Oxidative stress may account for the “lipid paradox,” a higher incidence of heart disease burden found in nonobese rheumatoid arthritis (RA) patients with lower levels of low-density lipoprotein (LDL). George Karpouzas, MD, an investigator at the Lundquist Institute of Biomedical Innovation, St, Torrance, Calif., discussed this exploratory finding at the virtual annual meeting of the American College of Rheumatology.

A complex dynamic exists between traditional risk factors and cardiovascular (CV) events in RA patients, said Dr. Karpouzas, professor of medicine at the University of California, Los Angeles, and chief of the division of rheumatology, Harbor-UCLA Medical Center. “Lower lipid levels, specifically total cholesterol and to a lesser extent LDL, may be associated with higher risk,” he said. One recent study found that coronary artery calcium (CAC) scores were four times higher in RA patients with lower LDL concentrations (> 70 mg/dL) than those in control groups. “This was especially true in patients who were nonobese, non-Hispanic Whites and never smokers,” said Dr. Karpouzas. Other studies have reported this association between low LDL and increased CVD risk.

These paradoxes led to several questions: Does obesity modify the effect of LDL on cardiovascular disease (CVD) risk in RA and does it moderate the effect of LDL on coronary plaque burden and progression? Do LDL particle composition and oxidation variations underlie the paradoxical association of low LDL with higher coronary atherosclerosis burden in RA? To find answers, Dr. Karpouzas’ team in the Prospective Evaluation of Latent Coronary Atherosclerosis in Rheumatoid Arthritis (PROTECT-RA) trial studied a cohort of 150 established RA patients without symptoms or diagnosis of CV disease.

Dr. Karpouzas presented two oral abstracts that summarized this research during the ACR 2020 session, “RA, diagnosis, manifestations and outcomes: heart of the matter,” which was held virtually.
 

Higher plaque burden seen in nonobese patients

In one part of the study, patients underwent baseline cardiac coronary CT angiography (CTA) over 1 year (2010-2011). Investigators evaluated CAC scores, segment involvement scores (SIS), segment stenosis scores (SSS), and extensive and obstructive disease. Low LDL was defined as < 70 mg/dL, obesity as a waist to height ratio of > 0.58 squared.

Investigators in follow-up work (2017-2018) evaluated for plaque progression, prospectively recording all cardiovascular disease events such as cardiac death, myocardial infarction, unstable angina, stroke, and heart failure hospitalization. Multivariable models assessed the effects of LDL lower than 70 mg/dL, obesity, and their interaction, accounting for factors such as age, sex, statin use, diabetes and hypertension.
 

Four LDL obesity cohorts

Nonobese RA patients with low LDL exhibited the highest plaque burden. “Despite no differences in RA inflammation, patients in this group were more likely to exhibit high levels of LDL oxidation,” Dr. Karpouzas said in an interview. “Nonobese patients with low LDL more likely exhibited new coronary plaque formation as well as increased stenotic severity of prevalent plaque after adjustments for relevant covariates,” he added.

The study’s observational nature exposed it to biases and unmeasured confounding, Dr. Karpouzas emphasized. Because it took place in a single center, the results might not be generalizable to ethnically and racially diverse cohorts. Patients with calcifications, extensive or obstructive coronary plaque at baseline scan received more aggressive treatments, which could have slowed CVD event risk and plaque progression. Investigators cautioned that the results should be seen as “exploratory,” given that CVD event analysis wasn’t applied to the original study design.
 

The oxidation-LDL connection

Another arm of the study examined the oxidation association question. Investigators did a similar analysis of the same patients but also evaluated for cholesterol content, Lp(a) mass, OxLDL levels, IgG and IgM anti-OxLDL and apoB100 immune complexes and proinflammatory cytokines.

RA patients with LDL lower than 70 mg/dL had higher SSS and CAC scores and were more likely to have extensive or obstructive plaque. Statin-naive patients with lower LDL exhibited greater LDL oxidation than higher LDL groups. In addition, those with lower LDL had higher anti-OxLDL and apoB100 than patients with higher LDL.

“Oxidation makes the cholesterol more ‘sticky,’ allowing it to penetrate into the walls of the endothelium, and changes macrophages to foam cells. This malignant process is very powerful and can potentially increase atheroma burden,” study coauthor Matthew Budoff, MD, professor of medicine at UCLA and endowed chair of preventive cardiology at the Lundquist Institute, said in an interview.

Investigators also found an independent association between Lp(a) content and LDL oxidation. This association seemed strong in patients with lower LDL compared to higher LDL groups. In addition, “greater oxidation and immune recognition of oxLDL further associated with higher IL-6 elaboration which may in turn augment atherosclerosis burden in the low LDL group,” said Dr. Karpouzas.

The analysis did not explore alternate mechanisms such as increased cholesterol loading capacity, lower efflux capacity or increased hepatocyte uptake through LDL-R upregulation, a key limitation. Dr. Karpouzas also acknowledged that higher cumulative inflammatory burden incurred before evaluating low LDL patients at baseline may have led to greater coronary plaque burden.

Overall, the study shows that low LDL is not protective in this population, said Dr. Budoff. “Low LDL patients who have atherosclerosis should be treated with statins and other therapies to lower their CV risk.”
 

Larger studies to confirm associations

Attendees of the ACR 2020 session called for additional studies to confirm that LDL oxidation leads to increased coronary atherosclerotic burden in RA patients.

The study provides “mechanistic insight into this important problem for patients with RA,” noted Jeffrey A. Sparks, MD, MMSc, assistant professor of medicine at Harvard Medical School and associate physician at Brigham and Women’s Hospital, Boston.

Some of the patients studied were on lipid-lowering drugs such as statins, though the statistical analysis adjusted for use of these medications, noted Dr. Sparks. “It is possible that excess systemic inflammation alone is responsible for changes in LDL oxidation that may ultimately lead to cardiovascular disease,” he offered.

Future mechanistic and interventional studies related specifically to LDL oxidation “should establish the importance of this pathway in the development of cardiovascular disease in patients with RA,” said Dr. Sparks.

Large studies of patients with different BMI and LDL values followed prospectively for CV events would be ideal, said Joel M. Kremer, MD, president of the Corrona Research Foundation and founder of Corrona, a biopharma data solutions firm. Investigators would need to follow patients for several years. And, such a venture might face some obstacles. “The practical impediments and cost would be substantial. Also, as LDL oxidation may be related to disease activity, there would be ethical and pragmatic issues associated with controlling disease activity in these patients. This would obscure these outcomes of interest,” said Dr. Kremer.

Dr. Karpouzas receives grant and research support from the American Heart Association and Pfizer-Aspire. Dr. Budoff receives grant support from General Electric.

rhnews@mdedge.com

SOURCE: Karpouzas G et al. ACR 2020. Abstract 0485 and Abstract 0486.

Oxidative stress may account for the “lipid paradox,” a higher incidence of heart disease burden found in nonobese rheumatoid arthritis (RA) patients with lower levels of low-density lipoprotein (LDL). George Karpouzas, MD, an investigator at the Lundquist Institute of Biomedical Innovation, St, Torrance, Calif., discussed this exploratory finding at the virtual annual meeting of the American College of Rheumatology.

A complex dynamic exists between traditional risk factors and cardiovascular (CV) events in RA patients, said Dr. Karpouzas, professor of medicine at the University of California, Los Angeles, and chief of the division of rheumatology, Harbor-UCLA Medical Center. “Lower lipid levels, specifically total cholesterol and to a lesser extent LDL, may be associated with higher risk,” he said. One recent study found that coronary artery calcium (CAC) scores were four times higher in RA patients with lower LDL concentrations (> 70 mg/dL) than those in control groups. “This was especially true in patients who were nonobese, non-Hispanic Whites and never smokers,” said Dr. Karpouzas. Other studies have reported this association between low LDL and increased CVD risk.

These paradoxes led to several questions: Does obesity modify the effect of LDL on cardiovascular disease (CVD) risk in RA and does it moderate the effect of LDL on coronary plaque burden and progression? Do LDL particle composition and oxidation variations underlie the paradoxical association of low LDL with higher coronary atherosclerosis burden in RA? To find answers, Dr. Karpouzas’ team in the Prospective Evaluation of Latent Coronary Atherosclerosis in Rheumatoid Arthritis (PROTECT-RA) trial studied a cohort of 150 established RA patients without symptoms or diagnosis of CV disease.

Dr. Karpouzas presented two oral abstracts that summarized this research during the ACR 2020 session, “RA, diagnosis, manifestations and outcomes: heart of the matter,” which was held virtually.
 

Higher plaque burden seen in nonobese patients

In one part of the study, patients underwent baseline cardiac coronary CT angiography (CTA) over 1 year (2010-2011). Investigators evaluated CAC scores, segment involvement scores (SIS), segment stenosis scores (SSS), and extensive and obstructive disease. Low LDL was defined as < 70 mg/dL, obesity as a waist to height ratio of > 0.58 squared.

Investigators in follow-up work (2017-2018) evaluated for plaque progression, prospectively recording all cardiovascular disease events such as cardiac death, myocardial infarction, unstable angina, stroke, and heart failure hospitalization. Multivariable models assessed the effects of LDL lower than 70 mg/dL, obesity, and their interaction, accounting for factors such as age, sex, statin use, diabetes and hypertension.
 

Four LDL obesity cohorts

Nonobese RA patients with low LDL exhibited the highest plaque burden. “Despite no differences in RA inflammation, patients in this group were more likely to exhibit high levels of LDL oxidation,” Dr. Karpouzas said in an interview. “Nonobese patients with low LDL more likely exhibited new coronary plaque formation as well as increased stenotic severity of prevalent plaque after adjustments for relevant covariates,” he added.

The study’s observational nature exposed it to biases and unmeasured confounding, Dr. Karpouzas emphasized. Because it took place in a single center, the results might not be generalizable to ethnically and racially diverse cohorts. Patients with calcifications, extensive or obstructive coronary plaque at baseline scan received more aggressive treatments, which could have slowed CVD event risk and plaque progression. Investigators cautioned that the results should be seen as “exploratory,” given that CVD event analysis wasn’t applied to the original study design.
 

The oxidation-LDL connection

Another arm of the study examined the oxidation association question. Investigators did a similar analysis of the same patients but also evaluated for cholesterol content, Lp(a) mass, OxLDL levels, IgG and IgM anti-OxLDL and apoB100 immune complexes and proinflammatory cytokines.

RA patients with LDL lower than 70 mg/dL had higher SSS and CAC scores and were more likely to have extensive or obstructive plaque. Statin-naive patients with lower LDL exhibited greater LDL oxidation than higher LDL groups. In addition, those with lower LDL had higher anti-OxLDL and apoB100 than patients with higher LDL.

“Oxidation makes the cholesterol more ‘sticky,’ allowing it to penetrate into the walls of the endothelium, and changes macrophages to foam cells. This malignant process is very powerful and can potentially increase atheroma burden,” study coauthor Matthew Budoff, MD, professor of medicine at UCLA and endowed chair of preventive cardiology at the Lundquist Institute, said in an interview.

Investigators also found an independent association between Lp(a) content and LDL oxidation. This association seemed strong in patients with lower LDL compared to higher LDL groups. In addition, “greater oxidation and immune recognition of oxLDL further associated with higher IL-6 elaboration which may in turn augment atherosclerosis burden in the low LDL group,” said Dr. Karpouzas.

The analysis did not explore alternate mechanisms such as increased cholesterol loading capacity, lower efflux capacity or increased hepatocyte uptake through LDL-R upregulation, a key limitation. Dr. Karpouzas also acknowledged that higher cumulative inflammatory burden incurred before evaluating low LDL patients at baseline may have led to greater coronary plaque burden.

Overall, the study shows that low LDL is not protective in this population, said Dr. Budoff. “Low LDL patients who have atherosclerosis should be treated with statins and other therapies to lower their CV risk.”
 

Larger studies to confirm associations

Attendees of the ACR 2020 session called for additional studies to confirm that LDL oxidation leads to increased coronary atherosclerotic burden in RA patients.

The study provides “mechanistic insight into this important problem for patients with RA,” noted Jeffrey A. Sparks, MD, MMSc, assistant professor of medicine at Harvard Medical School and associate physician at Brigham and Women’s Hospital, Boston.

Some of the patients studied were on lipid-lowering drugs such as statins, though the statistical analysis adjusted for use of these medications, noted Dr. Sparks. “It is possible that excess systemic inflammation alone is responsible for changes in LDL oxidation that may ultimately lead to cardiovascular disease,” he offered.

Future mechanistic and interventional studies related specifically to LDL oxidation “should establish the importance of this pathway in the development of cardiovascular disease in patients with RA,” said Dr. Sparks.

Large studies of patients with different BMI and LDL values followed prospectively for CV events would be ideal, said Joel M. Kremer, MD, president of the Corrona Research Foundation and founder of Corrona, a biopharma data solutions firm. Investigators would need to follow patients for several years. And, such a venture might face some obstacles. “The practical impediments and cost would be substantial. Also, as LDL oxidation may be related to disease activity, there would be ethical and pragmatic issues associated with controlling disease activity in these patients. This would obscure these outcomes of interest,” said Dr. Kremer.

Dr. Karpouzas receives grant and research support from the American Heart Association and Pfizer-Aspire. Dr. Budoff receives grant support from General Electric.

rhnews@mdedge.com

SOURCE: Karpouzas G et al. ACR 2020. Abstract 0485 and Abstract 0486.

Oxidative stress may account for the “lipid paradox,” a higher incidence of heart disease burden found in nonobese rheumatoid arthritis (RA) patients with lower levels of low-density lipoprotein (LDL). George Karpouzas, MD, an investigator at the Lundquist Institute of Biomedical Innovation, St, Torrance, Calif., discussed this exploratory finding at the virtual annual meeting of the American College of Rheumatology.

A complex dynamic exists between traditional risk factors and cardiovascular (CV) events in RA patients, said Dr. Karpouzas, professor of medicine at the University of California, Los Angeles, and chief of the division of rheumatology, Harbor-UCLA Medical Center. “Lower lipid levels, specifically total cholesterol and to a lesser extent LDL, may be associated with higher risk,” he said. One recent study found that coronary artery calcium (CAC) scores were four times higher in RA patients with lower LDL concentrations (> 70 mg/dL) than those in control groups. “This was especially true in patients who were nonobese, non-Hispanic Whites and never smokers,” said Dr. Karpouzas. Other studies have reported this association between low LDL and increased CVD risk.

These paradoxes led to several questions: Does obesity modify the effect of LDL on cardiovascular disease (CVD) risk in RA and does it moderate the effect of LDL on coronary plaque burden and progression? Do LDL particle composition and oxidation variations underlie the paradoxical association of low LDL with higher coronary atherosclerosis burden in RA? To find answers, Dr. Karpouzas’ team in the Prospective Evaluation of Latent Coronary Atherosclerosis in Rheumatoid Arthritis (PROTECT-RA) trial studied a cohort of 150 established RA patients without symptoms or diagnosis of CV disease.

Dr. Karpouzas presented two oral abstracts that summarized this research during the ACR 2020 session, “RA, diagnosis, manifestations and outcomes: heart of the matter,” which was held virtually.
 

Higher plaque burden seen in nonobese patients

In one part of the study, patients underwent baseline cardiac coronary CT angiography (CTA) over 1 year (2010-2011). Investigators evaluated CAC scores, segment involvement scores (SIS), segment stenosis scores (SSS), and extensive and obstructive disease. Low LDL was defined as < 70 mg/dL, obesity as a waist to height ratio of > 0.58 squared.

Investigators in follow-up work (2017-2018) evaluated for plaque progression, prospectively recording all cardiovascular disease events such as cardiac death, myocardial infarction, unstable angina, stroke, and heart failure hospitalization. Multivariable models assessed the effects of LDL lower than 70 mg/dL, obesity, and their interaction, accounting for factors such as age, sex, statin use, diabetes and hypertension.
 

Four LDL obesity cohorts

Nonobese RA patients with low LDL exhibited the highest plaque burden. “Despite no differences in RA inflammation, patients in this group were more likely to exhibit high levels of LDL oxidation,” Dr. Karpouzas said in an interview. “Nonobese patients with low LDL more likely exhibited new coronary plaque formation as well as increased stenotic severity of prevalent plaque after adjustments for relevant covariates,” he added.

The study’s observational nature exposed it to biases and unmeasured confounding, Dr. Karpouzas emphasized. Because it took place in a single center, the results might not be generalizable to ethnically and racially diverse cohorts. Patients with calcifications, extensive or obstructive coronary plaque at baseline scan received more aggressive treatments, which could have slowed CVD event risk and plaque progression. Investigators cautioned that the results should be seen as “exploratory,” given that CVD event analysis wasn’t applied to the original study design.
 

The oxidation-LDL connection

Another arm of the study examined the oxidation association question. Investigators did a similar analysis of the same patients but also evaluated for cholesterol content, Lp(a) mass, OxLDL levels, IgG and IgM anti-OxLDL and apoB100 immune complexes and proinflammatory cytokines.

RA patients with LDL lower than 70 mg/dL had higher SSS and CAC scores and were more likely to have extensive or obstructive plaque. Statin-naive patients with lower LDL exhibited greater LDL oxidation than higher LDL groups. In addition, those with lower LDL had higher anti-OxLDL and apoB100 than patients with higher LDL.

“Oxidation makes the cholesterol more ‘sticky,’ allowing it to penetrate into the walls of the endothelium, and changes macrophages to foam cells. This malignant process is very powerful and can potentially increase atheroma burden,” study coauthor Matthew Budoff, MD, professor of medicine at UCLA and endowed chair of preventive cardiology at the Lundquist Institute, said in an interview.

Investigators also found an independent association between Lp(a) content and LDL oxidation. This association seemed strong in patients with lower LDL compared to higher LDL groups. In addition, “greater oxidation and immune recognition of oxLDL further associated with higher IL-6 elaboration which may in turn augment atherosclerosis burden in the low LDL group,” said Dr. Karpouzas.

The analysis did not explore alternate mechanisms such as increased cholesterol loading capacity, lower efflux capacity or increased hepatocyte uptake through LDL-R upregulation, a key limitation. Dr. Karpouzas also acknowledged that higher cumulative inflammatory burden incurred before evaluating low LDL patients at baseline may have led to greater coronary plaque burden.

