awareness of the biological connection to substance addiction,” said Dr. Grant. “It’s important for clinicians who are screening substance use disorder folks to make sure they include gambling in that screening.”

The guide includes information on available screening and assessment instruments for diagnosing gambling disorder and for monitoring symptom changes.

Many clinicians may be unaware of the personal and social consequences of gambling disorder and its implications for public health. The new guide provides a detailed look at the effects of gambling on society and families, as well as on individual health and well-being.

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

Amid growing concerns about the impact of increased legalized online sports gambling, the American Psychiatric Association has issued an updated guide on gambling disorder.

The guide provides expert guidance based on current research and provides information on the etiology, psychopathology, neurobiology, and treatment of the disorder.

“For doctors who might think of gambling as either innocuous behavior or simply equivalent to, say, an alcohol problem, this guide not only shows the complexity and seriousness of gambling disorder but also evidence-based treatments that may help people actually get better,” the guide’s coeditor, Jon E. Grant, MD, MPH, JD, professor of psychiatry at the University of Chicago, said in an interview.

Online sports betting is booming. “It has really taken off” in recent years and is now a multibillion dollar industry worldwide, Dr. Grant added.

A recent CBS News report highlights a record volume of legally placed online sports bets during the first week of this year’s NFL season. All told, 26 states now have legalized sports betting.

The COVID-19 pandemic has played a large role in boosting online gambling; as in-person casinos shut down, customers shifted to online betting, said Dr. Grant. “They realized they could stay home, stay safe, and still gamble, so there was an uptick in that movement.”

However, the popularity of online gambling is also a sign of the times. “A whole generation of young adults have been raised on the Internet. A lot of companies realize this is not a market that would ever go to a land-based casino, so they essentially took their product to the young people,” said Dr. Grant.
 

Gambling meets technology

In addition to football, online gamblers can bet on other sports, including horse racing, or participate in “fantasy” sports where users assemble virtual teams of stand-ins for real professional players. There are also online casinos where users can play such things as blackjack and roulette.

The new guide devotes a chapter to online gambling and the complex interplay between gambling and technology. It highlights the growth of interactive platforms, the role of new player experiences and reward structures, and the integration into other online activities, such as social media.

Other chapters explore the interface between gambling and the legal system and differences in gender and between age groups.

There is also information on advances in treatments. Although there are no Food and Drug Administration–approved drugs for gambling disorder, new evidence supports the use of certain agents for this disorder, said Dr. Grant.

These include naltrexone, which has long been used for alcohol and drug addiction, and over-the-counter N-acetylcysteine (NAC), an amino acid that affects the reward system in the brain and has been used for cocaine and marijuana addiction.

Research also suggests that brief-format cognitive-behavioral therapy may be effective for gambling disorder, said Dr. Grant.

An estimated 1% of the population has such a disorder, which involves repeated, problem gambling with sufferers struggling to control their gambling behavior. Gambling disorder is associated with decreased self-esteem, comorbid substance abuse disorders, financial and legal difficulties, relationship and family stress, and suicidality.
 

Early intervention is key

Most gamblers don’t have a diagnosable disorder and can participate in the pastime without any long-term harm. However, some will show signs of problem gambling, Dr. Grant noted.

“We believe that’s where interventions may have an even bigger impact,” said Dr. Grant. “We want to get people early on in the illness.” He added that gambling “runs along a continuum” from simply dabbling to serious addiction.

Whereas previous versions of the DSM put gambling in an impulse control category, the latest version – DSM-5 – recognizes gambling as an addiction alongside substances.

“That shows greater awareness of the biological connection to substance addiction,” said Dr. Grant. “It’s important for clinicians who are screening substance use disorder folks to make sure they include gambling in that screening.”

The guide includes information on available screening and assessment instruments for diagnosing gambling disorder and for monitoring symptom changes.

Many clinicians may be unaware of the personal and social consequences of gambling disorder and its implications for public health. The new guide provides a detailed look at the effects of gambling on society and families, as well as on individual health and well-being.

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

Amid growing concerns about the impact of increased legalized online sports gambling, the American Psychiatric Association has issued an updated guide on gambling disorder.

The guide provides expert guidance based on current research and provides information on the etiology, psychopathology, neurobiology, and treatment of the disorder.

“For doctors who might think of gambling as either innocuous behavior or simply equivalent to, say, an alcohol problem, this guide not only shows the complexity and seriousness of gambling disorder but also evidence-based treatments that may help people actually get better,” the guide’s coeditor, Jon E. Grant, MD, MPH, JD, professor of psychiatry at the University of Chicago, said in an interview.

Online sports betting is booming. “It has really taken off” in recent years and is now a multibillion dollar industry worldwide, Dr. Grant added.

A recent CBS News report highlights a record volume of legally placed online sports bets during the first week of this year’s NFL season. All told, 26 states now have legalized sports betting.

The COVID-19 pandemic has played a large role in boosting online gambling; as in-person casinos shut down, customers shifted to online betting, said Dr. Grant. “They realized they could stay home, stay safe, and still gamble, so there was an uptick in that movement.”

However, the popularity of online gambling is also a sign of the times. “A whole generation of young adults have been raised on the Internet. A lot of companies realize this is not a market that would ever go to a land-based casino, so they essentially took their product to the young people,” said Dr. Grant.
 

Gambling meets technology

In addition to football, online gamblers can bet on other sports, including horse racing, or participate in “fantasy” sports where users assemble virtual teams of stand-ins for real professional players. There are also online casinos where users can play such things as blackjack and roulette.

The new guide devotes a chapter to online gambling and the complex interplay between gambling and technology. It highlights the growth of interactive platforms, the role of new player experiences and reward structures, and the integration into other online activities, such as social media.

Other chapters explore the interface between gambling and the legal system and differences in gender and between age groups.

There is also information on advances in treatments. Although there are no Food and Drug Administration–approved drugs for gambling disorder, new evidence supports the use of certain agents for this disorder, said Dr. Grant.

These include naltrexone, which has long been used for alcohol and drug addiction, and over-the-counter N-acetylcysteine (NAC), an amino acid that affects the reward system in the brain and has been used for cocaine and marijuana addiction.

Research also suggests that brief-format cognitive-behavioral therapy may be effective for gambling disorder, said Dr. Grant.

An estimated 1% of the population has such a disorder, which involves repeated, problem gambling with sufferers struggling to control their gambling behavior. Gambling disorder is associated with decreased self-esteem, comorbid substance abuse disorders, financial and legal difficulties, relationship and family stress, and suicidality.
 