Overall, the study shows that low LDL is not protective in this population, said Dr. Budoff. “Low LDL patients who have atherosclerosis should be treated with statins and other therapies to lower their CV risk.”
 

Larger studies to confirm associations

Attendees of the ACR 2020 session called for additional studies to confirm that LDL oxidation leads to increased coronary atherosclerotic burden in RA patients.

The study provides “mechanistic insight into this important problem for patients with RA,” noted Jeffrey A. Sparks, MD, MMSc, assistant professor of medicine at Harvard Medical School and associate physician at Brigham and Women’s Hospital, Boston.

Some of the patients studied were on lipid-lowering drugs such as statins, though the statistical analysis adjusted for use of these medications, noted Dr. Sparks. “It is possible that excess systemic inflammation alone is responsible for changes in LDL oxidation that may ultimately lead to cardiovascular disease,” he offered.

Future mechanistic and interventional studies related specifically to LDL oxidation “should establish the importance of this pathway in the development of cardiovascular disease in patients with RA,” said Dr. Sparks.

Large studies of patients with different BMI and LDL values followed prospectively for CV events would be ideal, said Joel M. Kremer, MD, president of the Corrona Research Foundation and founder of Corrona, a biopharma data solutions firm. Investigators would need to follow patients for several years. And, such a venture might face some obstacles. “The practical impediments and cost would be substantial. Also, as LDL oxidation may be related to disease activity, there would be ethical and pragmatic issues associated with controlling disease activity in these patients. This would obscure these outcomes of interest,” said Dr. Kremer.

Dr. Karpouzas receives grant and research support from the American Heart Association and Pfizer-Aspire. Dr. Budoff receives grant support from General Electric.

rhnews@mdedge.com

SOURCE: Karpouzas G et al. ACR 2020. Abstract 0485 and Abstract 0486.

Editor's Note: Due to updated statistics from the CDC, the online version of this article has been modified from the version that appears in the printed edition of the January 2021 issue of Current Psychiatry.

Individuals with mental health and substance use disorders (SUDs) are particularly susceptible to negative effects of the coronavirus disease 2019 (COVID-19) pandemic. The collision of the COVID-19 pandemic and the drug overdose epidemic has highlighted the urgent need for physicians, policymakers, and health care professionals to optimize care for individuals with SUDs because they may be particularly vulnerable to the effects of the virus due to compromised respiratory and immune function, and poor social support.¹  In this commentary, we highlight the challenges of the drug overdose epidemic, and recommend strategies to mitigate the impact of the COVID-19 pandemic among patients with SUDs.  

A crisis exacerbated by COVID-19 

The current drug overdose epidemic has become an American public health nightmare. According to preliminary data released by the CDC on December 17, 2020, there were more than 81,000 drug overdose deaths in the United States in the 12 months ending May 2020.^2,3 This is the highest number of overdose deaths ever recorded in a 12-month period. The CDC also noted that while overdose deaths were already increasing in the months preceding the COVID-19 pandemic, the latest numbers suggest an acceleration of overdose deaths during the pandemic.

What is causing this significant loss of life? Prescription opioids and illegal opioids such as heroin and illicitly manufactured fentanyl are the main agents associated with overdose deaths. These opioids were responsible for 61% (28,647) of drug overdose deaths in the United States in 2014.⁴ In 2015, the opioid overdose death rate increased by 15.6%.⁵  

The increase in the number of opioid overdose deaths in part coincides with a sharp increase in the availability and use of heroin. Heroin overdose deaths have more than tripled since 2010, but heroin is not the only opiate involved. Fentanyl, a synthetic, short-acting opioid that is approved for managing pain in patients with advanced cancers, is 50 times more potent than heroin. The abuse of prescribed fentanyl has been accelerating over the past decade, as is the use of illicitly produced fentanyl. Evidence from US Drug Enforcement Administration (DEA) seizure records shows heroin is being adulterated with illicit fentanyl to enhance the potency of the heroin.^6,7 Mixing illicit fentanyl with heroin may be contributing to the recent increase in heroin overdose fatalities. According to the CDC, overdose deaths related to synthetic opioids increased 38.4% from the 12-month period leading up to June 2019 compared with the 12-month period leading up to May 2020.^2,3 Postmortem studies of individuals who died from a heroin overdose have frequently found the presence of fentanyl along with heroin.⁸ Overdose deaths involving heroin may be occurring because individuals may be unknowingly using heroin adulterated with fentanyl.⁹ In addition, carfentanil, a powerful new synthetic fentanyl, has been recently identified in heroin mixtures. Carfentanil is 10,000 times stronger than morphine. Even in miniscule amounts, carfentanil can suppress breathing to the degree that multiple doses of naloxone are needed to restore respirations.

Initial studies indicate that the COVID-19 pandemic has been exacerbating this situation. Wainwright et al¹⁰ conducted an analysis of urine drug test results of patients with SUDs from 4 months before and 4 months after COVID-19 was declared a national emergency on March 13, 2020. Compared with before COVID-19, the proportion of specimens testing positive since COVID-19 increased from 3.80% to 7.32% for fentanyl and from 1.29% to 2.09% for heroin.¹⁰  

A similar drug testing study found that during the pandemic, the proportion of positive results (positivity) increased by 35% for non-prescribed fentanyl and 44% for heroin.¹¹ Positivity for non-prescribed fentanyl increased significantly among patients who tested positive for other drugs, including by 89% for amphetamines; 48% for benzodiazepines; 34% for cocaine; and 39% for opiates (P < .1 for all).¹¹ 

In a review of electronic medical records, Ochalek et al¹² found that the number of nonfatal opioid overdoses in an emergency department in Virginia increased from 102 in March-June 2019 to 227 in March-June 2020. In an issue brief published on October 31, 2020, the American Medical Association reported increase in opioid and other drug-related overdoses in more than 40 states during the COVID-19 pandemic.¹³ 

Continue to: Strategies for intervention...

Strategies for intervention 

A multi-dimensional approach is needed to protect the public from this growing opioid overdose epidemic. To address this challenging task, we recommend several strategies: 

Enhance access to virtual treatment 
Even when in-person treatment cannot take place due to COVID-19-related restrictions, it is vital that services are accessible to patients with SUDs during this pandemic. Examples of virtual treatment include: 

• Telehealth for medication-assisted treatment (MAT) using buprenorphine (recently updated guidance from the US DEA and Substance Abuse and Mental Health Services Administration [SAMHSA] allows this method of prescribing) 
• Teletherapy to prevent relapse  
• Remote drug screens by sending saliva or urine kits to patients' homes, visiting patients to collect fluid samples, or asking patients to come to a "drive-through" facility to provide samples  
• Virtual (online) Alcoholics Anonymous, Narcotics Anonymous, SMART Recovery, and similar meetings to provide support in the absence of in-person meetings.  

The American Society of Addiction Medicine (ASAM) offers guidance to treatment programs to focus on infection control and mitigation. The Table¹⁴ summarizes the ASAM recommendations for office-based opioid treatment during COVID-19.

Continue to: Increase education on naloxone...  

Increase education on naloxone  
Naloxone is a safe and effective opioid antagonist used to treat opioid overdoses. Timely access to naloxone is of the essence when treating opioid-related overdoses. Many states have enacted laws allowing health care professionals, law enforcement officers, and patients and relatives to obtain naloxone without a physician's prescription. It appears this approach may be yielding results. For example, the North Carolina Harm Reduction Coalition distributed >101,000 free overdose rescue kits that included naloxone and recorded 13,392 confirmed cases of overdose rescue with naloxone from 2013 to 2019.¹⁶ 

Divert patients with SUDs from the criminal justice system to treatment 
We need to develop programs to divert patients with SUDs from the criminal justice system, which is focused on punishment, to interventions that focus on treatment. Data indicates high recidivism rates for incarcerated individuals with SUDs who do not have access to treatment after they are released. Recognizing this, communities are developing programs that divert low-level offenders from the criminal justice system into treatment. For instance, in Seattle, the Law Enforcement Assisted Diversion is a pilot program developed to divert low-level drug and prostitution offenders into community-based treatment and support services. This helps provide housing, health care, job training, treatment, and mental health support. Innovative programs are needed to provide SUD treatment in the rehabilitation programs of correctional facilities and ensure case managers and discharge planners can transition participants to community treatment programs upon their release. 

Develop early identification and prevention programs  
These programs should focus on individuals at high risk, such as patients with comorbid SUDs and psychiatric disorders, those with chronic pain, and at-risk children whose parents abuse opiates. Traditional addiction treatment programs typically do not address patients with complex conditions or special populations, such as adolescents or pregnant women with substance use issues. Evidence-based approaches such as Screening, Brief Intervention, and Referral to Treatment (SBIRT), Integrated Dual Diagnosis Treatment (IDDT), and prevention approaches that target students in middle schools and high schools need to be more widely available. 

Improve education on opioid prescribing   
Responsible opioid prescribing for clinicians should include education about the regular use of prescription drug monitoring programs, urine drug screening, avoiding co-prescription of opioids with sedative-hypnotic medications, and better linkage with addiction treatment. 

Treat comorbid psychiatric conditions 
It is critical to both identify and effectively treat underlying affective, anxiety, and psychotic disorders in patients with SUDs. Anxiety, depression, and emotional dysregulation often contribute to worsening substance abuse, abuse of prescription drugs, diversion of prescribed drugs, and an increased risk of overdoses and suicides. Effective treatment of comorbid psychiatric conditions also may reduce relapses.  

Increase research on causes and treatments 
Through research, we must expand our knowledge to better understand the factors that contribute to this epidemic and develop better treatments. These efforts may allow for the development of prevention mechanisms. For example, a recent study found that the continued use of opioid medications after an overdose was associated with a high risk of a repeated overdosecall out material?.¹⁷ At the end of a 2-year observation, 17% (confidence interval [CI]: 14% to 20%) of patients receiving a high daily dosage of a prescribed opioid had a repeat overdose compared with 15% (CI: 10% to 21%) of those receiving a moderate dosage, 9% (CI: 6% to 14%) of those receiving a low dosage, and 8% (CI: 6% to 11%) of those receiving no opioids.¹⁷ Of the patients who overdosed on prescribed opiates, 30% switched to a new prescriber after their overdose, many of whom may not have been aware of the previous overdose. From a public health perspective, it would make sense for prescribers to know of prior opioid and/or benzodiazepine overdoses. This could be reported by emergency department clinicians, law enforcement, and hospitals into a prescription drug monitoring program, which is readily available to prescribers in most states. 

Acknowledgment 
The authors thank Scott Proescholdbell, MPH, Injury and Violence Prevention Branch, Chronic Disease and Injury Section, Division of Public Health, North Carolina Department of Health and Human Services, for his assistance. 

Bottom Line

The collision of the coronavirus disease 2019 pandemic and the drug overdose epidemic has highlighted the urgent need for health care professionals to optimize care for individuals with substance use disorders. Suggested interventions include enhancing access to medication-assisted treatment and virtual treatment, improving education about naloxone and safe opioid prescribing practices, and diverting at-risk patients from the criminal justice system to interventions that focus on treatment.

Editor's Note: Due to updated statistics from the CDC, the online version of this article has been modified from the version that appears in the printed edition of the January 2021 issue of Current Psychiatry.

Individuals with mental health and substance use disorders (SUDs) are particularly susceptible to negative effects of the coronavirus disease 2019 (COVID-19) pandemic. The collision of the COVID-19 pandemic and the drug overdose epidemic has highlighted the urgent need for physicians, policymakers, and health care professionals to optimize care for individuals with SUDs because they may be particularly vulnerable to the effects of the virus due to compromised respiratory and immune function, and poor social support.¹  In this commentary, we highlight the challenges of the drug overdose epidemic, and recommend strategies to mitigate the impact of the COVID-19 pandemic among patients with SUDs.  

A crisis exacerbated by COVID-19 

The current drug overdose epidemic has become an American public health nightmare. According to preliminary data released by the CDC on December 17, 2020, there were more than 81,000 drug overdose deaths in the United States in the 12 months ending May 2020.^2,3 This is the highest number of overdose deaths ever recorded in a 12-month period. The CDC also noted that while overdose deaths were already increasing in the months preceding the COVID-19 pandemic, the latest numbers suggest an acceleration of overdose deaths during the pandemic.

What is causing this significant loss of life? Prescription opioids and illegal opioids such as heroin and illicitly manufactured fentanyl are the main agents associated with overdose deaths. These opioids were responsible for 61% (28,647) of drug overdose deaths in the United States in 2014.⁴ In 2015, the opioid overdose death rate increased by 15.6%.⁵  

The increase in the number of opioid overdose deaths in part coincides with a sharp increase in the availability and use of heroin. Heroin overdose deaths have more than tripled since 2010, but heroin is not the only opiate involved. Fentanyl, a synthetic, short-acting opioid that is approved for managing pain in patients with advanced cancers, is 50 times more potent than heroin. The abuse of prescribed fentanyl has been accelerating over the past decade, as is the use of illicitly produced fentanyl. Evidence from US Drug Enforcement Administration (DEA) seizure records shows heroin is being adulterated with illicit fentanyl to enhance the potency of the heroin.^6,7 Mixing illicit fentanyl with heroin may be contributing to the recent increase in heroin overdose fatalities. According to the CDC, overdose deaths related to synthetic opioids increased 38.4% from the 12-month period leading up to June 2019 compared with the 12-month period leading up to May 2020.^2,3 Postmortem studies of individuals who died from a heroin overdose have frequently found the presence of fentanyl along with heroin.⁸ Overdose deaths involving heroin may be occurring because individuals may be unknowingly using heroin adulterated with fentanyl.⁹ In addition, carfentanil, a powerful new synthetic fentanyl, has been recently identified in heroin mixtures. Carfentanil is 10,000 times stronger than morphine. Even in miniscule amounts, carfentanil can suppress breathing to the degree that multiple doses of naloxone are needed to restore respirations.

Initial studies indicate that the COVID-19 pandemic has been exacerbating this situation. Wainwright et al¹⁰ conducted an analysis of urine drug test results of patients with SUDs from 4 months before and 4 months after COVID-19 was declared a national emergency on March 13, 2020. Compared with before COVID-19, the proportion of specimens testing positive since COVID-19 increased from 3.80% to 7.32% for fentanyl and from 1.29% to 2.09% for heroin.¹⁰  

A similar drug testing study found that during the pandemic, the proportion of positive results (positivity) increased by 35% for non-prescribed fentanyl and 44% for heroin.¹¹ Positivity for non-prescribed fentanyl increased significantly among patients who tested positive for other drugs, including by 89% for amphetamines; 48% for benzodiazepines; 34% for cocaine; and 39% for opiates (P < .1 for all).¹¹ 

In a review of electronic medical records, Ochalek et al¹² found that the number of nonfatal opioid overdoses in an emergency department in Virginia increased from 102 in March-June 2019 to 227 in March-June 2020. In an issue brief published on October 31, 2020, the American Medical Association reported increase in opioid and other drug-related overdoses in more than 40 states during the COVID-19 pandemic.¹³ 

Continue to: Strategies for intervention...

Strategies for intervention 

A multi-dimensional approach is needed to protect the public from this growing opioid overdose epidemic. To address this challenging task, we recommend several strategies: 

Enhance access to virtual treatment 
Even when in-person treatment cannot take place due to COVID-19-related restrictions, it is vital that services are accessible to patients with SUDs during this pandemic. Examples of virtual treatment include: 

• Telehealth for medication-assisted treatment (MAT) using buprenorphine (recently updated guidance from the US DEA and Substance Abuse and Mental Health Services Administration [SAMHSA] allows this method of prescribing) 
• Teletherapy to prevent relapse  
• Remote drug screens by sending saliva or urine kits to patients' homes, visiting patients to collect fluid samples, or asking patients to come to a "drive-through" facility to provide samples  
• Virtual (online) Alcoholics Anonymous, Narcotics Anonymous, SMART Recovery, and similar meetings to provide support in the absence of in-person meetings.  

The American Society of Addiction Medicine (ASAM) offers guidance to treatment programs to focus on infection control and mitigation. The Table¹⁴ summarizes the ASAM recommendations for office-based opioid treatment during COVID-19.

Continue to: Increase education on naloxone...  

Increase education on naloxone  
Naloxone is a safe and effective opioid antagonist used to treat opioid overdoses. Timely access to naloxone is of the essence when treating opioid-related overdoses. Many states have enacted laws allowing health care professionals, law enforcement officers, and patients and relatives to obtain naloxone without a physician's prescription. It appears this approach may be yielding results. For example, the North Carolina Harm Reduction Coalition distributed >101,000 free overdose rescue kits that included naloxone and recorded 13,392 confirmed cases of overdose rescue with naloxone from 2013 to 2019.¹⁶ 

Divert patients with SUDs from the criminal justice system to treatment 
We need to develop programs to divert patients with SUDs from the criminal justice system, which is focused on punishment, to interventions that focus on treatment. Data indicates high recidivism rates for incarcerated individuals with SUDs who do not have access to treatment after they are released. Recognizing this, communities are developing programs that divert low-level offenders from the criminal justice system into treatment. For instance, in Seattle, the Law Enforcement Assisted Diversion is a pilot program developed to divert low-level drug and prostitution offenders into community-based treatment and support services. This helps provide housing, health care, job training, treatment, and mental health support. Innovative programs are needed to provide SUD treatment in the rehabilitation programs of correctional facilities and ensure case managers and discharge planners can transition participants to community treatment programs upon their release. 

Develop early identification and prevention programs  
These programs should focus on individuals at high risk, such as patients with comorbid SUDs and psychiatric disorders, those with chronic pain, and at-risk children whose parents abuse opiates. Traditional addiction treatment programs typically do not address patients with complex conditions or special populations, such as adolescents or pregnant women with substance use issues. Evidence-based approaches such as Screening, Brief Intervention, and Referral to Treatment (SBIRT), Integrated Dual Diagnosis Treatment (IDDT), and prevention approaches that target students in middle schools and high schools need to be more widely available. 

Improve education on opioid prescribing   
Responsible opioid prescribing for clinicians should include education about the regular use of prescription drug monitoring programs, urine drug screening, avoiding co-prescription of opioids with sedative-hypnotic medications, and better linkage with addiction treatment. 

Treat comorbid psychiatric conditions 
It is critical to both identify and effectively treat underlying affective, anxiety, and psychotic disorders in patients with SUDs. Anxiety, depression, and emotional dysregulation often contribute to worsening substance abuse, abuse of prescription drugs, diversion of prescribed drugs, and an increased risk of overdoses and suicides. Effective treatment of comorbid psychiatric conditions also may reduce relapses.  

Increase research on causes and treatments 
Through research, we must expand our knowledge to better understand the factors that contribute to this epidemic and develop better treatments. These efforts may allow for the development of prevention mechanisms. For example, a recent study found that the continued use of opioid medications after an overdose was associated with a high risk of a repeated overdosecall out material?.¹⁷ At the end of a 2-year observation, 17% (confidence interval [CI]: 14% to 20%) of patients receiving a high daily dosage of a prescribed opioid had a repeat overdose compared with 15% (CI: 10% to 21%) of those receiving a moderate dosage, 9% (CI: 6% to 14%) of those receiving a low dosage, and 8% (CI: 6% to 11%) of those receiving no opioids.¹⁷ Of the patients who overdosed on prescribed opiates, 30% switched to a new prescriber after their overdose, many of whom may not have been aware of the previous overdose. From a public health perspective, it would make sense for prescribers to know of prior opioid and/or benzodiazepine overdoses. This could be reported by emergency department clinicians, law enforcement, and hospitals into a prescription drug monitoring program, which is readily available to prescribers in most states. 

Acknowledgment 
The authors thank Scott Proescholdbell, MPH, Injury and Violence Prevention Branch, Chronic Disease and Injury Section, Division of Public Health, North Carolina Department of Health and Human Services, for his assistance. 

Bottom Line

The collision of the coronavirus disease 2019 pandemic and the drug overdose epidemic has highlighted the urgent need for health care professionals to optimize care for individuals with substance use disorders. Suggested interventions include enhancing access to medication-assisted treatment and virtual treatment, improving education about naloxone and safe opioid prescribing practices, and diverting at-risk patients from the criminal justice system to interventions that focus on treatment.

Editor's Note: Due to updated statistics from the CDC, the online version of this article has been modified from the version that appears in the printed edition of the January 2021 issue of Current Psychiatry.

Individuals with mental health and substance use disorders (SUDs) are particularly susceptible to negative effects of the coronavirus disease 2019 (COVID-19) pandemic. The collision of the COVID-19 pandemic and the drug overdose epidemic has highlighted the urgent need for physicians, policymakers, and health care professionals to optimize care for individuals with SUDs because they may be particularly vulnerable to the effects of the virus due to compromised respiratory and immune function, and poor social support.¹  In this commentary, we highlight the challenges of the drug overdose epidemic, and recommend strategies to mitigate the impact of the COVID-19 pandemic among patients with SUDs.  

A crisis exacerbated by COVID-19 

The current drug overdose epidemic has become an American public health nightmare. According to preliminary data released by the CDC on December 17, 2020, there were more than 81,000 drug overdose deaths in the United States in the 12 months ending May 2020.^2,3 This is the highest number of overdose deaths ever recorded in a 12-month period. The CDC also noted that while overdose deaths were already increasing in the months preceding the COVID-19 pandemic, the latest numbers suggest an acceleration of overdose deaths during the pandemic.

What is causing this significant loss of life? Prescription opioids and illegal opioids such as heroin and illicitly manufactured fentanyl are the main agents associated with overdose deaths. These opioids were responsible for 61% (28,647) of drug overdose deaths in the United States in 2014.⁴ In 2015, the opioid overdose death rate increased by 15.6%.⁵  

The increase in the number of opioid overdose deaths in part coincides with a sharp increase in the availability and use of heroin. Heroin overdose deaths have more than tripled since 2010, but heroin is not the only opiate involved. Fentanyl, a synthetic, short-acting opioid that is approved for managing pain in patients with advanced cancers, is 50 times more potent than heroin. The abuse of prescribed fentanyl has been accelerating over the past decade, as is the use of illicitly produced fentanyl. Evidence from US Drug Enforcement Administration (DEA) seizure records shows heroin is being adulterated with illicit fentanyl to enhance the potency of the heroin.^6,7 Mixing illicit fentanyl with heroin may be contributing to the recent increase in heroin overdose fatalities. According to the CDC, overdose deaths related to synthetic opioids increased 38.4% from the 12-month period leading up to June 2019 compared with the 12-month period leading up to May 2020.^2,3 Postmortem studies of individuals who died from a heroin overdose have frequently found the presence of fentanyl along with heroin.⁸ Overdose deaths involving heroin may be occurring because individuals may be unknowingly using heroin adulterated with fentanyl.⁹ In addition, carfentanil, a powerful new synthetic fentanyl, has been recently identified in heroin mixtures. Carfentanil is 10,000 times stronger than morphine. Even in miniscule amounts, carfentanil can suppress breathing to the degree that multiple doses of naloxone are needed to restore respirations.

Initial studies indicate that the COVID-19 pandemic has been exacerbating this situation. Wainwright et al¹⁰ conducted an analysis of urine drug test results of patients with SUDs from 4 months before and 4 months after COVID-19 was declared a national emergency on March 13, 2020. Compared with before COVID-19, the proportion of specimens testing positive since COVID-19 increased from 3.80% to 7.32% for fentanyl and from 1.29% to 2.09% for heroin.¹⁰  

A similar drug testing study found that during the pandemic, the proportion of positive results (positivity) increased by 35% for non-prescribed fentanyl and 44% for heroin.¹¹ Positivity for non-prescribed fentanyl increased significantly among patients who tested positive for other drugs, including by 89% for amphetamines; 48% for benzodiazepines; 34% for cocaine; and 39% for opiates (P < .1 for all).¹¹ 

In a review of electronic medical records, Ochalek et al¹² found that the number of nonfatal opioid overdoses in an emergency department in Virginia increased from 102 in March-June 2019 to 227 in March-June 2020. In an issue brief published on October 31, 2020, the American Medical Association reported increase in opioid and other drug-related overdoses in more than 40 states during the COVID-19 pandemic.¹³ 

Continue to: Strategies for intervention...

Strategies for intervention 

A multi-dimensional approach is needed to protect the public from this growing opioid overdose epidemic. To address this challenging task, we recommend several strategies: 

Enhance access to virtual treatment 
Even when in-person treatment cannot take place due to COVID-19-related restrictions, it is vital that services are accessible to patients with SUDs during this pandemic. Examples of virtual treatment include: 

• Telehealth for medication-assisted treatment (MAT) using buprenorphine (recently updated guidance from the US DEA and Substance Abuse and Mental Health Services Administration [SAMHSA] allows this method of prescribing) 
• Teletherapy to prevent relapse  
• Remote drug screens by sending saliva or urine kits to patients' homes, visiting patients to collect fluid samples, or asking patients to come to a "drive-through" facility to provide samples  
• Virtual (online) Alcoholics Anonymous, Narcotics Anonymous, SMART Recovery, and similar meetings to provide support in the absence of in-person meetings.  

The American Society of Addiction Medicine (ASAM) offers guidance to treatment programs to focus on infection control and mitigation. The Table¹⁴ summarizes the ASAM recommendations for office-based opioid treatment during COVID-19.

Continue to: Increase education on naloxone...  

Increase education on naloxone  
Naloxone is a safe and effective opioid antagonist used to treat opioid overdoses. Timely access to naloxone is of the essence when treating opioid-related overdoses. Many states have enacted laws allowing health care professionals, law enforcement officers, and patients and relatives to obtain naloxone without a physician's prescription. It appears this approach may be yielding results. For example, the North Carolina Harm Reduction Coalition distributed >101,000 free overdose rescue kits that included naloxone and recorded 13,392 confirmed cases of overdose rescue with naloxone from 2013 to 2019.¹⁶ 

Divert patients with SUDs from the criminal justice system to treatment 
We need to develop programs to divert patients with SUDs from the criminal justice system, which is focused on punishment, to interventions that focus on treatment. Data indicates high recidivism rates for incarcerated individuals with SUDs who do not have access to treatment after they are released. Recognizing this, communities are developing programs that divert low-level offenders from the criminal justice system into treatment. For instance, in Seattle, the Law Enforcement Assisted Diversion is a pilot program developed to divert low-level drug and prostitution offenders into community-based treatment and support services. This helps provide housing, health care, job training, treatment, and mental health support. Innovative programs are needed to provide SUD treatment in the rehabilitation programs of correctional facilities and ensure case managers and discharge planners can transition participants to community treatment programs upon their release. 

Develop early identification and prevention programs  
These programs should focus on individuals at high risk, such as patients with comorbid SUDs and psychiatric disorders, those with chronic pain, and at-risk children whose parents abuse opiates. Traditional addiction treatment programs typically do not address patients with complex conditions or special populations, such as adolescents or pregnant women with substance use issues. Evidence-based approaches such as Screening, Brief Intervention, and Referral to Treatment (SBIRT), Integrated Dual Diagnosis Treatment (IDDT), and prevention approaches that target students in middle schools and high schools need to be more widely available. 

Improve education on opioid prescribing   
Responsible opioid prescribing for clinicians should include education about the regular use of prescription drug monitoring programs, urine drug screening, avoiding co-prescription of opioids with sedative-hypnotic medications, and better linkage with addiction treatment. 

Treat comorbid psychiatric conditions 
It is critical to both identify and effectively treat underlying affective, anxiety, and psychotic disorders in patients with SUDs. Anxiety, depression, and emotional dysregulation often contribute to worsening substance abuse, abuse of prescription drugs, diversion of prescribed drugs, and an increased risk of overdoses and suicides. Effective treatment of comorbid psychiatric conditions also may reduce relapses.  

Increase research on causes and treatments 
Through research, we must expand our knowledge to better understand the factors that contribute to this epidemic and develop better treatments. These efforts may allow for the development of prevention mechanisms. For example, a recent study found that the continued use of opioid medications after an overdose was associated with a high risk of a repeated overdosecall out material?.¹⁷ At the end of a 2-year observation, 17% (confidence interval [CI]: 14% to 20%) of patients receiving a high daily dosage of a prescribed opioid had a repeat overdose compared with 15% (CI: 10% to 21%) of those receiving a moderate dosage, 9% (CI: 6% to 14%) of those receiving a low dosage, and 8% (CI: 6% to 11%) of those receiving no opioids.¹⁷ Of the patients who overdosed on prescribed opiates, 30% switched to a new prescriber after their overdose, many of whom may not have been aware of the previous overdose. From a public health perspective, it would make sense for prescribers to know of prior opioid and/or benzodiazepine overdoses. This could be reported by emergency department clinicians, law enforcement, and hospitals into a prescription drug monitoring program, which is readily available to prescribers in most states. 

Acknowledgment 
The authors thank Scott Proescholdbell, MPH, Injury and Violence Prevention Branch, Chronic Disease and Injury Section, Division of Public Health, North Carolina Department of Health and Human Services, for his assistance. 

Bottom Line

The collision of the coronavirus disease 2019 pandemic and the drug overdose epidemic has highlighted the urgent need for health care professionals to optimize care for individuals with substance use disorders. Suggested interventions include enhancing access to medication-assisted treatment and virtual treatment, improving education about naloxone and safe opioid prescribing practices, and diverting at-risk patients from the criminal justice system to interventions that focus on treatment.

The COVID-19 pandemic has meant delays in cancer screening, diagnosis, and treatment — and a new study shows just how deadly delaying cancer treatment can be.

The study found evidence that longer time to starting treatment after diagnosis was generally associated with higher mortality across several common cancers, most notably for colon and early-stage lung cancer.

“There is a limit to how long we can safely defer treatment for cancer therapies, pandemic or not, which may be shorter than we think,” lead author Eugene Cone, MD, Combined Harvard Program in Urologic Oncology, Massachusetts General Hospital and Brigham & Women’s Hospital, Boston, told Medscape Medical News.

“When you consider that cancer screening may have been delayed during the pandemic, which would further increase the period between developing a disease and getting therapy, timely treatment for cancer has never been more important,” Cone added.

The study was published online December 14 in JAMA Network Open.
 

The sooner the better

Using the National Cancer Database, Cone and colleagues identified roughly 2.24 million patients diagnosed with nonmetastatic breast (52%), prostate (38%), colon (4%) and non-small cell lung cancer (NSCLC, 6%) between 2004 and 2015. Treatment and outcome data were analyzed from January to March 2020.

The time-to-treatment initiation (TTI) – the interval between cancer diagnosis and receipt of curative-intent therapy – was categorized as 8 to 60 days (reference), 61 to 120 days, 121 to 180 days, and 181 to 365 days. Median TTI was 32 days for breast, 79 days for prostate, 41 days for NSCLC, and 26 days for colon cancer.

All four cancers benefitted to some degree from a short interval between diagnosis and therapy, the researchers found.

Across all four cancers, increasing TTI was generally associated with higher predicted mortality at 5 and 10 years, although the degree varied by cancer type and stage. The most pronounced association between increasing TTI and mortality was observed for colon and lung cancer.

For example, for stage III colon cancer, 5- and 10-year predicted mortality was 38.9% and 54%, respectively, with TTI of 61 to 120 days, and increased to 47.8% and 63.8%, respectively, with TTI of 181 to 365 days.

Each additional 60-day delay was associated with a 3.2% to 6% increase in 5-year mortality for stage III colon cancer and a 0.9% to 4.6% increase for stage I colon cancer, with a longer 10-year time horizon showing larger effect sizes with increasing TTI.

For stage I NSCLC, 5- and 10-year predicted mortality was 47.4% and 72.6%, respectively, with TTI of 61 to 120 days compared with 47.6% and 72.8%, respectively, with TTI of 181 to 365 days.  

For stage I NSCLC, there was a 4% to 6.2% absolute increase in 5-year mortality for increased TTI groups compared with the 8- to 60-day reference group, with larger effect sizes on 10-year mortality. The data precluded conclusions about stage II NSCLC.

“For prostate cancer, deferral of treatment by even a few months was associated with a significant impact on mortality,” Cone told Medscape Medical News.

For high-risk prostate cancer, 5- and 10-year predicted mortality was 12.8% and 31.2%, respectively, with TTI of 61-120 days increasing to 14.1% and 33.8%, respectively with TTI at 181-365 days.

For intermediate-risk prostate cancer, 5- and 10-year predicted mortality was 7.4% and 20.4% with TTI of 61-120 days vs 8.3% and 22.6% with TTI at 181-365 days.

The data show all-cause mortality differences of 2.2% at 5 years and 4.6% at 10 years between high-risk prostate cancer patients who were treated expeditiously vs those waiting 4 to 6 months and differences of 0.9% at 5 years and 2.4% at 10 years for similar intermediate-risk patients.
 

No surprises

Turning to breast cancer, increased TTI was associated with the most negative survival effects for stage II and III breast cancer.

For stage II breast cancer, for example, 5- and 10-year predicted mortality was 17.7% and 30.5%, respectively, with TTI of 61-120 days vs 21.7% and 36.5% with TTI at 181-365 days. 

Even for stage I breast cancer patients, there were significant differences in all-cause mortality with delayed definitive therapy, although the effect size is clinically small, the researchers report.

Patients with stage IA or IB breast cancer who were not treated until 61 to 120 days after diagnosis had 1.3% and 2.3% increased mortality at 5 years and 10 years, respectively, and those waiting longer suffered even greater increases in mortality. “As such, our analysis underscores the importance of timely definitive treatment, even for stage I breast cancer,” the authors write.

Charles Shapiro, MD, director of translational breast cancer research for the Mount Sinai Health System, New York City, was not surprised by the data.

The observation that delays in initiating cancer treatment are associated with worse survival is “not new, as delays in primary surgical treatments and chemotherapy for early-stage disease is an adverse prognostic factor for clinical outcomes,” Shapiro told Medscape Medical News.

“The bottom line is primary surgery and the start of chemotherapy should probably occur as soon as clinically feasible,” said Shapiro, who was not involved in the study.

The authors of an accompanying editorial agree. 

This study supports avoiding unnecessary treatment delays and prioritizing timely cancer care, even during the COVID-19 pandemic, write Laura Van Metre Baum, MD, Division of Hematology and Oncology, Vanderbilt University, Nashville, Tennessee, and colleagues.

They note, however, that primary care, “the most important conduit for cancer screening and initial evaluation of new symptoms, has been the hardest hit economically and the most subject to profound disruption and restructuring during the current COVID-19 pandemic.

“In many centers, cancer care delivery has been disrupted and nonstandard therapies offered in an effort to minimize exposure of this high-risk group to the virus. The implications in appropriately balancing the urgency of cancer care and the threat of COVID-19 exposure in the pandemic are more complex,” the editorialists conclude.

Cone, Shapiro, and Van Metre Baum have disclosed no relevant financial relationships. This work won first prize in the Commission on Cancer 2020 Cancer Research Paper Competition and was virtually presented at the Commission on Cancer Plenary Session on October 30, 2020.

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

The COVID-19 pandemic has meant delays in cancer screening, diagnosis, and treatment — and a new study shows just how deadly delaying cancer treatment can be.

The study found evidence that longer time to starting treatment after diagnosis was generally associated with higher mortality across several common cancers, most notably for colon and early-stage lung cancer.

“There is a limit to how long we can safely defer treatment for cancer therapies, pandemic or not, which may be shorter than we think,” lead author Eugene Cone, MD, Combined Harvard Program in Urologic Oncology, Massachusetts General Hospital and Brigham & Women’s Hospital, Boston, told Medscape Medical News.

“When you consider that cancer screening may have been delayed during the pandemic, which would further increase the period between developing a disease and getting therapy, timely treatment for cancer has never been more important,” Cone added.

The study was published online December 14 in JAMA Network Open.
 

The sooner the better

Using the National Cancer Database, Cone and colleagues identified roughly 2.24 million patients diagnosed with nonmetastatic breast (52%), prostate (38%), colon (4%) and non-small cell lung cancer (NSCLC, 6%) between 2004 and 2015. Treatment and outcome data were analyzed from January to March 2020.

The time-to-treatment initiation (TTI) – the interval between cancer diagnosis and receipt of curative-intent therapy – was categorized as 8 to 60 days (reference), 61 to 120 days, 121 to 180 days, and 181 to 365 days. Median TTI was 32 days for breast, 79 days for prostate, 41 days for NSCLC, and 26 days for colon cancer.