Early intervention is key

Most gamblers don’t have a diagnosable disorder and can participate in the pastime without any long-term harm. However, some will show signs of problem gambling, Dr. Grant noted.

“We believe that’s where interventions may have an even bigger impact,” said Dr. Grant. “We want to get people early on in the illness.” He added that gambling “runs along a continuum” from simply dabbling to serious addiction.

Whereas previous versions of the DSM put gambling in an impulse control category, the latest version – DSM-5 – recognizes gambling as an addiction alongside substances.

“That shows greater awareness of the biological connection to substance addiction,” said Dr. Grant. “It’s important for clinicians who are screening substance use disorder folks to make sure they include gambling in that screening.”

The guide includes information on available screening and assessment instruments for diagnosing gambling disorder and for monitoring symptom changes.

Many clinicians may be unaware of the personal and social consequences of gambling disorder and its implications for public health. The new guide provides a detailed look at the effects of gambling on society and families, as well as on individual health and well-being.

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

Short-acting opioids may complement methadone and buprenorphine for opioid withdrawal symptoms in U.S. hospitals, say authors of an opinion piece calling for rethinking current strategies for opioid withdrawal in this country.

The commentary by Robert A. Kleinman, MD, with the Centre for Addiction and Mental Health, and department of psychiatry, University of Toronto, and Sarah E. Wakeman, MD, with the division of general internal medicine at Massachusetts General Hospital, and Harvard Medical School, Boston, was published in Annals of Internal Medicine.

Currently, short-acting opioids are not recommended in the United States for opioid withdrawal symptoms (OWS) management in the hospital, the authors wrote. Instead, withdrawal symptoms are typically treated, followed by methadone or buprenorphine or nonopioid medications, but many patients don’t get enough relief. Undertreated withdrawal can result in patients leaving the hospital against medical advice, which is linked with higher risk of death.

Addiction specialist Elisabeth Poorman, MD, of the University of Illinois Chicago, said in an interview that she agrees it’s time to start shifting the thinking on using short-acting opioids for OWS in hospitals. Use varies greatly by hospital and by clinician, she said.

“It’s time to let evidence guide us and to be flexible,” Dr. Poorman said.

The commentary authors noted that with methadone, patients must wait several hours for maximal symptom reduction, and the full benefits of methadone treatment are not realized until days after initiation.

Rapid initiation of methadone may be feasible in hospitals and has been proposed as an option, but further study is necessary before widespread use, the authors wrote.
 

Short-acting opioids may address limitations of other opioids

Lofexidine, an alpha-2-adrenergic agonist, is the only drug approved by the Food and Drug Administration specifically for OWS.

“However,” the authors said, “more than half of patients with OWS treated with lofexidine in phase 3 efficacy trials dropped out by day five. Clonidine, another alpha-2-agonist used off label to treat OWS, has similar effects to those of lofexidine. “

Therefore, short-acting opioids may complement methadone and buprenorphine in treating OWS in the hospital by addressing their limitations, the authors wrote.

Dr. Kleinman and Dr. Wakeman also say short-acting opioids may help with starting buprenorphine for patients exposed to fentanyl, because short-acting opioids can relieve withdrawal symptoms while fentanyl is metabolized and excreted.

Supplementation with short-acting opioids within the hospital can relieve withdrawal symptoms and help keep patients comfortable while methadone is titrated to more effective doses for long-term treatment, they wrote.

With short-acting opioids, patients may become more engaged in their care with, for example, a tamper-proof, patient-controlled analgesia pump, which would allow them to have more autonomy in administration of opioids to relieve pain and withdrawal symptoms, the authors wrote.

Dr. Kleinman and Dr. Wakeman noted that many patients who inject drugs already consume short-acting illicit drugs in the hospital, typically in washrooms and smoking areas, so supervised use of short-acting opioids helps eliminate the risk for unwitnessed overdoses.

Barriers to short-acting opioid use

Despite use of short-acting opioids internationally, barriers in the United States include limited prospective, randomized, controlled research on their benefits. There is limited institutional support for such approaches, and concerns and stigma around providing opioids to patients with OUD.

“[M]any institutions have insufficient numbers of providers who are both confident and competent with standard buprenorphine and methadone initiation approaches, a prerequisite before adopting more complex regimens,” the authors wrote.

Short-acting, full-agonist opioids, as a complement to methadone or buprenorphine, is already recommended for inpatients with OUD who are experiencing acute pain.

But the authors argue it should be an option when pain is not present, but methadone or buprenorphine have not provided enough OWS relief.
 

When short-acting opioids are helpful, according to outside expert

Dr. Poorman agrees and says she has found short-acting opioids simple to use in the hospital and very helpful in two situations.

One is when patients are very clear that they don’t want any medication for opioid use disorder, but they do want to be treated for their acute medical issue.

“I thought that was a fantastic tool to have to demonstrate we’re listening to them and weren’t trying to impose something on them and left the door open to come back when they did want treatment, which many of them did,” Dr. Poorman said.

The second situation is when the patient is uncertain about options but very afraid of precipitated withdrawal from buprenorphine.

She said she then found it easy to switch from those medications to buprenorphine and methadone.

Dr. Poorman described a situation she encountered previously where the patient was injecting heroin several times a day for 30-40 years. He was very clear he wasn’t going to stop injecting heroin, but he needed medical attention. He was willing to get medical attention, but he told his doctor he didn’t want to be uncomfortable while in the hospital.

It was very hard for his doctor to accept relieving his symptoms of withdrawal as part of her job, because she felt as though she was condoning his drug use, Dr. Poorman explained.

But Dr. Poorman said it’s not realistic to think that someone who clearly does not want to stop using is going to stop using because a doctor made that person go through painful withdrawal “that they’ve structured their whole life around avoiding.”
 

Take-home message

“We need to understand that addiction is very complex. A lot of times people come to us distressed, and it’s a great time to engage them in care but engaging them in care doesn’t mean imposing discomfort or pain on them,” Dr. Poorman noted. Instead, it means “listening to them, helping them be comfortable in a really stressful situation and then letting them know we are always there for them wherever they are on their disease process or recovery journey so that they can come back to us.”

Dr. Wakeman previously served on clinical advisory board for Celero Systems and receives textbook royalties from Springer and author payment from UpToDate. Dr. Kleinman and Dr. Poorman declared no relevant financial relationships.

Short-acting opioids may complement methadone and buprenorphine for opioid withdrawal symptoms in U.S. hospitals, say authors of an opinion piece calling for rethinking current strategies for opioid withdrawal in this country.