All four cancers benefitted to some degree from a short interval between diagnosis and therapy, the researchers found.

Across all four cancers, increasing TTI was generally associated with higher predicted mortality at 5 and 10 years, although the degree varied by cancer type and stage. The most pronounced association between increasing TTI and mortality was observed for colon and lung cancer.

For example, for stage III colon cancer, 5- and 10-year predicted mortality was 38.9% and 54%, respectively, with TTI of 61 to 120 days, and increased to 47.8% and 63.8%, respectively, with TTI of 181 to 365 days.

Each additional 60-day delay was associated with a 3.2% to 6% increase in 5-year mortality for stage III colon cancer and a 0.9% to 4.6% increase for stage I colon cancer, with a longer 10-year time horizon showing larger effect sizes with increasing TTI.

For stage I NSCLC, 5- and 10-year predicted mortality was 47.4% and 72.6%, respectively, with TTI of 61 to 120 days compared with 47.6% and 72.8%, respectively, with TTI of 181 to 365 days.  

For stage I NSCLC, there was a 4% to 6.2% absolute increase in 5-year mortality for increased TTI groups compared with the 8- to 60-day reference group, with larger effect sizes on 10-year mortality. The data precluded conclusions about stage II NSCLC.

“For prostate cancer, deferral of treatment by even a few months was associated with a significant impact on mortality,” Cone told Medscape Medical News.

For high-risk prostate cancer, 5- and 10-year predicted mortality was 12.8% and 31.2%, respectively, with TTI of 61-120 days increasing to 14.1% and 33.8%, respectively with TTI at 181-365 days.

For intermediate-risk prostate cancer, 5- and 10-year predicted mortality was 7.4% and 20.4% with TTI of 61-120 days vs 8.3% and 22.6% with TTI at 181-365 days.

The data show all-cause mortality differences of 2.2% at 5 years and 4.6% at 10 years between high-risk prostate cancer patients who were treated expeditiously vs those waiting 4 to 6 months and differences of 0.9% at 5 years and 2.4% at 10 years for similar intermediate-risk patients.
 

No surprises

Turning to breast cancer, increased TTI was associated with the most negative survival effects for stage II and III breast cancer.

For stage II breast cancer, for example, 5- and 10-year predicted mortality was 17.7% and 30.5%, respectively, with TTI of 61-120 days vs 21.7% and 36.5% with TTI at 181-365 days. 

Even for stage I breast cancer patients, there were significant differences in all-cause mortality with delayed definitive therapy, although the effect size is clinically small, the researchers report.

Patients with stage IA or IB breast cancer who were not treated until 61 to 120 days after diagnosis had 1.3% and 2.3% increased mortality at 5 years and 10 years, respectively, and those waiting longer suffered even greater increases in mortality. “As such, our analysis underscores the importance of timely definitive treatment, even for stage I breast cancer,” the authors write.

Charles Shapiro, MD, director of translational breast cancer research for the Mount Sinai Health System, New York City, was not surprised by the data.

The observation that delays in initiating cancer treatment are associated with worse survival is “not new, as delays in primary surgical treatments and chemotherapy for early-stage disease is an adverse prognostic factor for clinical outcomes,” Shapiro told Medscape Medical News.

“The bottom line is primary surgery and the start of chemotherapy should probably occur as soon as clinically feasible,” said Shapiro, who was not involved in the study.

The authors of an accompanying editorial agree. 

This study supports avoiding unnecessary treatment delays and prioritizing timely cancer care, even during the COVID-19 pandemic, write Laura Van Metre Baum, MD, Division of Hematology and Oncology, Vanderbilt University, Nashville, Tennessee, and colleagues.

They note, however, that primary care, “the most important conduit for cancer screening and initial evaluation of new symptoms, has been the hardest hit economically and the most subject to profound disruption and restructuring during the current COVID-19 pandemic.

“In many centers, cancer care delivery has been disrupted and nonstandard therapies offered in an effort to minimize exposure of this high-risk group to the virus. The implications in appropriately balancing the urgency of cancer care and the threat of COVID-19 exposure in the pandemic are more complex,” the editorialists conclude.

Cone, Shapiro, and Van Metre Baum have disclosed no relevant financial relationships. This work won first prize in the Commission on Cancer 2020 Cancer Research Paper Competition and was virtually presented at the Commission on Cancer Plenary Session on October 30, 2020.

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

The COVID-19 pandemic has meant delays in cancer screening, diagnosis, and treatment — and a new study shows just how deadly delaying cancer treatment can be.

The study found evidence that longer time to starting treatment after diagnosis was generally associated with higher mortality across several common cancers, most notably for colon and early-stage lung cancer.

“There is a limit to how long we can safely defer treatment for cancer therapies, pandemic or not, which may be shorter than we think,” lead author Eugene Cone, MD, Combined Harvard Program in Urologic Oncology, Massachusetts General Hospital and Brigham & Women’s Hospital, Boston, told Medscape Medical News.

“When you consider that cancer screening may have been delayed during the pandemic, which would further increase the period between developing a disease and getting therapy, timely treatment for cancer has never been more important,” Cone added.

The study was published online December 14 in JAMA Network Open.
 

The sooner the better

Using the National Cancer Database, Cone and colleagues identified roughly 2.24 million patients diagnosed with nonmetastatic breast (52%), prostate (38%), colon (4%) and non-small cell lung cancer (NSCLC, 6%) between 2004 and 2015. Treatment and outcome data were analyzed from January to March 2020.

The time-to-treatment initiation (TTI) – the interval between cancer diagnosis and receipt of curative-intent therapy – was categorized as 8 to 60 days (reference), 61 to 120 days, 121 to 180 days, and 181 to 365 days. Median TTI was 32 days for breast, 79 days for prostate, 41 days for NSCLC, and 26 days for colon cancer.

All four cancers benefitted to some degree from a short interval between diagnosis and therapy, the researchers found.

Across all four cancers, increasing TTI was generally associated with higher predicted mortality at 5 and 10 years, although the degree varied by cancer type and stage. The most pronounced association between increasing TTI and mortality was observed for colon and lung cancer.

For example, for stage III colon cancer, 5- and 10-year predicted mortality was 38.9% and 54%, respectively, with TTI of 61 to 120 days, and increased to 47.8% and 63.8%, respectively, with TTI of 181 to 365 days.

Each additional 60-day delay was associated with a 3.2% to 6% increase in 5-year mortality for stage III colon cancer and a 0.9% to 4.6% increase for stage I colon cancer, with a longer 10-year time horizon showing larger effect sizes with increasing TTI.

For stage I NSCLC, 5- and 10-year predicted mortality was 47.4% and 72.6%, respectively, with TTI of 61 to 120 days compared with 47.6% and 72.8%, respectively, with TTI of 181 to 365 days.  

For stage I NSCLC, there was a 4% to 6.2% absolute increase in 5-year mortality for increased TTI groups compared with the 8- to 60-day reference group, with larger effect sizes on 10-year mortality. The data precluded conclusions about stage II NSCLC.

“For prostate cancer, deferral of treatment by even a few months was associated with a significant impact on mortality,” Cone told Medscape Medical News.

For high-risk prostate cancer, 5- and 10-year predicted mortality was 12.8% and 31.2%, respectively, with TTI of 61-120 days increasing to 14.1% and 33.8%, respectively with TTI at 181-365 days.

For intermediate-risk prostate cancer, 5- and 10-year predicted mortality was 7.4% and 20.4% with TTI of 61-120 days vs 8.3% and 22.6% with TTI at 181-365 days.

The data show all-cause mortality differences of 2.2% at 5 years and 4.6% at 10 years between high-risk prostate cancer patients who were treated expeditiously vs those waiting 4 to 6 months and differences of 0.9% at 5 years and 2.4% at 10 years for similar intermediate-risk patients.
 

No surprises

Turning to breast cancer, increased TTI was associated with the most negative survival effects for stage II and III breast cancer.

For stage II breast cancer, for example, 5- and 10-year predicted mortality was 17.7% and 30.5%, respectively, with TTI of 61-120 days vs 21.7% and 36.5% with TTI at 181-365 days. 

Even for stage I breast cancer patients, there were significant differences in all-cause mortality with delayed definitive therapy, although the effect size is clinically small, the researchers report.

Patients with stage IA or IB breast cancer who were not treated until 61 to 120 days after diagnosis had 1.3% and 2.3% increased mortality at 5 years and 10 years, respectively, and those waiting longer suffered even greater increases in mortality. “As such, our analysis underscores the importance of timely definitive treatment, even for stage I breast cancer,” the authors write.

Charles Shapiro, MD, director of translational breast cancer research for the Mount Sinai Health System, New York City, was not surprised by the data.

The observation that delays in initiating cancer treatment are associated with worse survival is “not new, as delays in primary surgical treatments and chemotherapy for early-stage disease is an adverse prognostic factor for clinical outcomes,” Shapiro told Medscape Medical News.

“The bottom line is primary surgery and the start of chemotherapy should probably occur as soon as clinically feasible,” said Shapiro, who was not involved in the study.

The authors of an accompanying editorial agree. 

This study supports avoiding unnecessary treatment delays and prioritizing timely cancer care, even during the COVID-19 pandemic, write Laura Van Metre Baum, MD, Division of Hematology and Oncology, Vanderbilt University, Nashville, Tennessee, and colleagues.

They note, however, that primary care, “the most important conduit for cancer screening and initial evaluation of new symptoms, has been the hardest hit economically and the most subject to profound disruption and restructuring during the current COVID-19 pandemic.

“In many centers, cancer care delivery has been disrupted and nonstandard therapies offered in an effort to minimize exposure of this high-risk group to the virus. The implications in appropriately balancing the urgency of cancer care and the threat of COVID-19 exposure in the pandemic are more complex,” the editorialists conclude.

Cone, Shapiro, and Van Metre Baum have disclosed no relevant financial relationships. This work won first prize in the Commission on Cancer 2020 Cancer Research Paper Competition and was virtually presented at the Commission on Cancer Plenary Session on October 30, 2020.

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

Mr. S, age 64, presents for an outpatient follow-up after a recent hospital discharge for alcohol detoxification. He reports a long history of alcohol use, which has resulted in numerous hospital admissions. He has recently been receiving care from a gastroenterologist because the results of laboratory testing suggested hepatic impairment (Table 1). Mr. S says that a friend of his was able to stop drinking by taking a medication, and he wonders if he can be prescribed a medication to help him as well.

A chart review shows that Mr. S recently underwent paracentesis, during which 6 liters of fluid were removed. Additionally, an abdominal ultrasound confirmed hepatic cirrhosis.

According to the World Health Organization, alcohol consumption contributes to 3 million deaths annually.² The highest proportion of these deaths (21.3%) is due to alcohol-associated gastrointestinal complications, including alcoholic and infectious hepatitis, pancreatitis, and cirrhosis. Because the liver is the primary site of ethanol metabolism, it sustains the greatest degree of tissue injury with heavy alcohol consumption. Additionally, the association of harmful use of alcohol with risky sexual behavior may partially explain the higher prevalence of viral hepatitis among persons with alcohol use disorder (AUD) compared with the general population. Alcoholic liver disease (ALD) progresses through several stages, beginning with hepatic steatosis and progressing through alcohol-related hepatitis, fibrosis, cirrhosis, and potentially hepatocellular carcinoma.³

Liver markers of alcohol use

Although biological markers can be used in clinical practice to screen and monitor for alcohol abuse, making a diagnosis of ALD can be challenging. Typically, a history of heavy alcohol consumption in addition to certain physical signs and laboratory tests for liver disease are the best indicators of ALD. However, the clinical assessment can be confounded by patients who deny or minimize how much alcohol they have consumed. Furthermore, physical and laboratory findings may not be specific to ALD.

Liver enzymes, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyltransferase (GGT), have historically been used as the basis of diagnosing ALD. In addition to elevated bilirubin and evidence of macrocytic anemia, elevations in these enzymes may suggest heavy alcohol use, but these values alone are inadequate to establish ALD. Gamma-glutamyltransferase is found in cell membranes of several body tissues, including the liver and spleen, and therefore is not specific to liver damage. However, elevated GGT is the best indicator of excessive alcohol consumption because it has greater sensitivity than AST and ALT.^1,3,4

Although these biomarkers are helpful in diagnosing ALD, they lose some of their utility in patients with advanced liver disease. Patients with severe liver dysfunction may not have elevated serum aminotransferase levels because the degree of liver enzyme elevation does not correlate well with the severity of ALD. For example, patients with advanced cirrhosis may have liver enzyme levels that appear normal. However, the pattern of elevation in transaminases can be helpful in making a diagnosis of liver dysfunction; using the ratio of AST to ALT may aid in diagnosing ALD, because AST is elevated more than twice that of ALT in >80% of patients with ALD.^1,3,4

Table 2^1,3,4 shows the progression of ALD from steatohepatitis to alcoholic hepatitis to cirrhosis. In steatohepatitis, transaminitis is present but all other biomarkers normal. In alcoholic hepatitis, transaminitis is present along with elevated alkaline phosphatase, elevated bilirubin, and elevated international normalized ratio (INR). In alcoholic cirrhosis, the AST-to-ALT ratio is >2, and hypoalbuminemia, hyperbilirubinemia, and coagulopathy (evidenced by elevated INR) are present, consistent with long-term liver damage.^1,3,4

Continue to: FDA-approved medications

FDA-approved medications

Three medications—acamprosate, naltrexone, and disulfiram—currently are FDA-approved for treating AUD.^5,6 Additionally, several other medications have shown varying levels of efficacy in treating patients with AUD but are not FDA-approved for this indication (Table 3).^5-8

Acamprosate is thought to create a balance of inhibitor and excitatory neurotransmitters by functioning as a glutamate antagonist and gamma-aminobutyric acid (GABA) agonist. This is speculated to aid in abstinence from alcohol. Data suggests that acamprosate may be more effective for maintaining abstinence than for inducing remission in individuals who have not yet detoxified from alcohol. Because of its renal excretion, acamprosate is the only FDA-approved medication for AUD that is not associated with liver toxicity. The most commonly reported adverse effect with acamprosate use is diarrhea.

Naltrexone, a mu-opioid receptor antagonist, is available in both tablet and long-acting IM injection formulations. Naltrexone blocks the binding of endorphins created by alcohol consumption to opioid receptors. This results in diminished dopamine release and is speculated to decrease reward and positive reinforcement with alcohol consumption, leading to fewer heavy drinking days. Due to hepatic metabolism, naltrexone use carries a risk of liver injury. Cases of hepatitis and clinically significant liver dysfunction as well as transient, asymptomatic, hepatic transaminase elevations have been observed in patients who receive naltrexone. Because of the absence of first-pass metabolism, long-acting IM naltrexone may produce less hepatotoxicity than the oral formulation. When the FDA approved both formulations of naltrexone, a “black-box” warning was issued concerning the risk of liver damage; however, these warnings have since been removed from their respective prescribing information.

Disulfiram inhibits acetaldehyde dehydrogenase, resulting in elevated acetaldehyde concentrations after consuming alcohol. In theory, this medication reduces a person’s desire to drink due to the negative physiological and physical effects associated with increased acetaldehyde, including hypotension, flushing, nausea, and vomiting. Although most of these reactions are short-lived, disulfiram can induce hepatotoxicity and liver failure that may prove fatal. Disulfiram should be avoided in patients with advanced ALD.

Off-label medications for AUD

Additional pharmacotherapeutic agents have been evaluated in patients with AUD. Baclofen, topiramate, gabapentin, and ondansetron have shown varying levels of efficacy and pose minimal concern in patients with ALD.

Continue to: Baclofen

Baclofen. Although findings are conflicting, baclofen is the only agent that has been specifically studied for treating AUD in patients with ALD. A GABA B receptor antagonist, baclofen is currently FDA-approved for treating spasticity. In a series of open-label and double-blind studies, baclofen has been shown to effectively reduce alcohol intake, promote abstinence, and prevent relapse.^5,6 Further studies identified a possible dose-related response, noting that 20 mg taken 3 times daily may confer additional response over 10 mg taken 3 times daily.^5,6 Conversely, the ALPADIR study failed to demonstrate superiority of baclofen vs placebo in the maintenance of abstinence from alcohol despite dosing at 180 mg/d.⁹ This study did, however, find a significant reduction in alcohol craving in favor of baclofen.⁹ Further, in a randomized controlled trial (RCT) conducted in veterans with chronic hepatitis C, baclofen 30 mg/d failed to show superiority over placebo with regard to increasing abstinence or reducing alcohol use.¹⁰

Topiramate. A recent meta-analysis found that topiramate use may result in fewer drinking days, heavy drinking days, and number of drinks per drinking day.⁷ Additionally, topiramate has demonstrated a statistically significant reduction in alcohol craving as well as the ability to decrease all liver function test values.⁵ This agent should be used with caution in patients with hepatic encephalopathy because the adverse cognitive effects associated with topiramate may confound the clinical course and treatment of such.

Gabapentin. The use of gabapentin to treat patients with AUD is supported by multiple RCTs. In studies that evaluated dose-related response, higher doses of gabapentin (up to 1,800 mg/d) showed greater efficacy than lower doses (ie, 900 mg/d).⁸ Because gabapentin does not undergo hepatic metabolism, its use in patients with ALD is considered safe. Although the abuse potential of gabapentin is less defined in patients with AUD, there have been reports of abuse in other high-risk populations (ie, those with opioid use disorder, incarcerated persons, and those who misuse prescriptions recreationally).⁸

Ondansetron is speculated to decrease the reward from alcohol via the down-regulation of dopaminergic neurons. Studies examining ondansetron for patients with AUD have found that it decreases alcohol cravings in those with early-onset alcoholism (initial onset at age ≤25), but not in late-onset alcoholism (initial onset at age >25).⁵ However, the ondansetron doses used in these trials were very low (4 mcg/kg), and those doses are not available commercially.⁵

CASE CONTINUED

Following a discussion of available pharma­cotherapeutic options for AUD, Mr. S is started on baclofen, 10 mg 3 times daily, with plans for dose titration. At a 2-week follow-up appointment, Mr. S reports that he had not been taking baclofen as often as instructed; however, he denies further alcohol consumption and re-commits to baclofen treatment. Unfortunately, Mr. S is soon admitted to hospice care due to continued decompensation and is unable to attend any additional outpatient follow-up appointments. Three months after his initial outpatient contact, Mr. S dies due to alcoholic cirrhosis.