The commentary by Robert A. Kleinman, MD, with the Centre for Addiction and Mental Health, and department of psychiatry, University of Toronto, and Sarah E. Wakeman, MD, with the division of general internal medicine at Massachusetts General Hospital, and Harvard Medical School, Boston, was published in Annals of Internal Medicine.

Currently, short-acting opioids are not recommended in the United States for opioid withdrawal symptoms (OWS) management in the hospital, the authors wrote. Instead, withdrawal symptoms are typically treated, followed by methadone or buprenorphine or nonopioid medications, but many patients don’t get enough relief. Undertreated withdrawal can result in patients leaving the hospital against medical advice, which is linked with higher risk of death.

Addiction specialist Elisabeth Poorman, MD, of the University of Illinois Chicago, said in an interview that she agrees it’s time to start shifting the thinking on using short-acting opioids for OWS in hospitals. Use varies greatly by hospital and by clinician, she said.

“It’s time to let evidence guide us and to be flexible,” Dr. Poorman said.

The commentary authors noted that with methadone, patients must wait several hours for maximal symptom reduction, and the full benefits of methadone treatment are not realized until days after initiation.

Rapid initiation of methadone may be feasible in hospitals and has been proposed as an option, but further study is necessary before widespread use, the authors wrote.
 

Short-acting opioids may address limitations of other opioids

Lofexidine, an alpha-2-adrenergic agonist, is the only drug approved by the Food and Drug Administration specifically for OWS.

“However,” the authors said, “more than half of patients with OWS treated with lofexidine in phase 3 efficacy trials dropped out by day five. Clonidine, another alpha-2-agonist used off label to treat OWS, has similar effects to those of lofexidine. “

Therefore, short-acting opioids may complement methadone and buprenorphine in treating OWS in the hospital by addressing their limitations, the authors wrote.

Dr. Kleinman and Dr. Wakeman also say short-acting opioids may help with starting buprenorphine for patients exposed to fentanyl, because short-acting opioids can relieve withdrawal symptoms while fentanyl is metabolized and excreted.

Supplementation with short-acting opioids within the hospital can relieve withdrawal symptoms and help keep patients comfortable while methadone is titrated to more effective doses for long-term treatment, they wrote.

With short-acting opioids, patients may become more engaged in their care with, for example, a tamper-proof, patient-controlled analgesia pump, which would allow them to have more autonomy in administration of opioids to relieve pain and withdrawal symptoms, the authors wrote.

Dr. Kleinman and Dr. Wakeman noted that many patients who inject drugs already consume short-acting illicit drugs in the hospital, typically in washrooms and smoking areas, so supervised use of short-acting opioids helps eliminate the risk for unwitnessed overdoses.

Barriers to short-acting opioid use

Despite use of short-acting opioids internationally, barriers in the United States include limited prospective, randomized, controlled research on their benefits. There is limited institutional support for such approaches, and concerns and stigma around providing opioids to patients with OUD.

“[M]any institutions have insufficient numbers of providers who are both confident and competent with standard buprenorphine and methadone initiation approaches, a prerequisite before adopting more complex regimens,” the authors wrote.

Short-acting, full-agonist opioids, as a complement to methadone or buprenorphine, is already recommended for inpatients with OUD who are experiencing acute pain.

But the authors argue it should be an option when pain is not present, but methadone or buprenorphine have not provided enough OWS relief.
 

When short-acting opioids are helpful, according to outside expert

Dr. Poorman agrees and says she has found short-acting opioids simple to use in the hospital and very helpful in two situations.

One is when patients are very clear that they don’t want any medication for opioid use disorder, but they do want to be treated for their acute medical issue.

“I thought that was a fantastic tool to have to demonstrate we’re listening to them and weren’t trying to impose something on them and left the door open to come back when they did want treatment, which many of them did,” Dr. Poorman said.

The second situation is when the patient is uncertain about options but very afraid of precipitated withdrawal from buprenorphine.

She said she then found it easy to switch from those medications to buprenorphine and methadone.

Dr. Poorman described a situation she encountered previously where the patient was injecting heroin several times a day for 30-40 years. He was very clear he wasn’t going to stop injecting heroin, but he needed medical attention. He was willing to get medical attention, but he told his doctor he didn’t want to be uncomfortable while in the hospital.

It was very hard for his doctor to accept relieving his symptoms of withdrawal as part of her job, because she felt as though she was condoning his drug use, Dr. Poorman explained.

But Dr. Poorman said it’s not realistic to think that someone who clearly does not want to stop using is going to stop using because a doctor made that person go through painful withdrawal “that they’ve structured their whole life around avoiding.”
 

Take-home message

“We need to understand that addiction is very complex. A lot of times people come to us distressed, and it’s a great time to engage them in care but engaging them in care doesn’t mean imposing discomfort or pain on them,” Dr. Poorman noted. Instead, it means “listening to them, helping them be comfortable in a really stressful situation and then letting them know we are always there for them wherever they are on their disease process or recovery journey so that they can come back to us.”

Dr. Wakeman previously served on clinical advisory board for Celero Systems and receives textbook royalties from Springer and author payment from UpToDate. Dr. Kleinman and Dr. Poorman declared no relevant financial relationships.

Short-acting opioids may complement methadone and buprenorphine for opioid withdrawal symptoms in U.S. hospitals, say authors of an opinion piece calling for rethinking current strategies for opioid withdrawal in this country.

The commentary by Robert A. Kleinman, MD, with the Centre for Addiction and Mental Health, and department of psychiatry, University of Toronto, and Sarah E. Wakeman, MD, with the division of general internal medicine at Massachusetts General Hospital, and Harvard Medical School, Boston, was published in Annals of Internal Medicine.

Currently, short-acting opioids are not recommended in the United States for opioid withdrawal symptoms (OWS) management in the hospital, the authors wrote. Instead, withdrawal symptoms are typically treated, followed by methadone or buprenorphine or nonopioid medications, but many patients don’t get enough relief. Undertreated withdrawal can result in patients leaving the hospital against medical advice, which is linked with higher risk of death.

Addiction specialist Elisabeth Poorman, MD, of the University of Illinois Chicago, said in an interview that she agrees it’s time to start shifting the thinking on using short-acting opioids for OWS in hospitals. Use varies greatly by hospital and by clinician, she said.

“It’s time to let evidence guide us and to be flexible,” Dr. Poorman said.

The commentary authors noted that with methadone, patients must wait several hours for maximal symptom reduction, and the full benefits of methadone treatment are not realized until days after initiation.

Rapid initiation of methadone may be feasible in hospitals and has been proposed as an option, but further study is necessary before widespread use, the authors wrote.
 