Related Resources

• Crabb DW, Im GY, Szabo G, et al. Diagnosis and treatment of alcohol-related liver diseases: 2019 practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2020;71(1):306-333.
• Murail AR, Carey WD. Disease management. Liver test interpretation - approach to the patient with liver disease: a guide to commonly used liver tests. Cleveland Clinic Center for Continuing Education. Updated August 2017. www.clevelandclinicmeded. com/medicalpubs/diseasemanagement/hepatology/ guide-to-common-liver-tests/

Drug Brand Names

Acamprosate • Campral
Baclofen • Lioresal
Disulfiram • Antabuse
Gabapentin • Neurontin
Naltrexone • Revia, Vivitrol
Ondansetron • Zofran
Topiramate • Topamax

Mr. S, age 64, presents for an outpatient follow-up after a recent hospital discharge for alcohol detoxification. He reports a long history of alcohol use, which has resulted in numerous hospital admissions. He has recently been receiving care from a gastroenterologist because the results of laboratory testing suggested hepatic impairment (Table 1). Mr. S says that a friend of his was able to stop drinking by taking a medication, and he wonders if he can be prescribed a medication to help him as well.

A chart review shows that Mr. S recently underwent paracentesis, during which 6 liters of fluid were removed. Additionally, an abdominal ultrasound confirmed hepatic cirrhosis.

According to the World Health Organization, alcohol consumption contributes to 3 million deaths annually.² The highest proportion of these deaths (21.3%) is due to alcohol-associated gastrointestinal complications, including alcoholic and infectious hepatitis, pancreatitis, and cirrhosis. Because the liver is the primary site of ethanol metabolism, it sustains the greatest degree of tissue injury with heavy alcohol consumption. Additionally, the association of harmful use of alcohol with risky sexual behavior may partially explain the higher prevalence of viral hepatitis among persons with alcohol use disorder (AUD) compared with the general population. Alcoholic liver disease (ALD) progresses through several stages, beginning with hepatic steatosis and progressing through alcohol-related hepatitis, fibrosis, cirrhosis, and potentially hepatocellular carcinoma.³

Liver markers of alcohol use

Although biological markers can be used in clinical practice to screen and monitor for alcohol abuse, making a diagnosis of ALD can be challenging. Typically, a history of heavy alcohol consumption in addition to certain physical signs and laboratory tests for liver disease are the best indicators of ALD. However, the clinical assessment can be confounded by patients who deny or minimize how much alcohol they have consumed. Furthermore, physical and laboratory findings may not be specific to ALD.

Liver enzymes, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyltransferase (GGT), have historically been used as the basis of diagnosing ALD. In addition to elevated bilirubin and evidence of macrocytic anemia, elevations in these enzymes may suggest heavy alcohol use, but these values alone are inadequate to establish ALD. Gamma-glutamyltransferase is found in cell membranes of several body tissues, including the liver and spleen, and therefore is not specific to liver damage. However, elevated GGT is the best indicator of excessive alcohol consumption because it has greater sensitivity than AST and ALT.^1,3,4

Although these biomarkers are helpful in diagnosing ALD, they lose some of their utility in patients with advanced liver disease. Patients with severe liver dysfunction may not have elevated serum aminotransferase levels because the degree of liver enzyme elevation does not correlate well with the severity of ALD. For example, patients with advanced cirrhosis may have liver enzyme levels that appear normal. However, the pattern of elevation in transaminases can be helpful in making a diagnosis of liver dysfunction; using the ratio of AST to ALT may aid in diagnosing ALD, because AST is elevated more than twice that of ALT in >80% of patients with ALD.^1,3,4

Table 2^1,3,4 shows the progression of ALD from steatohepatitis to alcoholic hepatitis to cirrhosis. In steatohepatitis, transaminitis is present but all other biomarkers normal. In alcoholic hepatitis, transaminitis is present along with elevated alkaline phosphatase, elevated bilirubin, and elevated international normalized ratio (INR). In alcoholic cirrhosis, the AST-to-ALT ratio is >2, and hypoalbuminemia, hyperbilirubinemia, and coagulopathy (evidenced by elevated INR) are present, consistent with long-term liver damage.^1,3,4

Continue to: FDA-approved medications

FDA-approved medications

Three medications—acamprosate, naltrexone, and disulfiram—currently are FDA-approved for treating AUD.^5,6 Additionally, several other medications have shown varying levels of efficacy in treating patients with AUD but are not FDA-approved for this indication (Table 3).^5-8

Acamprosate is thought to create a balance of inhibitor and excitatory neurotransmitters by functioning as a glutamate antagonist and gamma-aminobutyric acid (GABA) agonist. This is speculated to aid in abstinence from alcohol. Data suggests that acamprosate may be more effective for maintaining abstinence than for inducing remission in individuals who have not yet detoxified from alcohol. Because of its renal excretion, acamprosate is the only FDA-approved medication for AUD that is not associated with liver toxicity. The most commonly reported adverse effect with acamprosate use is diarrhea.

Naltrexone, a mu-opioid receptor antagonist, is available in both tablet and long-acting IM injection formulations. Naltrexone blocks the binding of endorphins created by alcohol consumption to opioid receptors. This results in diminished dopamine release and is speculated to decrease reward and positive reinforcement with alcohol consumption, leading to fewer heavy drinking days. Due to hepatic metabolism, naltrexone use carries a risk of liver injury. Cases of hepatitis and clinically significant liver dysfunction as well as transient, asymptomatic, hepatic transaminase elevations have been observed in patients who receive naltrexone. Because of the absence of first-pass metabolism, long-acting IM naltrexone may produce less hepatotoxicity than the oral formulation. When the FDA approved both formulations of naltrexone, a “black-box” warning was issued concerning the risk of liver damage; however, these warnings have since been removed from their respective prescribing information.

Disulfiram inhibits acetaldehyde dehydrogenase, resulting in elevated acetaldehyde concentrations after consuming alcohol. In theory, this medication reduces a person’s desire to drink due to the negative physiological and physical effects associated with increased acetaldehyde, including hypotension, flushing, nausea, and vomiting. Although most of these reactions are short-lived, disulfiram can induce hepatotoxicity and liver failure that may prove fatal. Disulfiram should be avoided in patients with advanced ALD.

Off-label medications for AUD

Additional pharmacotherapeutic agents have been evaluated in patients with AUD. Baclofen, topiramate, gabapentin, and ondansetron have shown varying levels of efficacy and pose minimal concern in patients with ALD.

Continue to: Baclofen

Baclofen. Although findings are conflicting, baclofen is the only agent that has been specifically studied for treating AUD in patients with ALD. A GABA B receptor antagonist, baclofen is currently FDA-approved for treating spasticity. In a series of open-label and double-blind studies, baclofen has been shown to effectively reduce alcohol intake, promote abstinence, and prevent relapse.^5,6 Further studies identified a possible dose-related response, noting that 20 mg taken 3 times daily may confer additional response over 10 mg taken 3 times daily.^5,6 Conversely, the ALPADIR study failed to demonstrate superiority of baclofen vs placebo in the maintenance of abstinence from alcohol despite dosing at 180 mg/d.⁹ This study did, however, find a significant reduction in alcohol craving in favor of baclofen.⁹ Further, in a randomized controlled trial (RCT) conducted in veterans with chronic hepatitis C, baclofen 30 mg/d failed to show superiority over placebo with regard to increasing abstinence or reducing alcohol use.¹⁰

Topiramate. A recent meta-analysis found that topiramate use may result in fewer drinking days, heavy drinking days, and number of drinks per drinking day.⁷ Additionally, topiramate has demonstrated a statistically significant reduction in alcohol craving as well as the ability to decrease all liver function test values.⁵ This agent should be used with caution in patients with hepatic encephalopathy because the adverse cognitive effects associated with topiramate may confound the clinical course and treatment of such.

Gabapentin. The use of gabapentin to treat patients with AUD is supported by multiple RCTs. In studies that evaluated dose-related response, higher doses of gabapentin (up to 1,800 mg/d) showed greater efficacy than lower doses (ie, 900 mg/d).⁸ Because gabapentin does not undergo hepatic metabolism, its use in patients with ALD is considered safe. Although the abuse potential of gabapentin is less defined in patients with AUD, there have been reports of abuse in other high-risk populations (ie, those with opioid use disorder, incarcerated persons, and those who misuse prescriptions recreationally).⁸

Ondansetron is speculated to decrease the reward from alcohol via the down-regulation of dopaminergic neurons. Studies examining ondansetron for patients with AUD have found that it decreases alcohol cravings in those with early-onset alcoholism (initial onset at age ≤25), but not in late-onset alcoholism (initial onset at age >25).⁵ However, the ondansetron doses used in these trials were very low (4 mcg/kg), and those doses are not available commercially.⁵

CASE CONTINUED

Following a discussion of available pharma­cotherapeutic options for AUD, Mr. S is started on baclofen, 10 mg 3 times daily, with plans for dose titration. At a 2-week follow-up appointment, Mr. S reports that he had not been taking baclofen as often as instructed; however, he denies further alcohol consumption and re-commits to baclofen treatment. Unfortunately, Mr. S is soon admitted to hospice care due to continued decompensation and is unable to attend any additional outpatient follow-up appointments. Three months after his initial outpatient contact, Mr. S dies due to alcoholic cirrhosis.

Related Resources

• Crabb DW, Im GY, Szabo G, et al. Diagnosis and treatment of alcohol-related liver diseases: 2019 practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2020;71(1):306-333.
• Murail AR, Carey WD. Disease management. Liver test interpretation - approach to the patient with liver disease: a guide to commonly used liver tests. Cleveland Clinic Center for Continuing Education. Updated August 2017. www.clevelandclinicmeded. com/medicalpubs/diseasemanagement/hepatology/ guide-to-common-liver-tests/

Drug Brand Names

Acamprosate • Campral
Baclofen • Lioresal
Disulfiram • Antabuse
Gabapentin • Neurontin
Naltrexone • Revia, Vivitrol
Ondansetron • Zofran
Topiramate • Topamax

Mr. S, age 64, presents for an outpatient follow-up after a recent hospital discharge for alcohol detoxification. He reports a long history of alcohol use, which has resulted in numerous hospital admissions. He has recently been receiving care from a gastroenterologist because the results of laboratory testing suggested hepatic impairment (Table 1). Mr. S says that a friend of his was able to stop drinking by taking a medication, and he wonders if he can be prescribed a medication to help him as well.

A chart review shows that Mr. S recently underwent paracentesis, during which 6 liters of fluid were removed. Additionally, an abdominal ultrasound confirmed hepatic cirrhosis.

According to the World Health Organization, alcohol consumption contributes to 3 million deaths annually.² The highest proportion of these deaths (21.3%) is due to alcohol-associated gastrointestinal complications, including alcoholic and infectious hepatitis, pancreatitis, and cirrhosis. Because the liver is the primary site of ethanol metabolism, it sustains the greatest degree of tissue injury with heavy alcohol consumption. Additionally, the association of harmful use of alcohol with risky sexual behavior may partially explain the higher prevalence of viral hepatitis among persons with alcohol use disorder (AUD) compared with the general population. Alcoholic liver disease (ALD) progresses through several stages, beginning with hepatic steatosis and progressing through alcohol-related hepatitis, fibrosis, cirrhosis, and potentially hepatocellular carcinoma.³

Liver markers of alcohol use

Although biological markers can be used in clinical practice to screen and monitor for alcohol abuse, making a diagnosis of ALD can be challenging. Typically, a history of heavy alcohol consumption in addition to certain physical signs and laboratory tests for liver disease are the best indicators of ALD. However, the clinical assessment can be confounded by patients who deny or minimize how much alcohol they have consumed. Furthermore, physical and laboratory findings may not be specific to ALD.

Liver enzymes, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyltransferase (GGT), have historically been used as the basis of diagnosing ALD. In addition to elevated bilirubin and evidence of macrocytic anemia, elevations in these enzymes may suggest heavy alcohol use, but these values alone are inadequate to establish ALD. Gamma-glutamyltransferase is found in cell membranes of several body tissues, including the liver and spleen, and therefore is not specific to liver damage. However, elevated GGT is the best indicator of excessive alcohol consumption because it has greater sensitivity than AST and ALT.^1,3,4

Although these biomarkers are helpful in diagnosing ALD, they lose some of their utility in patients with advanced liver disease. Patients with severe liver dysfunction may not have elevated serum aminotransferase levels because the degree of liver enzyme elevation does not correlate well with the severity of ALD. For example, patients with advanced cirrhosis may have liver enzyme levels that appear normal. However, the pattern of elevation in transaminases can be helpful in making a diagnosis of liver dysfunction; using the ratio of AST to ALT may aid in diagnosing ALD, because AST is elevated more than twice that of ALT in >80% of patients with ALD.^1,3,4

Table 2^1,3,4 shows the progression of ALD from steatohepatitis to alcoholic hepatitis to cirrhosis. In steatohepatitis, transaminitis is present but all other biomarkers normal. In alcoholic hepatitis, transaminitis is present along with elevated alkaline phosphatase, elevated bilirubin, and elevated international normalized ratio (INR). In alcoholic cirrhosis, the AST-to-ALT ratio is >2, and hypoalbuminemia, hyperbilirubinemia, and coagulopathy (evidenced by elevated INR) are present, consistent with long-term liver damage.^1,3,4

Continue to: FDA-approved medications

FDA-approved medications

Three medications—acamprosate, naltrexone, and disulfiram—currently are FDA-approved for treating AUD.^5,6 Additionally, several other medications have shown varying levels of efficacy in treating patients with AUD but are not FDA-approved for this indication (Table 3).^5-8

Acamprosate is thought to create a balance of inhibitor and excitatory neurotransmitters by functioning as a glutamate antagonist and gamma-aminobutyric acid (GABA) agonist. This is speculated to aid in abstinence from alcohol. Data suggests that acamprosate may be more effective for maintaining abstinence than for inducing remission in individuals who have not yet detoxified from alcohol. Because of its renal excretion, acamprosate is the only FDA-approved medication for AUD that is not associated with liver toxicity. The most commonly reported adverse effect with acamprosate use is diarrhea.

Naltrexone, a mu-opioid receptor antagonist, is available in both tablet and long-acting IM injection formulations. Naltrexone blocks the binding of endorphins created by alcohol consumption to opioid receptors. This results in diminished dopamine release and is speculated to decrease reward and positive reinforcement with alcohol consumption, leading to fewer heavy drinking days. Due to hepatic metabolism, naltrexone use carries a risk of liver injury. Cases of hepatitis and clinically significant liver dysfunction as well as transient, asymptomatic, hepatic transaminase elevations have been observed in patients who receive naltrexone. Because of the absence of first-pass metabolism, long-acting IM naltrexone may produce less hepatotoxicity than the oral formulation. When the FDA approved both formulations of naltrexone, a “black-box” warning was issued concerning the risk of liver damage; however, these warnings have since been removed from their respective prescribing information.

Disulfiram inhibits acetaldehyde dehydrogenase, resulting in elevated acetaldehyde concentrations after consuming alcohol. In theory, this medication reduces a person’s desire to drink due to the negative physiological and physical effects associated with increased acetaldehyde, including hypotension, flushing, nausea, and vomiting. Although most of these reactions are short-lived, disulfiram can induce hepatotoxicity and liver failure that may prove fatal. Disulfiram should be avoided in patients with advanced ALD.

Off-label medications for AUD

Additional pharmacotherapeutic agents have been evaluated in patients with AUD. Baclofen, topiramate, gabapentin, and ondansetron have shown varying levels of efficacy and pose minimal concern in patients with ALD.

Continue to: Baclofen

Baclofen. Although findings are conflicting, baclofen is the only agent that has been specifically studied for treating AUD in patients with ALD. A GABA B receptor antagonist, baclofen is currently FDA-approved for treating spasticity. In a series of open-label and double-blind studies, baclofen has been shown to effectively reduce alcohol intake, promote abstinence, and prevent relapse.^5,6 Further studies identified a possible dose-related response, noting that 20 mg taken 3 times daily may confer additional response over 10 mg taken 3 times daily.^5,6 Conversely, the ALPADIR study failed to demonstrate superiority of baclofen vs placebo in the maintenance of abstinence from alcohol despite dosing at 180 mg/d.⁹ This study did, however, find a significant reduction in alcohol craving in favor of baclofen.⁹ Further, in a randomized controlled trial (RCT) conducted in veterans with chronic hepatitis C, baclofen 30 mg/d failed to show superiority over placebo with regard to increasing abstinence or reducing alcohol use.¹⁰

Topiramate. A recent meta-analysis found that topiramate use may result in fewer drinking days, heavy drinking days, and number of drinks per drinking day.⁷ Additionally, topiramate has demonstrated a statistically significant reduction in alcohol craving as well as the ability to decrease all liver function test values.⁵ This agent should be used with caution in patients with hepatic encephalopathy because the adverse cognitive effects associated with topiramate may confound the clinical course and treatment of such.

Gabapentin. The use of gabapentin to treat patients with AUD is supported by multiple RCTs. In studies that evaluated dose-related response, higher doses of gabapentin (up to 1,800 mg/d) showed greater efficacy than lower doses (ie, 900 mg/d).⁸ Because gabapentin does not undergo hepatic metabolism, its use in patients with ALD is considered safe. Although the abuse potential of gabapentin is less defined in patients with AUD, there have been reports of abuse in other high-risk populations (ie, those with opioid use disorder, incarcerated persons, and those who misuse prescriptions recreationally).⁸

Ondansetron is speculated to decrease the reward from alcohol via the down-regulation of dopaminergic neurons. Studies examining ondansetron for patients with AUD have found that it decreases alcohol cravings in those with early-onset alcoholism (initial onset at age ≤25), but not in late-onset alcoholism (initial onset at age >25).⁵ However, the ondansetron doses used in these trials were very low (4 mcg/kg), and those doses are not available commercially.⁵

CASE CONTINUED

Following a discussion of available pharma­cotherapeutic options for AUD, Mr. S is started on baclofen, 10 mg 3 times daily, with plans for dose titration. At a 2-week follow-up appointment, Mr. S reports that he had not been taking baclofen as often as instructed; however, he denies further alcohol consumption and re-commits to baclofen treatment. Unfortunately, Mr. S is soon admitted to hospice care due to continued decompensation and is unable to attend any additional outpatient follow-up appointments. Three months after his initial outpatient contact, Mr. S dies due to alcoholic cirrhosis.