Short-acting opioids may address limitations of other opioids

Lofexidine, an alpha-2-adrenergic agonist, is the only drug approved by the Food and Drug Administration specifically for OWS.

“However,” the authors said, “more than half of patients with OWS treated with lofexidine in phase 3 efficacy trials dropped out by day five. Clonidine, another alpha-2-agonist used off label to treat OWS, has similar effects to those of lofexidine. “

Therefore, short-acting opioids may complement methadone and buprenorphine in treating OWS in the hospital by addressing their limitations, the authors wrote.

Dr. Kleinman and Dr. Wakeman also say short-acting opioids may help with starting buprenorphine for patients exposed to fentanyl, because short-acting opioids can relieve withdrawal symptoms while fentanyl is metabolized and excreted.

Supplementation with short-acting opioids within the hospital can relieve withdrawal symptoms and help keep patients comfortable while methadone is titrated to more effective doses for long-term treatment, they wrote.

With short-acting opioids, patients may become more engaged in their care with, for example, a tamper-proof, patient-controlled analgesia pump, which would allow them to have more autonomy in administration of opioids to relieve pain and withdrawal symptoms, the authors wrote.

Dr. Kleinman and Dr. Wakeman noted that many patients who inject drugs already consume short-acting illicit drugs in the hospital, typically in washrooms and smoking areas, so supervised use of short-acting opioids helps eliminate the risk for unwitnessed overdoses.

Barriers to short-acting opioid use

Despite use of short-acting opioids internationally, barriers in the United States include limited prospective, randomized, controlled research on their benefits. There is limited institutional support for such approaches, and concerns and stigma around providing opioids to patients with OUD.

“[M]any institutions have insufficient numbers of providers who are both confident and competent with standard buprenorphine and methadone initiation approaches, a prerequisite before adopting more complex regimens,” the authors wrote.

Short-acting, full-agonist opioids, as a complement to methadone or buprenorphine, is already recommended for inpatients with OUD who are experiencing acute pain.

But the authors argue it should be an option when pain is not present, but methadone or buprenorphine have not provided enough OWS relief.
 

When short-acting opioids are helpful, according to outside expert

Dr. Poorman agrees and says she has found short-acting opioids simple to use in the hospital and very helpful in two situations.

One is when patients are very clear that they don’t want any medication for opioid use disorder, but they do want to be treated for their acute medical issue.

“I thought that was a fantastic tool to have to demonstrate we’re listening to them and weren’t trying to impose something on them and left the door open to come back when they did want treatment, which many of them did,” Dr. Poorman said.

The second situation is when the patient is uncertain about options but very afraid of precipitated withdrawal from buprenorphine.

She said she then found it easy to switch from those medications to buprenorphine and methadone.

Dr. Poorman described a situation she encountered previously where the patient was injecting heroin several times a day for 30-40 years. He was very clear he wasn’t going to stop injecting heroin, but he needed medical attention. He was willing to get medical attention, but he told his doctor he didn’t want to be uncomfortable while in the hospital.

It was very hard for his doctor to accept relieving his symptoms of withdrawal as part of her job, because she felt as though she was condoning his drug use, Dr. Poorman explained.

But Dr. Poorman said it’s not realistic to think that someone who clearly does not want to stop using is going to stop using because a doctor made that person go through painful withdrawal “that they’ve structured their whole life around avoiding.”
 

Take-home message

“We need to understand that addiction is very complex. A lot of times people come to us distressed, and it’s a great time to engage them in care but engaging them in care doesn’t mean imposing discomfort or pain on them,” Dr. Poorman noted. Instead, it means “listening to them, helping them be comfortable in a really stressful situation and then letting them know we are always there for them wherever they are on their disease process or recovery journey so that they can come back to us.”

Dr. Wakeman previously served on clinical advisory board for Celero Systems and receives textbook royalties from Springer and author payment from UpToDate. Dr. Kleinman and Dr. Poorman declared no relevant financial relationships.

Adding lithium to usual care does not decrease the risk of suicide-related events in those with major depressive disorder (MDD) or bipolar disorder (BD) who have survived a recent suicidal event, new research shows.

The results of a randomized, double-blind, placebo-controlled trial in veterans showed no apparent advantage of the drug in preventing self-injury, suicide attempts, or urgent hospitalization to prevent suicide.

“Lithium is an important therapy for bipolar disorders and depression subsets. Our study indicates that, in patients who are actively followed and treated in a system of care that the VA provides, simply adding lithium to their existing management, including medications, is unlikely to be effective for preventing a broad range of suicide-related events,” study investigator Ryan Ferguson, MPH, ScD, Boston Cooperative Studies Coordinating Center, VA Boston Healthcare System, told this news organization.

The study was published online JAMA Psychiatry.
 

Surprising findings

The results were somewhat surprising, Dr. Ferguson added. “Lithium showed little or no effect in our study, compared to observational data and results from previous trials. Many clinicians and practice guidelines had assumed that lithium was an effective agent in preventing suicide,” he said.

However, the authors of an accompanying editorial urge caution in concluding that lithium has no antisuicidal effects.

This “rigorously designed and conducted trial has much to teach but cannot be taken as evidence that lithium treatment is ineffective regarding suicidal risk,” write Ross Baldessarini, MD, and Leonardo Tondo, MD, department of psychiatry, Harvard Medical School, Boston.

Study participants were veterans with MDD or BD receiving care at one of 29 Veterans Administration medical centers who survived a recent suicide-related event. In addition to usual care, they were randomly assigned to receive oral extended-release lithium carbonate starting at 600 mg/day or matching placebo for 52 weeks.

The primary outcome was time to the first repeated suicide-related event, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide.

The trial was stopped for futility after 519 veterans (mean age, 42.8 years; 84% male) were randomly assigned to receive lithium (n = 255) or placebo (n = 264). At 3 months, mean lithium concentrations were 0.54 mEq/L for patients with BD and 0.46 mEq/L for those with MDD.

There was no significant difference in the primary outcome (hazard ratio, 1.10; 95% confidence interval, 0.77-1.55; P = .61).

A total of 127 participants (24.5%) had suicide-related outcomes – 65 in the lithium group and 62 in the placebo group. One death occurred in the lithium group and three in the placebo group. There were no unanticipated drug-related safety concerns.
 

Caveats, cautionary notes

The researchers note that the study did not reach its original recruitment goal. “One of the barriers to recruitment was the perception of many of the clinicians caring for potential participants that the effectiveness of lithium was already established; in fact, this perception was supported by the VA/U.S. Department of Defense Clinical Practice Guideline,” they point out.