Related Resources

• Crabb DW, Im GY, Szabo G, et al. Diagnosis and treatment of alcohol-related liver diseases: 2019 practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2020;71(1):306-333.
• Murail AR, Carey WD. Disease management. Liver test interpretation - approach to the patient with liver disease: a guide to commonly used liver tests. Cleveland Clinic Center for Continuing Education. Updated August 2017. www.clevelandclinicmeded. com/medicalpubs/diseasemanagement/hepatology/ guide-to-common-liver-tests/

Drug Brand Names

Acamprosate • Campral
Baclofen • Lioresal
Disulfiram • Antabuse
Gabapentin • Neurontin
Naltrexone • Revia, Vivitrol
Ondansetron • Zofran
Topiramate • Topamax

Newer therapies for actinic keratoses (AKs) are expected to provide high rates of skin clearance with high rates of local skin reactions, according to an expert speaking at the annual Coastal Dermatology Symposium, held virtually.

This relationship is not new. In a review of treatments for AKs, Neal Bhatia, MD, a dermatologist and researcher at Therapeutics Dermatology, San Diego, advised that most effective agents trade a higher risk of inflammatory reactions – including erythema, flaking, and scaling – for greater therapeutic gain. In many cases, local skin reactions are an inevitable consequence of their mechanism of action.

Data from the completed phase 3 trials of tirbanibulin 1% ointment (KX01-AK-003 and KX01-AK-004), are illustrative. (Tirbanibulin 1% ointment was approved by the Food and Drug Administration in mid-December, after the Coastal Derm meeting was held.)

In the phase 3 trials, which have not yet been published, tirbanibulin, an inhibitor of Src kinase, which has an antiproliferative action, was four to five times more effective than vehicle by day 57 for overall complete clearance (P < .0001) of AKs and complete clearance of the face (P < .0001), but rates of local skin reactions were generally two to three times higher, according to Dr. Bhatia.

In the KX01-AK-004 trial, for example, 61% of patients had complete clearance of the face, versus 14% of those randomized to vehicle. The difference for overall partial clearance (76% vs. 20%; P < .0001), partial clearance of the face (80% vs. 22%; P < .0001), and partial clearance of the scalp (69% vs. 15%; P < .0001) was even greater. When compared with placebo, tirbanibulin was also associated with greater rates of erythema (90% vs. 31%), crusting (45% vs. 8%), flaking (84% vs. 35%), swelling (38% vs. 2%) and erosions or ulcers (12% vs. 1%).

Although these events might be a challenge with regard to tolerability for some patients, they might best be described as evidence that the drug is working.

“Local skin reactions are anticipated. They are not adverse events. They are not side effects,” Dr. Bhatia said at the meeting, jointly presented by the University of Louisville and Global Academy for Medical Education. “Patients are going to get red, and you need to counsel patients about the 5 days when they can expected to be red. It is a sign of the civil war, if you will, that your skin is taking on with the actinic keratoses.”

Both 3- and 5-day courses of the drug were tested in the clinical trials. (The approved prescribing information recommends treatment on the face or scalp once a day for 5 consecutive days).

Other studies evaluating treatments for AKs have also associated an increased risk of local skin reactions with greater efficacy, Dr. Bhatia noted. As an example, he cited a phase 4 study comparing 0.015% ingenol mebutate gel to diclofenac sodium 3% gel in people with facial and scalp AK lesions.

At the end of the 3-month study, complete clearance was higher among those on ingenol mebutate, which was applied for 3 days, when compared with diclofenac sodium gel, which was applied daily for 3 months (34% vs. 23%; P = .006). However, patients randomized to ingenol mebutate gel had to first weather a higher rate of application-site erythema (19% vs. 12%) before achieving a greater level of clearance.

The correlation between efficacy and local reactions at the site of treatment application emphasizes the importance of educating patients about this relationship and in engaging in shared decision-making, Dr. Bhatia said.

“It is basically a tradeoff between local skin reactions, between frequency [of applications], compliance, and, of course, duration of therapy, even though both drugs served their purposes well,” said Dr. Bhatia, referring to the comparison of the ingenol mebutate and diclofenac gels.

Although not absolute, efficacy and tolerability were also generally inversely related in a recent four-treatment comparison of four commonly used field-directed therapies. In that trial, the primary endpoint was at least a 75% reduction from baseline in the number of AKs to 12 months after treatment ended.

For that outcome, 5% fluorouracil (5-FU) cream (74.7%) was significantly more effective than 5% imiquimod cream (53.9%), methyl aminolevulinate photodynamic therapy (37.7%), and 0.015% ingenol mebutate gel (28.9%). Also, 5-FU treatment was associated with the moderate or severe erythema (81.5%), severe pain (16.%), and a severe burning sensation (21.5%).

Other therapies on the horizon, some of which are already available in Europe or Canada, show a relationship between efficacy and local skin reactions. Of two that Dr. Bhatia cited, 5-FU and salicylic acid combined in a solution and 5-FU and calcipotriene combined in an ointment have demonstrated high rates of efficacy but at the cost of substantial rates of erythema and flaking.

Transient skin reactions can be made acceptable to patients who are informed of the goals of clearing AKs, which includes lowering the risk of cancer, as well as cosmetic improvement. In the phase 4 study comparing ingenol mebutate gel to diclofenac sodium gel, the end-of-study global satisfaction rates were higher (P < .001) for those randomized to the most effective therapy despite the local skin reactions.

Preparing patients for the consequences of therapy for AKs is essential, because optimal therapy involves treating uninvolved skin, according to Hassan Galadari, MD, assistant professor of dermatology, United Arab Emirates University, Dubai. A coauthor of a recent review article on actinic keratoses, Dr. Galadari said in an interview that field treatment means patients might have local skin reactions where they did not previously have lesions.

“Actinic damage may not be visible with the naked eye. That is why field treatment, which is applying medicine in adjacent areas that may appear normal, is indicated,” he said. As a result, “areas that otherwise may have appeared as normal start to react by becoming red, itchy, and even inflamed.”

He agreed with Dr. Bhatia that local skin reactions are typically the price paid for effective control of these precancerous lesions.

This publication and Global Academy for Medical Education are owned by the same parent company.

Dr. Bhatia reports financial relationships with more than 30 pharmaceutical companies with dermatologic products, including Almirall and other companies with products relevant to AK therapies.

Newer therapies for actinic keratoses (AKs) are expected to provide high rates of skin clearance with high rates of local skin reactions, according to an expert speaking at the annual Coastal Dermatology Symposium, held virtually.

This relationship is not new. In a review of treatments for AKs, Neal Bhatia, MD, a dermatologist and researcher at Therapeutics Dermatology, San Diego, advised that most effective agents trade a higher risk of inflammatory reactions – including erythema, flaking, and scaling – for greater therapeutic gain. In many cases, local skin reactions are an inevitable consequence of their mechanism of action.

Data from the completed phase 3 trials of tirbanibulin 1% ointment (KX01-AK-003 and KX01-AK-004), are illustrative. (Tirbanibulin 1% ointment was approved by the Food and Drug Administration in mid-December, after the Coastal Derm meeting was held.)

In the phase 3 trials, which have not yet been published, tirbanibulin, an inhibitor of Src kinase, which has an antiproliferative action, was four to five times more effective than vehicle by day 57 for overall complete clearance (P < .0001) of AKs and complete clearance of the face (P < .0001), but rates of local skin reactions were generally two to three times higher, according to Dr. Bhatia.

In the KX01-AK-004 trial, for example, 61% of patients had complete clearance of the face, versus 14% of those randomized to vehicle. The difference for overall partial clearance (76% vs. 20%; P < .0001), partial clearance of the face (80% vs. 22%; P < .0001), and partial clearance of the scalp (69% vs. 15%; P < .0001) was even greater. When compared with placebo, tirbanibulin was also associated with greater rates of erythema (90% vs. 31%), crusting (45% vs. 8%), flaking (84% vs. 35%), swelling (38% vs. 2%) and erosions or ulcers (12% vs. 1%).

Although these events might be a challenge with regard to tolerability for some patients, they might best be described as evidence that the drug is working.

“Local skin reactions are anticipated. They are not adverse events. They are not side effects,” Dr. Bhatia said at the meeting, jointly presented by the University of Louisville and Global Academy for Medical Education. “Patients are going to get red, and you need to counsel patients about the 5 days when they can expected to be red. It is a sign of the civil war, if you will, that your skin is taking on with the actinic keratoses.”

Both 3- and 5-day courses of the drug were tested in the clinical trials. (The approved prescribing information recommends treatment on the face or scalp once a day for 5 consecutive days).

Other studies evaluating treatments for AKs have also associated an increased risk of local skin reactions with greater efficacy, Dr. Bhatia noted. As an example, he cited a phase 4 study comparing 0.015% ingenol mebutate gel to diclofenac sodium 3% gel in people with facial and scalp AK lesions.

At the end of the 3-month study, complete clearance was higher among those on ingenol mebutate, which was applied for 3 days, when compared with diclofenac sodium gel, which was applied daily for 3 months (34% vs. 23%; P = .006). However, patients randomized to ingenol mebutate gel had to first weather a higher rate of application-site erythema (19% vs. 12%) before achieving a greater level of clearance.

The correlation between efficacy and local reactions at the site of treatment application emphasizes the importance of educating patients about this relationship and in engaging in shared decision-making, Dr. Bhatia said.

“It is basically a tradeoff between local skin reactions, between frequency [of applications], compliance, and, of course, duration of therapy, even though both drugs served their purposes well,” said Dr. Bhatia, referring to the comparison of the ingenol mebutate and diclofenac gels.

Although not absolute, efficacy and tolerability were also generally inversely related in a recent four-treatment comparison of four commonly used field-directed therapies. In that trial, the primary endpoint was at least a 75% reduction from baseline in the number of AKs to 12 months after treatment ended.

For that outcome, 5% fluorouracil (5-FU) cream (74.7%) was significantly more effective than 5% imiquimod cream (53.9%), methyl aminolevulinate photodynamic therapy (37.7%), and 0.015% ingenol mebutate gel (28.9%). Also, 5-FU treatment was associated with the moderate or severe erythema (81.5%), severe pain (16.%), and a severe burning sensation (21.5%).

Other therapies on the horizon, some of which are already available in Europe or Canada, show a relationship between efficacy and local skin reactions. Of two that Dr. Bhatia cited, 5-FU and salicylic acid combined in a solution and 5-FU and calcipotriene combined in an ointment have demonstrated high rates of efficacy but at the cost of substantial rates of erythema and flaking.

Transient skin reactions can be made acceptable to patients who are informed of the goals of clearing AKs, which includes lowering the risk of cancer, as well as cosmetic improvement. In the phase 4 study comparing ingenol mebutate gel to diclofenac sodium gel, the end-of-study global satisfaction rates were higher (P < .001) for those randomized to the most effective therapy despite the local skin reactions.

Preparing patients for the consequences of therapy for AKs is essential, because optimal therapy involves treating uninvolved skin, according to Hassan Galadari, MD, assistant professor of dermatology, United Arab Emirates University, Dubai. A coauthor of a recent review article on actinic keratoses, Dr. Galadari said in an interview that field treatment means patients might have local skin reactions where they did not previously have lesions.

“Actinic damage may not be visible with the naked eye. That is why field treatment, which is applying medicine in adjacent areas that may appear normal, is indicated,” he said. As a result, “areas that otherwise may have appeared as normal start to react by becoming red, itchy, and even inflamed.”

He agreed with Dr. Bhatia that local skin reactions are typically the price paid for effective control of these precancerous lesions.

This publication and Global Academy for Medical Education are owned by the same parent company.

Dr. Bhatia reports financial relationships with more than 30 pharmaceutical companies with dermatologic products, including Almirall and other companies with products relevant to AK therapies.

Newer therapies for actinic keratoses (AKs) are expected to provide high rates of skin clearance with high rates of local skin reactions, according to an expert speaking at the annual Coastal Dermatology Symposium, held virtually.

This relationship is not new. In a review of treatments for AKs, Neal Bhatia, MD, a dermatologist and researcher at Therapeutics Dermatology, San Diego, advised that most effective agents trade a higher risk of inflammatory reactions – including erythema, flaking, and scaling – for greater therapeutic gain. In many cases, local skin reactions are an inevitable consequence of their mechanism of action.

Data from the completed phase 3 trials of tirbanibulin 1% ointment (KX01-AK-003 and KX01-AK-004), are illustrative. (Tirbanibulin 1% ointment was approved by the Food and Drug Administration in mid-December, after the Coastal Derm meeting was held.)

In the phase 3 trials, which have not yet been published, tirbanibulin, an inhibitor of Src kinase, which has an antiproliferative action, was four to five times more effective than vehicle by day 57 for overall complete clearance (P < .0001) of AKs and complete clearance of the face (P < .0001), but rates of local skin reactions were generally two to three times higher, according to Dr. Bhatia.

In the KX01-AK-004 trial, for example, 61% of patients had complete clearance of the face, versus 14% of those randomized to vehicle. The difference for overall partial clearance (76% vs. 20%; P < .0001), partial clearance of the face (80% vs. 22%; P < .0001), and partial clearance of the scalp (69% vs. 15%; P < .0001) was even greater. When compared with placebo, tirbanibulin was also associated with greater rates of erythema (90% vs. 31%), crusting (45% vs. 8%), flaking (84% vs. 35%), swelling (38% vs. 2%) and erosions or ulcers (12% vs. 1%).

Although these events might be a challenge with regard to tolerability for some patients, they might best be described as evidence that the drug is working.

“Local skin reactions are anticipated. They are not adverse events. They are not side effects,” Dr. Bhatia said at the meeting, jointly presented by the University of Louisville and Global Academy for Medical Education. “Patients are going to get red, and you need to counsel patients about the 5 days when they can expected to be red. It is a sign of the civil war, if you will, that your skin is taking on with the actinic keratoses.”

Both 3- and 5-day courses of the drug were tested in the clinical trials. (The approved prescribing information recommends treatment on the face or scalp once a day for 5 consecutive days).

Other studies evaluating treatments for AKs have also associated an increased risk of local skin reactions with greater efficacy, Dr. Bhatia noted. As an example, he cited a phase 4 study comparing 0.015% ingenol mebutate gel to diclofenac sodium 3% gel in people with facial and scalp AK lesions.

At the end of the 3-month study, complete clearance was higher among those on ingenol mebutate, which was applied for 3 days, when compared with diclofenac sodium gel, which was applied daily for 3 months (34% vs. 23%; P = .006). However, patients randomized to ingenol mebutate gel had to first weather a higher rate of application-site erythema (19% vs. 12%) before achieving a greater level of clearance.

The correlation between efficacy and local reactions at the site of treatment application emphasizes the importance of educating patients about this relationship and in engaging in shared decision-making, Dr. Bhatia said.

“It is basically a tradeoff between local skin reactions, between frequency [of applications], compliance, and, of course, duration of therapy, even though both drugs served their purposes well,” said Dr. Bhatia, referring to the comparison of the ingenol mebutate and diclofenac gels.

Although not absolute, efficacy and tolerability were also generally inversely related in a recent four-treatment comparison of four commonly used field-directed therapies. In that trial, the primary endpoint was at least a 75% reduction from baseline in the number of AKs to 12 months after treatment ended.

For that outcome, 5% fluorouracil (5-FU) cream (74.7%) was significantly more effective than 5% imiquimod cream (53.9%), methyl aminolevulinate photodynamic therapy (37.7%), and 0.015% ingenol mebutate gel (28.9%). Also, 5-FU treatment was associated with the moderate or severe erythema (81.5%), severe pain (16.%), and a severe burning sensation (21.5%).

Other therapies on the horizon, some of which are already available in Europe or Canada, show a relationship between efficacy and local skin reactions. Of two that Dr. Bhatia cited, 5-FU and salicylic acid combined in a solution and 5-FU and calcipotriene combined in an ointment have demonstrated high rates of efficacy but at the cost of substantial rates of erythema and flaking.

Transient skin reactions can be made acceptable to patients who are informed of the goals of clearing AKs, which includes lowering the risk of cancer, as well as cosmetic improvement. In the phase 4 study comparing ingenol mebutate gel to diclofenac sodium gel, the end-of-study global satisfaction rates were higher (P < .001) for those randomized to the most effective therapy despite the local skin reactions.

Preparing patients for the consequences of therapy for AKs is essential, because optimal therapy involves treating uninvolved skin, according to Hassan Galadari, MD, assistant professor of dermatology, United Arab Emirates University, Dubai. A coauthor of a recent review article on actinic keratoses, Dr. Galadari said in an interview that field treatment means patients might have local skin reactions where they did not previously have lesions.

“Actinic damage may not be visible with the naked eye. That is why field treatment, which is applying medicine in adjacent areas that may appear normal, is indicated,” he said. As a result, “areas that otherwise may have appeared as normal start to react by becoming red, itchy, and even inflamed.”

He agreed with Dr. Bhatia that local skin reactions are typically the price paid for effective control of these precancerous lesions.

This publication and Global Academy for Medical Education are owned by the same parent company.

Dr. Bhatia reports financial relationships with more than 30 pharmaceutical companies with dermatologic products, including Almirall and other companies with products relevant to AK therapies.

Everywhere they look within hospitals, researchers find RNA from SARS-CoV-2 in the air. But viable viruses typically are found only close to patients, according to a review of published studies.

The finding supports recommendations to use surgical masks in most parts of the hospital, reserving respirators (such as N95 or FFP2) for aerosol-generating procedures on patients’ respiratory tracts, said Gabriel Birgand, PhD, an infectious disease researcher at Imperial College London.

“When the virus is spreading a lot in the community, it’s probably more likely for you to be contaminated in your friends’ areas or in your building than in your work area, where you are well equipped and compliant with all the measures,” he said in an interview. “So it’s pretty good news.”

The systematic review by Dr. Birgand and colleagues was published in JAMA Network Open.

Recommended precautions to protect health care workers from SARS-CoV-2 infections remain controversial. Most authorities believe droplets are the primary route of transmission, which would mean surgical masks may be sufficient protection. But some research has suggested transmission by aerosols as well, making N95 respirators seem necessary. There is even disagreement about the definitions of the words “aerosol” and “droplet.”

To better understand where traces of the virus can be found in the air in hospitals, Dr. Birgand and colleagues analyzed all the studies they could find on the subject in English.

They identified 24 articles with original data. All of the studies used reverse transcription–polymerase chain reaction (PCR) tests to identify SARS-CoV-2 RNA. In five studies, attempts were also made to culture viable viruses. Three studies assessed the particle size relative to RNA concentration or viral titer.

Of 893 air samples across the 24 studies, 52.7% were taken from areas close to patients, 26.5% were taken in clinical areas, 13.7% in staff areas, 4.7% in public areas, and 2.4% in toilets or bathrooms.

Among those studies that quantified RNA, the median interquartile range of concentrations varied from 1.0 x 103 copies/m3 in clinical areas to 9.7 x 10³ copies/m³ in toilets or bathrooms.

One study found an RNA concentration of 2.0 x 10³ copies for particle sizes >4 mcm and 1.3 x 103 copies/m³ for particle sizes ≤4 mcm, both in patients’ rooms.

Three studies included viral cultures; of those, two resulted in positive cultures, both in a non-ICU setting. In one study, 3 of 39 samples were positive, and in the other, 4 of 4 were positive. Viral cultures in toilets, clinical areas, staff areas, and public areas were negative.

One of these studies assessed viral concentration and found that the median interquartile range was 4.8 tissue culture infectious dose (TCID50)/m³ for particles <1 mcm, 4.27 TCID50/m³ for particles 1-4 mcm, and 1.82 TCID50/m³ for particles >4 mcm.

Although viable viruses weren’t found in staff areas, the presence of viral RNA in places such as dining rooms and meeting rooms raises a concern, Dr. Birgand said.

“All of these staff areas are probably playing an important role in contamination,” he said. “It’s pretty easy to see when you are dining, you are not wearing a face mask, and it’s associated with a strong risk when there is a strong dissemination of the virus in the community.”

Studies on contact tracing among health care workers have also identified meeting rooms and dining rooms as the second most common source of infection after community contact, he said.

In general, the findings of the review correspond to epidemiologic studies, said Angela Rasmussen, PhD, a virologist with the Georgetown University Center for Global Health Science and Security, Washington, who was not involved in the review. “Absent aerosol-generating procedures, health care workers are largely not getting infected when they take droplet precautions.”

One reason may be that patients shed the most infectious viruses a couple of days before and after symptoms begin. By the time they’re hospitalized, they’re less likely to be contagious but may continue to shed viral RNA.

“We don’t really know the basis for the persistence of RNA being produced long after people have been infected and have recovered from the acute infection,” she said, “but it has been observed quite frequently.”

Although the virus cannot remain viable for very long in the air, remnants may still be detected in the form of RNA, Dr. Rasmussen said. In addition, hospitals often do a good job of ventilation.

She pointed out that it can be difficult to cultivate viruses in air samples because of contaminants such as bacteria and fungi. “That’s one of the limitations of a study like this. You’re not really sure if it’s because there’s no viable virus there or because you just aren’t able to collect samples that would allow you to determine that.”

Dr. Birgand and colleagues acknowledged other limitations. The studies they reviewed used different approaches to sampling. Different procedures may have been underway in the rooms being sampled, and factors such as temperature and humidity could have affected the results. In addition, the studies used different cycle thresholds for PCR positivity.

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

Everywhere they look within hospitals, researchers find RNA from SARS-CoV-2 in the air. But viable viruses typically are found only close to patients, according to a review of published studies.

The finding supports recommendations to use surgical masks in most parts of the hospital, reserving respirators (such as N95 or FFP2) for aerosol-generating procedures on patients’ respiratory tracts, said Gabriel Birgand, PhD, an infectious disease researcher at Imperial College London.

“When the virus is spreading a lot in the community, it’s probably more likely for you to be contaminated in your friends’ areas or in your building than in your work area, where you are well equipped and compliant with all the measures,” he said in an interview. “So it’s pretty good news.”

The systematic review by Dr. Birgand and colleagues was published in JAMA Network Open.

Recommended precautions to protect health care workers from SARS-CoV-2 infections remain controversial. Most authorities believe droplets are the primary route of transmission, which would mean surgical masks may be sufficient protection. But some research has suggested transmission by aerosols as well, making N95 respirators seem necessary. There is even disagreement about the definitions of the words “aerosol” and “droplet.”

To better understand where traces of the virus can be found in the air in hospitals, Dr. Birgand and colleagues analyzed all the studies they could find on the subject in English.

They identified 24 articles with original data. All of the studies used reverse transcription–polymerase chain reaction (PCR) tests to identify SARS-CoV-2 RNA. In five studies, attempts were also made to culture viable viruses. Three studies assessed the particle size relative to RNA concentration or viral titer.

Of 893 air samples across the 24 studies, 52.7% were taken from areas close to patients, 26.5% were taken in clinical areas, 13.7% in staff areas, 4.7% in public areas, and 2.4% in toilets or bathrooms.

Among those studies that quantified RNA, the median interquartile range of concentrations varied from 1.0 x 103 copies/m3 in clinical areas to 9.7 x 10³ copies/m³ in toilets or bathrooms.

One study found an RNA concentration of 2.0 x 10³ copies for particle sizes >4 mcm and 1.3 x 103 copies/m³ for particle sizes ≤4 mcm, both in patients’ rooms.

Three studies included viral cultures; of those, two resulted in positive cultures, both in a non-ICU setting. In one study, 3 of 39 samples were positive, and in the other, 4 of 4 were positive. Viral cultures in toilets, clinical areas, staff areas, and public areas were negative.

One of these studies assessed viral concentration and found that the median interquartile range was 4.8 tissue culture infectious dose (TCID50)/m³ for particles <1 mcm, 4.27 TCID50/m³ for particles 1-4 mcm, and 1.82 TCID50/m³ for particles >4 mcm.

Although viable viruses weren’t found in staff areas, the presence of viral RNA in places such as dining rooms and meeting rooms raises a concern, Dr. Birgand said.

“All of these staff areas are probably playing an important role in contamination,” he said. “It’s pretty easy to see when you are dining, you are not wearing a face mask, and it’s associated with a strong risk when there is a strong dissemination of the virus in the community.”

Studies on contact tracing among health care workers have also identified meeting rooms and dining rooms as the second most common source of infection after community contact, he said.

In general, the findings of the review correspond to epidemiologic studies, said Angela Rasmussen, PhD, a virologist with the Georgetown University Center for Global Health Science and Security, Washington, who was not involved in the review. “Absent aerosol-generating procedures, health care workers are largely not getting infected when they take droplet precautions.”

One reason may be that patients shed the most infectious viruses a couple of days before and after symptoms begin. By the time they’re hospitalized, they’re less likely to be contagious but may continue to shed viral RNA.

“We don’t really know the basis for the persistence of RNA being produced long after people have been infected and have recovered from the acute infection,” she said, “but it has been observed quite frequently.”

Although the virus cannot remain viable for very long in the air, remnants may still be detected in the form of RNA, Dr. Rasmussen said. In addition, hospitals often do a good job of ventilation.

She pointed out that it can be difficult to cultivate viruses in air samples because of contaminants such as bacteria and fungi. “That’s one of the limitations of a study like this. You’re not really sure if it’s because there’s no viable virus there or because you just aren’t able to collect samples that would allow you to determine that.”

Dr. Birgand and colleagues acknowledged other limitations. The studies they reviewed used different approaches to sampling. Different procedures may have been underway in the rooms being sampled, and factors such as temperature and humidity could have affected the results. In addition, the studies used different cycle thresholds for PCR positivity.

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

Everywhere they look within hospitals, researchers find RNA from SARS-CoV-2 in the air. But viable viruses typically are found only close to patients, according to a review of published studies.

The finding supports recommendations to use surgical masks in most parts of the hospital, reserving respirators (such as N95 or FFP2) for aerosol-generating procedures on patients’ respiratory tracts, said Gabriel Birgand, PhD, an infectious disease researcher at Imperial College London.

“When the virus is spreading a lot in the community, it’s probably more likely for you to be contaminated in your friends’ areas or in your building than in your work area, where you are well equipped and compliant with all the measures,” he said in an interview. “So it’s pretty good news.”

The systematic review by Dr. Birgand and colleagues was published in JAMA Network Open.

Recommended precautions to protect health care workers from SARS-CoV-2 infections remain controversial. Most authorities believe droplets are the primary route of transmission, which would mean surgical masks may be sufficient protection. But some research has suggested transmission by aerosols as well, making N95 respirators seem necessary. There is even disagreement about the definitions of the words “aerosol” and “droplet.”

To better understand where traces of the virus can be found in the air in hospitals, Dr. Birgand and colleagues analyzed all the studies they could find on the subject in English.

They identified 24 articles with original data. All of the studies used reverse transcription–polymerase chain reaction (PCR) tests to identify SARS-CoV-2 RNA. In five studies, attempts were also made to culture viable viruses. Three studies assessed the particle size relative to RNA concentration or viral titer.

Of 893 air samples across the 24 studies, 52.7% were taken from areas close to patients, 26.5% were taken in clinical areas, 13.7% in staff areas, 4.7% in public areas, and 2.4% in toilets or bathrooms.

Among those studies that quantified RNA, the median interquartile range of concentrations varied from 1.0 x 103 copies/m3 in clinical areas to 9.7 x 10³ copies/m³ in toilets or bathrooms.

One study found an RNA concentration of 2.0 x 10³ copies for particle sizes >4 mcm and 1.3 x 103 copies/m³ for particle sizes ≤4 mcm, both in patients’ rooms.

Three studies included viral cultures; of those, two resulted in positive cultures, both in a non-ICU setting. In one study, 3 of 39 samples were positive, and in the other, 4 of 4 were positive. Viral cultures in toilets, clinical areas, staff areas, and public areas were negative.

One of these studies assessed viral concentration and found that the median interquartile range was 4.8 tissue culture infectious dose (TCID50)/m³ for particles <1 mcm, 4.27 TCID50/m³ for particles 1-4 mcm, and 1.82 TCID50/m³ for particles >4 mcm.

Although viable viruses weren’t found in staff areas, the presence of viral RNA in places such as dining rooms and meeting rooms raises a concern, Dr. Birgand said.

“All of these staff areas are probably playing an important role in contamination,” he said. “It’s pretty easy to see when you are dining, you are not wearing a face mask, and it’s associated with a strong risk when there is a strong dissemination of the virus in the community.”

Studies on contact tracing among health care workers have also identified meeting rooms and dining rooms as the second most common source of infection after community contact, he said.

In general, the findings of the review correspond to epidemiologic studies, said Angela Rasmussen, PhD, a virologist with the Georgetown University Center for Global Health Science and Security, Washington, who was not involved in the review. “Absent aerosol-generating procedures, health care workers are largely not getting infected when they take droplet precautions.”

One reason may be that patients shed the most infectious viruses a couple of days before and after symptoms begin. By the time they’re hospitalized, they’re less likely to be contagious but may continue to shed viral RNA.

“We don’t really know the basis for the persistence of RNA being produced long after people have been infected and have recovered from the acute infection,” she said, “but it has been observed quite frequently.”

Although the virus cannot remain viable for very long in the air, remnants may still be detected in the form of RNA, Dr. Rasmussen said. In addition, hospitals often do a good job of ventilation.

She pointed out that it can be difficult to cultivate viruses in air samples because of contaminants such as bacteria and fungi. “That’s one of the limitations of a study like this. You’re not really sure if it’s because there’s no viable virus there or because you just aren’t able to collect samples that would allow you to determine that.”

Dr. Birgand and colleagues acknowledged other limitations. The studies they reviewed used different approaches to sampling. Different procedures may have been underway in the rooms being sampled, and factors such as temperature and humidity could have affected the results. In addition, the studies used different cycle thresholds for PCR positivity.

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

A physician assistant participating in a virtual workshop began to cry, confessing that she felt overwhelmed with guilt because New Yorkers were hailing her as a frontline hero in the pandemic. That was when Joe Ciavarro knew he was in the right place.

rclassenlayouts/Getty Images

“She was saying all the things I could not verbalize because I, too, didn’t feel like I deserved all this praise and thousands of people cheering for us every evening when people were losing jobs, didn’t have money for food, and their loved ones were dying without family at their side,” says Mr. Ciavarro, a PA at Mount Sinai Medical Center in New York.

Mr. Ciavarro, who also manages 170 other PAs on two of Mount Sinai’s campuses in Manhattan, has been on the front lines since COVID-19 first hit; he lost a colleague and friend to suicide in September.

The mental anguish from his job prompted him to sign up for the resilience workshop offered by Mount Sinai’s Center for Stress, Resilience, and Personal Growth. The center – the first of its kind in North America – was launched in June to help health care workers like him cope with the intense psychological pressures they were facing. The weekly workshops became a safe place where Mr. Ciavarro and other staff members could share their darkest fears and learn ways to help them deal with their situation.

“It’s been grueling but we learned how to take care of ourselves so we can take care of our patients,” said Mr. Ciavarro. “This has become like a guided group therapy session on ways to manage and develop resilience. And I feel like my emotions are validated, knowing that others feel the same way.”
 

Caring for their own

Medical professionals treating patients with COVID-19 are in similar predicaments, and the psychological fallout is enormous: They’re exhausted by the seemingly never-ending patient load and staffing shortages, and haunted by fears for their own safety and that of their families. Studies in China, Canada, and Italy have revealed that a significant number of doctors and nurses in the early days of the pandemic experienced high levels of distress, depression, anxiety, nightmares, and insomnia.

Trauma experts at Mount Sinai believe that, globally, up to 40% of first responders and health care workers – tens of thousands of people – will suffer from PTSD after witnessing the deaths of so many patients who were alone, without family.

How to protect in midst of trauma

In formulating the program’s platform, Mount Sinai experts drew upon their extensive experience aiding 9/11 responders at the World Trade Center (WTC), as well as their system-wide wellness program that aids demoralized and burned-out physicians. While the reach of the pandemic is much broader than 9/11, experts see some commonalities in conditions that emerge after traumatic events, and they also discovered what can help.

“We learned from our WTC experience about what are protective factors – what are the social supports that buffer against depression, anxiety, and PTSD,” said Jonathan DePierro, PhD, clinical director of CSRPG and a psychologist at the Mount Sinai WTC Mental Health Program. “We also learned that people who have more prolonged exposures are at greater risk of developing mental health difficulties.”

The program itself reflects these lessons – and that’s why it’s open to all employees, not just medical professionals. Housekeepers, security staffers, even construction workers are also dealing with their lives being in danger. “That wasn’t in their job description,” said Dr. DePierro. “These people tend to have fewer social and economic resources, make less money and have fewer structural supports, which makes them even more vulnerable.”

Dr. Charney’s strategies on building resilience became a bible of sorts for the workshops, according to Dr. Katz, who authored the training curriculum. Sessions deal with how to build up reservoirs of realistic optimism, keep gratitude journals, find spiritual meaning in their lives, maintain physical wellness and create networks of social support. The workshops are meant to help participants create action plans, to reach out for support in their social networks, and keep the focus on the positives.

The goal is to give demoralized health care workers a renewed sense of competence. “The resilience workshop is a launching point to get people to show up and talk,” said Dr. Katz. “And if we do that, we’ve accomplished a lot just getting people in the door.”

The center will also have a research component to identify what works and what doesn’t so their platform can provide a template for other institutions; Dr. Marin said they’ve gotten inquiries about the program from major hospital systems in Michigan and California. They’ll also conduct longitudinal research to determine what lingering problems persist among healthcare workers over time.

Since the center opened its virtual doors, the curriculum has also been altered in response to feedback from the support staff, many of whom live in the community that surrounds Mount Sinai in northern Manhattan, which is largely lower-income Latinx and Black individuals. Workshop materials have been translated into Spanish and now feature people who reflect a more diverse set of experiences.

“Many of our employees and the population we serve identify as non-White so we’ve been doing outreach with a lot of the local unions,” said Dr. Marin. “Our next step is to take what we’re doing and work with local community organizations.”

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

A physician assistant participating in a virtual workshop began to cry, confessing that she felt overwhelmed with guilt because New Yorkers were hailing her as a frontline hero in the pandemic. That was when Joe Ciavarro knew he was in the right place.

rclassenlayouts/Getty Images

“She was saying all the things I could not verbalize because I, too, didn’t feel like I deserved all this praise and thousands of people cheering for us every evening when people were losing jobs, didn’t have money for food, and their loved ones were dying without family at their side,” says Mr. Ciavarro, a PA at Mount Sinai Medical Center in New York.

Mr. Ciavarro, who also manages 170 other PAs on two of Mount Sinai’s campuses in Manhattan, has been on the front lines since COVID-19 first hit; he lost a colleague and friend to suicide in September.

The mental anguish from his job prompted him to sign up for the resilience workshop offered by Mount Sinai’s Center for Stress, Resilience, and Personal Growth. The center – the first of its kind in North America – was launched in June to help health care workers like him cope with the intense psychological pressures they were facing. The weekly workshops became a safe place where Mr. Ciavarro and other staff members could share their darkest fears and learn ways to help them deal with their situation.

“It’s been grueling but we learned how to take care of ourselves so we can take care of our patients,” said Mr. Ciavarro. “This has become like a guided group therapy session on ways to manage and develop resilience. And I feel like my emotions are validated, knowing that others feel the same way.”
 

Caring for their own

Medical professionals treating patients with COVID-19 are in similar predicaments, and the psychological fallout is enormous: They’re exhausted by the seemingly never-ending patient load and staffing shortages, and haunted by fears for their own safety and that of their families. Studies in China, Canada, and Italy have revealed that a significant number of doctors and nurses in the early days of the pandemic experienced high levels of distress, depression, anxiety, nightmares, and insomnia.

Trauma experts at Mount Sinai believe that, globally, up to 40% of first responders and health care workers – tens of thousands of people – will suffer from PTSD after witnessing the deaths of so many patients who were alone, without family.