They also note that most veterans in the study had depression rather than BD, which is the most common indication for lithium use. Most also had substance use disorders, posttraumatic stress disorder, or both, which could influence outcomes.

As a result of small numbers, it wasn’t possible to evaluate outcomes for patients with BD, test whether outcomes differed among patients with BD and MDD, or assess whether comorbidities attenuated the effects of lithium.

The study’s protocol increased participants’ contacts with the VA, which also may have affected outcomes, the researchers note.

In addition, high rates of attrition and low rates of substantial adherence to lithium meant only about half (48.1%) of the study population achieved target serum lithium concentrations.

Editorial writers Dr. Baldessarini and Dr. Tondo note that the low circulating concentrations of lithium and the fact that adherence to assigned treatment was considered adequate in only 17% of participants are key limitations of the study.

“In general, controlled treatment trials aimed at detecting suicide preventive effects are difficult to design, perform, and interpret,” they point out.

Evidence supporting an antisuicidal effect of lithium treatment includes nearly three dozen observational trials that have shown fewer suicides or attempts with lithium treatment, as well as “marked, temporary” increases in suicidal behavior soon after stopping lithium treatment.

Dr. Baldessarini and Dr. Tondo note the current findings “cannot be taken as evidence that lithium lacks antisuicidal effects. An ironic final note is that recruiting participants to such trials may be made difficult by an evidently prevalent belief that the question of antisuicidal effects of lithium is already settled, which it certainly is not,” they write.

Dr. Ferguson “agrees that more work needs to be done to understand the antisuicidal effect of lithium.

The study received financial and material support from a grant from the Cooperative Studies Program, Office of Research and Development, U.S. Department of Veterans Affairs. Dr. Ferguson has disclosed no relevant financial relationships. A complete list of author disclosures is available with the original article.

Dr. Baldessarini and Dr. Tondo have disclosed no relevant financial relationships. Their editorial was supported by grants from the Bruce J. Anderson Foundation, the McLean Private Donors Fund for Psychiatric Research, and the Aretaeus Foundation of Rome.

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

Adding lithium to usual care does not decrease the risk of suicide-related events in those with major depressive disorder (MDD) or bipolar disorder (BD) who have survived a recent suicidal event, new research shows.

The results of a randomized, double-blind, placebo-controlled trial in veterans showed no apparent advantage of the drug in preventing self-injury, suicide attempts, or urgent hospitalization to prevent suicide.

“Lithium is an important therapy for bipolar disorders and depression subsets. Our study indicates that, in patients who are actively followed and treated in a system of care that the VA provides, simply adding lithium to their existing management, including medications, is unlikely to be effective for preventing a broad range of suicide-related events,” study investigator Ryan Ferguson, MPH, ScD, Boston Cooperative Studies Coordinating Center, VA Boston Healthcare System, told this news organization.

The study was published online JAMA Psychiatry.
 

Surprising findings

The results were somewhat surprising, Dr. Ferguson added. “Lithium showed little or no effect in our study, compared to observational data and results from previous trials. Many clinicians and practice guidelines had assumed that lithium was an effective agent in preventing suicide,” he said.

However, the authors of an accompanying editorial urge caution in concluding that lithium has no antisuicidal effects.

This “rigorously designed and conducted trial has much to teach but cannot be taken as evidence that lithium treatment is ineffective regarding suicidal risk,” write Ross Baldessarini, MD, and Leonardo Tondo, MD, department of psychiatry, Harvard Medical School, Boston.

Study participants were veterans with MDD or BD receiving care at one of 29 Veterans Administration medical centers who survived a recent suicide-related event. In addition to usual care, they were randomly assigned to receive oral extended-release lithium carbonate starting at 600 mg/day or matching placebo for 52 weeks.

The primary outcome was time to the first repeated suicide-related event, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide.

The trial was stopped for futility after 519 veterans (mean age, 42.8 years; 84% male) were randomly assigned to receive lithium (n = 255) or placebo (n = 264). At 3 months, mean lithium concentrations were 0.54 mEq/L for patients with BD and 0.46 mEq/L for those with MDD.

There was no significant difference in the primary outcome (hazard ratio, 1.10; 95% confidence interval, 0.77-1.55; P = .61).

A total of 127 participants (24.5%) had suicide-related outcomes – 65 in the lithium group and 62 in the placebo group. One death occurred in the lithium group and three in the placebo group. There were no unanticipated drug-related safety concerns.
 

Caveats, cautionary notes

The researchers note that the study did not reach its original recruitment goal. “One of the barriers to recruitment was the perception of many of the clinicians caring for potential participants that the effectiveness of lithium was already established; in fact, this perception was supported by the VA/U.S. Department of Defense Clinical Practice Guideline,” they point out.

They also note that most veterans in the study had depression rather than BD, which is the most common indication for lithium use. Most also had substance use disorders, posttraumatic stress disorder, or both, which could influence outcomes.

As a result of small numbers, it wasn’t possible to evaluate outcomes for patients with BD, test whether outcomes differed among patients with BD and MDD, or assess whether comorbidities attenuated the effects of lithium.

The study’s protocol increased participants’ contacts with the VA, which also may have affected outcomes, the researchers note.

In addition, high rates of attrition and low rates of substantial adherence to lithium meant only about half (48.1%) of the study population achieved target serum lithium concentrations.

Editorial writers Dr. Baldessarini and Dr. Tondo note that the low circulating concentrations of lithium and the fact that adherence to assigned treatment was considered adequate in only 17% of participants are key limitations of the study.

“In general, controlled treatment trials aimed at detecting suicide preventive effects are difficult to design, perform, and interpret,” they point out.

Evidence supporting an antisuicidal effect of lithium treatment includes nearly three dozen observational trials that have shown fewer suicides or attempts with lithium treatment, as well as “marked, temporary” increases in suicidal behavior soon after stopping lithium treatment.

Dr. Baldessarini and Dr. Tondo note the current findings “cannot be taken as evidence that lithium lacks antisuicidal effects. An ironic final note is that recruiting participants to such trials may be made difficult by an evidently prevalent belief that the question of antisuicidal effects of lithium is already settled, which it certainly is not,” they write.

Dr. Ferguson “agrees that more work needs to be done to understand the antisuicidal effect of lithium.

The study received financial and material support from a grant from the Cooperative Studies Program, Office of Research and Development, U.S. Department of Veterans Affairs. Dr. Ferguson has disclosed no relevant financial relationships. A complete list of author disclosures is available with the original article.

Dr. Baldessarini and Dr. Tondo have disclosed no relevant financial relationships. Their editorial was supported by grants from the Bruce J. Anderson Foundation, the McLean Private Donors Fund for Psychiatric Research, and the Aretaeus Foundation of Rome.

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

Adding lithium to usual care does not decrease the risk of suicide-related events in those with major depressive disorder (MDD) or bipolar disorder (BD) who have survived a recent suicidal event, new research shows.

The results of a randomized, double-blind, placebo-controlled trial in veterans showed no apparent advantage of the drug in preventing self-injury, suicide attempts, or urgent hospitalization to prevent suicide.

“Lithium is an important therapy for bipolar disorders and depression subsets. Our study indicates that, in patients who are actively followed and treated in a system of care that the VA provides, simply adding lithium to their existing management, including medications, is unlikely to be effective for preventing a broad range of suicide-related events,” study investigator Ryan Ferguson, MPH, ScD, Boston Cooperative Studies Coordinating Center, VA Boston Healthcare System, told this news organization.

The study was published online JAMA Psychiatry.
 

Surprising findings

The results were somewhat surprising, Dr. Ferguson added. “Lithium showed little or no effect in our study, compared to observational data and results from previous trials. Many clinicians and practice guidelines had assumed that lithium was an effective agent in preventing suicide,” he said.

However, the authors of an accompanying editorial urge caution in concluding that lithium has no antisuicidal effects.

This “rigorously designed and conducted trial has much to teach but cannot be taken as evidence that lithium treatment is ineffective regarding suicidal risk,” write Ross Baldessarini, MD, and Leonardo Tondo, MD, department of psychiatry, Harvard Medical School, Boston.

Study participants were veterans with MDD or BD receiving care at one of 29 Veterans Administration medical centers who survived a recent suicide-related event. In addition to usual care, they were randomly assigned to receive oral extended-release lithium carbonate starting at 600 mg/day or matching placebo for 52 weeks.

The primary outcome was time to the first repeated suicide-related event, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide.

The trial was stopped for futility after 519 veterans (mean age, 42.8 years; 84% male) were randomly assigned to receive lithium (n = 255) or placebo (n = 264). At 3 months, mean lithium concentrations were 0.54 mEq/L for patients with BD and 0.46 mEq/L for those with MDD.

There was no significant difference in the primary outcome (hazard ratio, 1.10; 95% confidence interval, 0.77-1.55; P = .61).

A total of 127 participants (24.5%) had suicide-related outcomes – 65 in the lithium group and 62 in the placebo group. One death occurred in the lithium group and three in the placebo group. There were no unanticipated drug-related safety concerns.
 

Caveats, cautionary notes

The researchers note that the study did not reach its original recruitment goal. “One of the barriers to recruitment was the perception of many of the clinicians caring for potential participants that the effectiveness of lithium was already established; in fact, this perception was supported by the VA/U.S. Department of Defense Clinical Practice Guideline,” they point out.

They also note that most veterans in the study had depression rather than BD, which is the most common indication for lithium use. Most also had substance use disorders, posttraumatic stress disorder, or both, which could influence outcomes.

As a result of small numbers, it wasn’t possible to evaluate outcomes for patients with BD, test whether outcomes differed among patients with BD and MDD, or assess whether comorbidities attenuated the effects of lithium.

The study’s protocol increased participants’ contacts with the VA, which also may have affected outcomes, the researchers note.

In addition, high rates of attrition and low rates of substantial adherence to lithium meant only about half (48.1%) of the study population achieved target serum lithium concentrations.

Editorial writers Dr. Baldessarini and Dr. Tondo note that the low circulating concentrations of lithium and the fact that adherence to assigned treatment was considered adequate in only 17% of participants are key limitations of the study.

“In general, controlled treatment trials aimed at detecting suicide preventive effects are difficult to design, perform, and interpret,” they point out.

Evidence supporting an antisuicidal effect of lithium treatment includes nearly three dozen observational trials that have shown fewer suicides or attempts with lithium treatment, as well as “marked, temporary” increases in suicidal behavior soon after stopping lithium treatment.

Dr. Baldessarini and Dr. Tondo note the current findings “cannot be taken as evidence that lithium lacks antisuicidal effects. An ironic final note is that recruiting participants to such trials may be made difficult by an evidently prevalent belief that the question of antisuicidal effects of lithium is already settled, which it certainly is not,” they write.

Dr. Ferguson “agrees that more work needs to be done to understand the antisuicidal effect of lithium.

The study received financial and material support from a grant from the Cooperative Studies Program, Office of Research and Development, U.S. Department of Veterans Affairs. Dr. Ferguson has disclosed no relevant financial relationships. A complete list of author disclosures is available with the original article.

Dr. Baldessarini and Dr. Tondo have disclosed no relevant financial relationships. Their editorial was supported by grants from the Bruce J. Anderson Foundation, the McLean Private Donors Fund for Psychiatric Research, and the Aretaeus Foundation of Rome.

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

Mothers who use cannabis during pregnancy risk disrupting immune gene networks in the placenta and potentially increasing the risk of anxiety and hyperactivity in their children.

These findings emerged from a study led by Yasmin Hurd, PhD, a professor of psychiatry and director of the Addiction Institute at the Icahn School of Medicine at Mount Sinai, New York, and Yoko Nomura, PhD, a professor of behavioral neuroscience at Queen’s College, City University of New York, that was published online in Proceedings of the National Academy of Sciences.

The analysis assessed the effects of gestational maternal cannabis use on psychosocial and physiological measures in young children as well as its potentially immunomodulatory effect on the in utero environment as reflected in the placental transcriptome.

Participants were drawn from a larger cohort in a study launched in 2012; the investigators evaluated offspring aged 3-6 years for hair hormone levels, neurobehavioral traits on the Behavioral Assessment System for Children survey, and heart rate variability (HRV) at rest and during auditory startle.

The cohort consisted of 322 mother-child dyads and children with prenatal exposure to cannabis were compared with those having no exposure. The cohort consisted of 251 non–cannabis-using mothers and 71 cannabis-using mothers, with mean maternal ages in the two groups of 28.46 years and 25.91 years, respectively, The mothers gave birth at Mount Sinai and they and their children were assessed annually at affiliated medical centers in Mount Sinai’s catchment area.

For a subset of children with behavioral assessments, placental specimens collected at birth were processed for RNA sequencing.

Among the findings:

• Maternal cannabis use was associated with reduced maternal and paternal age, more single-mother pregnancies, state anxiety, trait anxiety, depression, cigarette smoking, and African American race.
• Hair hormone analysis revealed increased cortisol levels in the children of cannabis-using mothers, and was associated with greater anxiety, aggression, and hyperactivity.
• Affected children showed a reduction in the high-frequency component of HRV at baseline, reflecting reduced vagal tone.
• In the placenta, there was reduced expression of many genes involved in immune system function. These included genes for type I interferon, neutrophil, and cytokine-signaling pathways.

Several of these genes organized into coexpression networks that correlated with child anxiety and hyperactivity.

The principal active component of cannabis, tetrahydrocannabinol (THC), targets the endocannabinoid system in placental tissue and the developing brain, the authors noted. Exposure during pregnancy is associated with a range of adverse outcomes from fetal growth restriction to low birth weight and preterm birth.

“There are cannabinoid receptors on immune cells, and it is known that cannabinoids can alter immune function, which is important for maintaining maternal tolerance and protecting the fetus,” Dr. Hurd said. “It’s not surprising that something that affects the immune cells can have an impact on the developing fetus.”

“Overall, our findings reveal a relationship between [maternal cannabis use] and immune response gene networks in the placenta as a potential mediator of risk for anxiety-related problems in early childhood,” Dr. Hurd and colleagues wrote, adding that the results have significant implications for defining mental health issues in the children gestated by cannabis-smoking mothers.

Their results align with previous research indicating a greater risk for psychiatric illness in children with prenatal cannabis exposure from maternal use.

“While data are pretty limited in this realm, there are other studies that demonstrate a relationship between early child developmental and behavioral measures and cannabis use during pregnancy,” Camille Hoffman, MD, MSc, a high-risk obstetrics specialist and an associate professor at the University of Colorado at Denver, Aurora, said in an interview. “Our research group found children exposed to cannabis in utero at 10 weeks’ gestation and beyond were less interactive and more withdrawn than children who were not exposed.”

And THC remains in maternal breast milk even 6 weeks after usage stops.

The long-term effects of prenatal cannabis exposure remain to be determined and it is unknown whether the effects of gestational THC might attenuate as a child grows older. “We use early childhood measures in research as a proxy for the later development of diagnosed mental health conditions or behavioral problems,” Dr. Hoffman explained. “We know when we do this that not every child with an abnormal score early will go on to develop an actual condition. Fortunately, or unfortunately, other factors and exposures during childhood can change the trajectory for the better or worse.”

According to Dr. Hurd, child development is a dynamic process and epigenetic events in utero need not be deterministic. “The important thing is to identify children at risk early and to be able to go in and try to improve the environment they’re being raised in – not in terms of impoverishment but in terms of positive nurturing and giving the mother and family support.”

At the prenatal level, what’s the best advice for cannabis-using mothers-to-be? “If a woman doesn’t know she’s pregnant and has been using cannabis, taking extra choline for the remainder of the pregnancy can help buffer the potential negative impact of the cannabis exposure,” Dr. Hoffman said. The Food and Drug Administration and the American Medical Association recommend a dose of 550 mg daily. “The same is true for alcohol, which we know is also very bad for fetal brain development. This is not to say go ahead and use these substances and just take choline. The choline is more to try and salvage damage to the fetal brain that may have already occurred.”

This study was supported by the National Institute of Mental Health and the National Institute on Drug Abuse. The authors declared no competing interests. Dr. Hoffman disclosed no conflicts of interest with respect to her comments.

Mothers who use cannabis during pregnancy risk disrupting immune gene networks in the placenta and potentially increasing the risk of anxiety and hyperactivity in their children.

These findings emerged from a study led by Yasmin Hurd, PhD, a professor of psychiatry and director of the Addiction Institute at the Icahn School of Medicine at Mount Sinai, New York, and Yoko Nomura, PhD, a professor of behavioral neuroscience at Queen’s College, City University of New York, that was published online in Proceedings of the National Academy of Sciences.

The analysis assessed the effects of gestational maternal cannabis use on psychosocial and physiological measures in young children as well as its potentially immunomodulatory effect on the in utero environment as reflected in the placental transcriptome.

Participants were drawn from a larger cohort in a study launched in 2012; the investigators evaluated offspring aged 3-6 years for hair hormone levels, neurobehavioral traits on the Behavioral Assessment System for Children survey, and heart rate variability (HRV) at rest and during auditory startle.

The cohort consisted of 322 mother-child dyads and children with prenatal exposure to cannabis were compared with those having no exposure. The cohort consisted of 251 non–cannabis-using mothers and 71 cannabis-using mothers, with mean maternal ages in the two groups of 28.46 years and 25.91 years, respectively, The mothers gave birth at Mount Sinai and they and their children were assessed annually at affiliated medical centers in Mount Sinai’s catchment area.

For a subset of children with behavioral assessments, placental specimens collected at birth were processed for RNA sequencing.

Among the findings:

• Maternal cannabis use was associated with reduced maternal and paternal age, more single-mother pregnancies, state anxiety, trait anxiety, depression, cigarette smoking, and African American race.
• Hair hormone analysis revealed increased cortisol levels in the children of cannabis-using mothers, and was associated with greater anxiety, aggression, and hyperactivity.
• Affected children showed a reduction in the high-frequency component of HRV at baseline, reflecting reduced vagal tone.
• In the placenta, there was reduced expression of many genes involved in immune system function. These included genes for type I interferon, neutrophil, and cytokine-signaling pathways.

Several of these genes organized into coexpression networks that correlated with child anxiety and hyperactivity.

The principal active component of cannabis, tetrahydrocannabinol (THC), targets the endocannabinoid system in placental tissue and the developing brain, the authors noted. Exposure during pregnancy is associated with a range of adverse outcomes from fetal growth restriction to low birth weight and preterm birth.

“There are cannabinoid receptors on immune cells, and it is known that cannabinoids can alter immune function, which is important for maintaining maternal tolerance and protecting the fetus,” Dr. Hurd said. “It’s not surprising that something that affects the immune cells can have an impact on the developing fetus.”

“Overall, our findings reveal a relationship between [maternal cannabis use] and immune response gene networks in the placenta as a potential mediator of risk for anxiety-related problems in early childhood,” Dr. Hurd and colleagues wrote, adding that the results have significant implications for defining mental health issues in the children gestated by cannabis-smoking mothers.

Their results align with previous research indicating a greater risk for psychiatric illness in children with prenatal cannabis exposure from maternal use.

“While data are pretty limited in this realm, there are other studies that demonstrate a relationship between early child developmental and behavioral measures and cannabis use during pregnancy,” Camille Hoffman, MD, MSc, a high-risk obstetrics specialist and an associate professor at the University of Colorado at Denver, Aurora, said in an interview. “Our research group found children exposed to cannabis in utero at 10 weeks’ gestation and beyond were less interactive and more withdrawn than children who were not exposed.”

And THC remains in maternal breast milk even 6 weeks after usage stops.

The long-term effects of prenatal cannabis exposure remain to be determined and it is unknown whether the effects of gestational THC might attenuate as a child grows older. “We use early childhood measures in research as a proxy for the later development of diagnosed mental health conditions or behavioral problems,” Dr. Hoffman explained. “We know when we do this that not every child with an abnormal score early will go on to develop an actual condition. Fortunately, or unfortunately, other factors and exposures during childhood can change the trajectory for the better or worse.”

According to Dr. Hurd, child development is a dynamic process and epigenetic events in utero need not be deterministic. “The important thing is to identify children at risk early and to be able to go in and try to improve the environment they’re being raised in – not in terms of impoverishment but in terms of positive nurturing and giving the mother and family support.”

At the prenatal level, what’s the best advice for cannabis-using mothers-to-be? “If a woman doesn’t know she’s pregnant and has been using cannabis, taking extra choline for the remainder of the pregnancy can help buffer the potential negative impact of the cannabis exposure,” Dr. Hoffman said. The Food and Drug Administration and the American Medical Association recommend a dose of 550 mg daily. “The same is true for alcohol, which we know is also very bad for fetal brain development. This is not to say go ahead and use these substances and just take choline. The choline is more to try and salvage damage to the fetal brain that may have already occurred.”

This study was supported by the National Institute of Mental Health and the National Institute on Drug Abuse. The authors declared no competing interests. Dr. Hoffman disclosed no conflicts of interest with respect to her comments.

Mothers who use cannabis during pregnancy risk disrupting immune gene networks in the placenta and potentially increasing the risk of anxiety and hyperactivity in their children.

These findings emerged from a study led by Yasmin Hurd, PhD, a professor of psychiatry and director of the Addiction Institute at the Icahn School of Medicine at Mount Sinai, New York, and Yoko Nomura, PhD, a professor of behavioral neuroscience at Queen’s College, City University of New York, that was published online in Proceedings of the National Academy of Sciences.

The analysis assessed the effects of gestational maternal cannabis use on psychosocial and physiological measures in young children as well as its potentially immunomodulatory effect on the in utero environment as reflected in the placental transcriptome.

Participants were drawn from a larger cohort in a study launched in 2012; the investigators evaluated offspring aged 3-6 years for hair hormone levels, neurobehavioral traits on the Behavioral Assessment System for Children survey, and heart rate variability (HRV) at rest and during auditory startle.

The cohort consisted of 322 mother-child dyads and children with prenatal exposure to cannabis were compared with those having no exposure. The cohort consisted of 251 non–cannabis-using mothers and 71 cannabis-using mothers, with mean maternal ages in the two groups of 28.46 years and 25.91 years, respectively, The mothers gave birth at Mount Sinai and they and their children were assessed annually at affiliated medical centers in Mount Sinai’s catchment area.

For a subset of children with behavioral assessments, placental specimens collected at birth were processed for RNA sequencing.

Among the findings:

• Maternal cannabis use was associated with reduced maternal and paternal age, more single-mother pregnancies, state anxiety, trait anxiety, depression, cigarette smoking, and African American race.
• Hair hormone analysis revealed increased cortisol levels in the children of cannabis-using mothers, and was associated with greater anxiety, aggression, and hyperactivity.
• Affected children showed a reduction in the high-frequency component of HRV at baseline, reflecting reduced vagal tone.
• In the placenta, there was reduced expression of many genes involved in immune system function. These included genes for type I interferon, neutrophil, and cytokine-signaling pathways.

Several of these genes organized into coexpression networks that correlated with child anxiety and hyperactivity.

The principal active component of cannabis, tetrahydrocannabinol (THC), targets the endocannabinoid system in placental tissue and the developing brain, the authors noted. Exposure during pregnancy is associated with a range of adverse outcomes from fetal growth restriction to low birth weight and preterm birth.

“There are cannabinoid receptors on immune cells, and it is known that cannabinoids can alter immune function, which is important for maintaining maternal tolerance and protecting the fetus,” Dr. Hurd said. “It’s not surprising that something that affects the immune cells can have an impact on the developing fetus.”

“Overall, our findings reveal a relationship between [maternal cannabis use] and immune response gene networks in the placenta as a potential mediator of risk for anxiety-related problems in early childhood,” Dr. Hurd and colleagues wrote, adding that the results have significant implications for defining mental health issues in the children gestated by cannabis-smoking mothers.

Their results align with previous research indicating a greater risk for psychiatric illness in children with prenatal cannabis exposure from maternal use.

“While data are pretty limited in this realm, there are other studies that demonstrate a relationship between early child developmental and behavioral measures and cannabis use during pregnancy,” Camille Hoffman, MD, MSc, a high-risk obstetrics specialist and an associate professor at the University of Colorado at Denver, Aurora, said in an interview. “Our research group found children exposed to cannabis in utero at 10 weeks’ gestation and beyond were less interactive and more withdrawn than children who were not exposed.”

And THC remains in maternal breast milk even 6 weeks after usage stops.

The long-term effects of prenatal cannabis exposure remain to be determined and it is unknown whether the effects of gestational THC might attenuate as a child grows older. “We use early childhood measures in research as a proxy for the later development of diagnosed mental health conditions or behavioral problems,” Dr. Hoffman explained. “We know when we do this that not every child with an abnormal score early will go on to develop an actual condition. Fortunately, or unfortunately, other factors and exposures during childhood can change the trajectory for the better or worse.”

According to Dr. Hurd, child development is a dynamic process and epigenetic events in utero need not be deterministic. “The important thing is to identify children at risk early and to be able to go in and try to improve the environment they’re being raised in – not in terms of impoverishment but in terms of positive nurturing and giving the mother and family support.”

At the prenatal level, what’s the best advice for cannabis-using mothers-to-be? “If a woman doesn’t know she’s pregnant and has been using cannabis, taking extra choline for the remainder of the pregnancy can help buffer the potential negative impact of the cannabis exposure,” Dr. Hoffman said. The Food and Drug Administration and the American Medical Association recommend a dose of 550 mg daily. “The same is true for alcohol, which we know is also very bad for fetal brain development. This is not to say go ahead and use these substances and just take choline. The choline is more to try and salvage damage to the fetal brain that may have already occurred.”

This study was supported by the National Institute of Mental Health and the National Institute on Drug Abuse. The authors declared no competing interests. Dr. Hoffman disclosed no conflicts of interest with respect to her comments.