How to protect in midst of trauma

In formulating the program’s platform, Mount Sinai experts drew upon their extensive experience aiding 9/11 responders at the World Trade Center (WTC), as well as their system-wide wellness program that aids demoralized and burned-out physicians. While the reach of the pandemic is much broader than 9/11, experts see some commonalities in conditions that emerge after traumatic events, and they also discovered what can help.

“We learned from our WTC experience about what are protective factors – what are the social supports that buffer against depression, anxiety, and PTSD,” said Jonathan DePierro, PhD, clinical director of CSRPG and a psychologist at the Mount Sinai WTC Mental Health Program. “We also learned that people who have more prolonged exposures are at greater risk of developing mental health difficulties.”

The program itself reflects these lessons – and that’s why it’s open to all employees, not just medical professionals. Housekeepers, security staffers, even construction workers are also dealing with their lives being in danger. “That wasn’t in their job description,” said Dr. DePierro. “These people tend to have fewer social and economic resources, make less money and have fewer structural supports, which makes them even more vulnerable.”

Dr. Charney’s strategies on building resilience became a bible of sorts for the workshops, according to Dr. Katz, who authored the training curriculum. Sessions deal with how to build up reservoirs of realistic optimism, keep gratitude journals, find spiritual meaning in their lives, maintain physical wellness and create networks of social support. The workshops are meant to help participants create action plans, to reach out for support in their social networks, and keep the focus on the positives.

The goal is to give demoralized health care workers a renewed sense of competence. “The resilience workshop is a launching point to get people to show up and talk,” said Dr. Katz. “And if we do that, we’ve accomplished a lot just getting people in the door.”

The center will also have a research component to identify what works and what doesn’t so their platform can provide a template for other institutions; Dr. Marin said they’ve gotten inquiries about the program from major hospital systems in Michigan and California. They’ll also conduct longitudinal research to determine what lingering problems persist among healthcare workers over time.

Since the center opened its virtual doors, the curriculum has also been altered in response to feedback from the support staff, many of whom live in the community that surrounds Mount Sinai in northern Manhattan, which is largely lower-income Latinx and Black individuals. Workshop materials have been translated into Spanish and now feature people who reflect a more diverse set of experiences.

“Many of our employees and the population we serve identify as non-White so we’ve been doing outreach with a lot of the local unions,” said Dr. Marin. “Our next step is to take what we’re doing and work with local community organizations.”

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

A physician assistant participating in a virtual workshop began to cry, confessing that she felt overwhelmed with guilt because New Yorkers were hailing her as a frontline hero in the pandemic. That was when Joe Ciavarro knew he was in the right place.

rclassenlayouts/Getty Images

“She was saying all the things I could not verbalize because I, too, didn’t feel like I deserved all this praise and thousands of people cheering for us every evening when people were losing jobs, didn’t have money for food, and their loved ones were dying without family at their side,” says Mr. Ciavarro, a PA at Mount Sinai Medical Center in New York.

Mr. Ciavarro, who also manages 170 other PAs on two of Mount Sinai’s campuses in Manhattan, has been on the front lines since COVID-19 first hit; he lost a colleague and friend to suicide in September.

The mental anguish from his job prompted him to sign up for the resilience workshop offered by Mount Sinai’s Center for Stress, Resilience, and Personal Growth. The center – the first of its kind in North America – was launched in June to help health care workers like him cope with the intense psychological pressures they were facing. The weekly workshops became a safe place where Mr. Ciavarro and other staff members could share their darkest fears and learn ways to help them deal with their situation.

“It’s been grueling but we learned how to take care of ourselves so we can take care of our patients,” said Mr. Ciavarro. “This has become like a guided group therapy session on ways to manage and develop resilience. And I feel like my emotions are validated, knowing that others feel the same way.”
 

Caring for their own

Medical professionals treating patients with COVID-19 are in similar predicaments, and the psychological fallout is enormous: They’re exhausted by the seemingly never-ending patient load and staffing shortages, and haunted by fears for their own safety and that of their families. Studies in China, Canada, and Italy have revealed that a significant number of doctors and nurses in the early days of the pandemic experienced high levels of distress, depression, anxiety, nightmares, and insomnia.

Trauma experts at Mount Sinai believe that, globally, up to 40% of first responders and health care workers – tens of thousands of people – will suffer from PTSD after witnessing the deaths of so many patients who were alone, without family.

How to protect in midst of trauma

In formulating the program’s platform, Mount Sinai experts drew upon their extensive experience aiding 9/11 responders at the World Trade Center (WTC), as well as their system-wide wellness program that aids demoralized and burned-out physicians. While the reach of the pandemic is much broader than 9/11, experts see some commonalities in conditions that emerge after traumatic events, and they also discovered what can help.

“We learned from our WTC experience about what are protective factors – what are the social supports that buffer against depression, anxiety, and PTSD,” said Jonathan DePierro, PhD, clinical director of CSRPG and a psychologist at the Mount Sinai WTC Mental Health Program. “We also learned that people who have more prolonged exposures are at greater risk of developing mental health difficulties.”

The program itself reflects these lessons – and that’s why it’s open to all employees, not just medical professionals. Housekeepers, security staffers, even construction workers are also dealing with their lives being in danger. “That wasn’t in their job description,” said Dr. DePierro. “These people tend to have fewer social and economic resources, make less money and have fewer structural supports, which makes them even more vulnerable.”

Dr. Charney’s strategies on building resilience became a bible of sorts for the workshops, according to Dr. Katz, who authored the training curriculum. Sessions deal with how to build up reservoirs of realistic optimism, keep gratitude journals, find spiritual meaning in their lives, maintain physical wellness and create networks of social support. The workshops are meant to help participants create action plans, to reach out for support in their social networks, and keep the focus on the positives.

The goal is to give demoralized health care workers a renewed sense of competence. “The resilience workshop is a launching point to get people to show up and talk,” said Dr. Katz. “And if we do that, we’ve accomplished a lot just getting people in the door.”

The center will also have a research component to identify what works and what doesn’t so their platform can provide a template for other institutions; Dr. Marin said they’ve gotten inquiries about the program from major hospital systems in Michigan and California. They’ll also conduct longitudinal research to determine what lingering problems persist among healthcare workers over time.

Since the center opened its virtual doors, the curriculum has also been altered in response to feedback from the support staff, many of whom live in the community that surrounds Mount Sinai in northern Manhattan, which is largely lower-income Latinx and Black individuals. Workshop materials have been translated into Spanish and now feature people who reflect a more diverse set of experiences.

“Many of our employees and the population we serve identify as non-White so we’ve been doing outreach with a lot of the local unions,” said Dr. Marin. “Our next step is to take what we’re doing and work with local community organizations.”

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

An intense and assertive “won’t take no for an answer” approach is effective for engaging in treatment young adults with substance abuse who have been in and out of various recovery programs for years, new research suggests.

The Youth Opioid Recovery Support (YORS) program is a team effort that includes home delivery of the prescribed medication, family engagement, assertive outreach, and contingency management.

In a new study of 42 patients in recovery for substance use disorder (SUD), those who were treated with extended-release naltrexone or extended-release buprenorphine plus YORS received more outpatient doses of their medication, and rates of opioid relapse at 12 and 24 weeks were lower compared with their peers who received only treatment as usual.

“These developmentally vulnerable youths need something extra that is specifically targeted to who they are and their vulnerabilities,” coinvestigator Marc Fishman, MD, director of the Maryland Treatment Centers, Johns Hopkins University, Baltimore, said in an interview.

The findings were presented at the virtual American Academy of Addiction Psychiatry 31st Annual Meeting.
 

Treatment barriers

Young adults with SUD are difficult to reach, which leads to decreased addiction program retention, decreased medication adherence, early drop out, waxing and waning motivation, and worse outcomes, compared with older adults with SUD, Dr. Fishman said.

In July, positive results from a pilot trial conducted by the investigators of YORS were published online in Addiction.

In that study, 41 young adults aged 18-26 years who intended to undergo treatment for SUD with extended-release naltrexone were randomly assigned to also undergo YORS or treatment as usual, which consisted of a standard referral to outpatient care following an inpatient stay.

The primary outcomes were number of medication doses received over 24 weeks and relapse to opioid use, which was defined as 10 or more days of use within 28 days at 24 weeks.

Participants in the YORS group received more doses of extended-release naltrexone (mean, 4.28; standard deviation, 2.3) than participants in the treatment-as-usual group (mean, 0.70; SD, 1.2; P < .01).

In the YORS group, rates of relapse at both 12 and 24 weeks were lower, and there were fewer overall days of opioid use.

For the current study, the investigators wanted to test whether there was a possible effect when patients were given a choice of medication. In the earlier trial, patients did not have a choice – they had to take extended-release naltrexone. In this study, they could opt for it or extended-release buprenorphine.

The researchers recruited 22 young adults (aged 18-26 years) from their inpatient clinic to participate. Half the patients chose to take extended-release naltrexone, and the other half chose extended-release buprenorphine.

The groups were then compared to a historical group of 20 patients who received treatment as usual and served as the control group.
 

Positive outcomes

As in the first study, outcomes in the new study were better with YORS.

All participants who underwent YORS received more outpatient medication doses at 12 weeks and 24 weeks than those who received treatment as usual (1.91 vs. 0.40 and 3.76 vs. 0.70, respectively; P < .001).

For the YORS group, rates of opioid relapse were lower at 12 weeks (27.3% vs. 75.0%) and at 24 weeks (52.9% vs. 95.0%; P < .01.)

All components of YORS work together to improve retention, Dr. Fishman noted. Patients do much better if a relative such as a mother, father, or grandmother is closely involved, he added.

Also important is drug delivery.

“In some ways, this is similar to the assertive community treatment, or ACT, for schizophrenia. Like substance use disorder, schizophrenia requires long-acting injectable antipsychotics. When that is delivered to the patient through an organized delivery service like YORS, it improves outcomes,” said Dr. Fishman.

SUD is a chronic, relapsing illness in which an individual’s judgment is impaired, he added.

“ACT has become a relatively standard feature of treatment in most communities in this country and internationally and is sustainable under public sector funding, so it’s not an impossible leap to say it could be done. But it will not be cheap,” Dr. Fishman said.
 

Removing barriers

In a comment, Serra Akyar, MD, a psychiatry resident at Northwell Health’s Staten Island University Hospital, New York, said that the YORS program may appear to be labor intensive.

“However, the combination of medication-assisted treatment and support are essential to the treatment of opioid use disorder, especially for young adults. Developing effective interventions for young adults is particularly important, given the plasticity of their brains,” said Dr. Akyar, who was not involved with the research.

Inability to access medication and a lack of a supportive environment, both in everyday life and in regards to therapy, are barriers to successful treatment, she noted.

“The YORS intervention aims to remove these barriers to further enhance engagement to care through a combination of medication delivery and family engagement and assertive outreach via text messaging, a modality presumed to be well received by youth,” Dr. Akyar said.

Despite having a limited sample size, the study shows how a comprehensive intervention can have a large impact on the maintenance of medication adherence and reduction of relapse in young adults, she added.

“Its early success is encouraging and warrants further study on a larger scale to determine long-term effectiveness, overall costs and feasibility, generalizability, and whether certain independent factors exist that may predict medication adherence and reduction of relapse,” she said.
 

Wraparound support

The study is also a significant reminder that the opioid crisis has affected the young adult population, who are very vulnerable to OUD, said Jose Vito, MD, child, adolescent, and addiction psychiatrist at New York University.

“The study made me realize the importance of the four components of YORS, which were the outreach, family involvement, home delivery, and monetary incentives,” Dr. Vito said in an interview.

All of these components, in addition to extended-release naltrexone or extended-release buprenorphine, “have contributed to lower rates of opioid relapse, and the relapses are much later in the course of treatment if they do occur,” he said.

Overall, the findings demonstrate the importance of not giving up on these youths, he noted.

“Programs like YORS that provide wraparound support can help alleviate the opioid health care crisis by keeping these young adults in treatment,” Dr. Vito concluded.

The study was funded by the University of Maryland Center for Addiction Research, Education, and Service. Dr. Fishman has a financial relationship with Alkermes.

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

An intense and assertive “won’t take no for an answer” approach is effective for engaging in treatment young adults with substance abuse who have been in and out of various recovery programs for years, new research suggests.

The Youth Opioid Recovery Support (YORS) program is a team effort that includes home delivery of the prescribed medication, family engagement, assertive outreach, and contingency management.

In a new study of 42 patients in recovery for substance use disorder (SUD), those who were treated with extended-release naltrexone or extended-release buprenorphine plus YORS received more outpatient doses of their medication, and rates of opioid relapse at 12 and 24 weeks were lower compared with their peers who received only treatment as usual.

“These developmentally vulnerable youths need something extra that is specifically targeted to who they are and their vulnerabilities,” coinvestigator Marc Fishman, MD, director of the Maryland Treatment Centers, Johns Hopkins University, Baltimore, said in an interview.

The findings were presented at the virtual American Academy of Addiction Psychiatry 31st Annual Meeting.
 

Treatment barriers

Young adults with SUD are difficult to reach, which leads to decreased addiction program retention, decreased medication adherence, early drop out, waxing and waning motivation, and worse outcomes, compared with older adults with SUD, Dr. Fishman said.

In July, positive results from a pilot trial conducted by the investigators of YORS were published online in Addiction.

In that study, 41 young adults aged 18-26 years who intended to undergo treatment for SUD with extended-release naltrexone were randomly assigned to also undergo YORS or treatment as usual, which consisted of a standard referral to outpatient care following an inpatient stay.

The primary outcomes were number of medication doses received over 24 weeks and relapse to opioid use, which was defined as 10 or more days of use within 28 days at 24 weeks.

Participants in the YORS group received more doses of extended-release naltrexone (mean, 4.28; standard deviation, 2.3) than participants in the treatment-as-usual group (mean, 0.70; SD, 1.2; P < .01).

In the YORS group, rates of relapse at both 12 and 24 weeks were lower, and there were fewer overall days of opioid use.

For the current study, the investigators wanted to test whether there was a possible effect when patients were given a choice of medication. In the earlier trial, patients did not have a choice – they had to take extended-release naltrexone. In this study, they could opt for it or extended-release buprenorphine.

The researchers recruited 22 young adults (aged 18-26 years) from their inpatient clinic to participate. Half the patients chose to take extended-release naltrexone, and the other half chose extended-release buprenorphine.

The groups were then compared to a historical group of 20 patients who received treatment as usual and served as the control group.
 

Positive outcomes

As in the first study, outcomes in the new study were better with YORS.

All participants who underwent YORS received more outpatient medication doses at 12 weeks and 24 weeks than those who received treatment as usual (1.91 vs. 0.40 and 3.76 vs. 0.70, respectively; P < .001).

For the YORS group, rates of opioid relapse were lower at 12 weeks (27.3% vs. 75.0%) and at 24 weeks (52.9% vs. 95.0%; P < .01.)

All components of YORS work together to improve retention, Dr. Fishman noted. Patients do much better if a relative such as a mother, father, or grandmother is closely involved, he added.

Also important is drug delivery.

“In some ways, this is similar to the assertive community treatment, or ACT, for schizophrenia. Like substance use disorder, schizophrenia requires long-acting injectable antipsychotics. When that is delivered to the patient through an organized delivery service like YORS, it improves outcomes,” said Dr. Fishman.

SUD is a chronic, relapsing illness in which an individual’s judgment is impaired, he added.

“ACT has become a relatively standard feature of treatment in most communities in this country and internationally and is sustainable under public sector funding, so it’s not an impossible leap to say it could be done. But it will not be cheap,” Dr. Fishman said.
 

Removing barriers

In a comment, Serra Akyar, MD, a psychiatry resident at Northwell Health’s Staten Island University Hospital, New York, said that the YORS program may appear to be labor intensive.

“However, the combination of medication-assisted treatment and support are essential to the treatment of opioid use disorder, especially for young adults. Developing effective interventions for young adults is particularly important, given the plasticity of their brains,” said Dr. Akyar, who was not involved with the research.

Inability to access medication and a lack of a supportive environment, both in everyday life and in regards to therapy, are barriers to successful treatment, she noted.

“The YORS intervention aims to remove these barriers to further enhance engagement to care through a combination of medication delivery and family engagement and assertive outreach via text messaging, a modality presumed to be well received by youth,” Dr. Akyar said.

Despite having a limited sample size, the study shows how a comprehensive intervention can have a large impact on the maintenance of medication adherence and reduction of relapse in young adults, she added.

“Its early success is encouraging and warrants further study on a larger scale to determine long-term effectiveness, overall costs and feasibility, generalizability, and whether certain independent factors exist that may predict medication adherence and reduction of relapse,” she said.
 

Wraparound support

The study is also a significant reminder that the opioid crisis has affected the young adult population, who are very vulnerable to OUD, said Jose Vito, MD, child, adolescent, and addiction psychiatrist at New York University.

“The study made me realize the importance of the four components of YORS, which were the outreach, family involvement, home delivery, and monetary incentives,” Dr. Vito said in an interview.

All of these components, in addition to extended-release naltrexone or extended-release buprenorphine, “have contributed to lower rates of opioid relapse, and the relapses are much later in the course of treatment if they do occur,” he said.

Overall, the findings demonstrate the importance of not giving up on these youths, he noted.

“Programs like YORS that provide wraparound support can help alleviate the opioid health care crisis by keeping these young adults in treatment,” Dr. Vito concluded.

The study was funded by the University of Maryland Center for Addiction Research, Education, and Service. Dr. Fishman has a financial relationship with Alkermes.

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

An intense and assertive “won’t take no for an answer” approach is effective for engaging in treatment young adults with substance abuse who have been in and out of various recovery programs for years, new research suggests.

The Youth Opioid Recovery Support (YORS) program is a team effort that includes home delivery of the prescribed medication, family engagement, assertive outreach, and contingency management.

In a new study of 42 patients in recovery for substance use disorder (SUD), those who were treated with extended-release naltrexone or extended-release buprenorphine plus YORS received more outpatient doses of their medication, and rates of opioid relapse at 12 and 24 weeks were lower compared with their peers who received only treatment as usual.

“These developmentally vulnerable youths need something extra that is specifically targeted to who they are and their vulnerabilities,” coinvestigator Marc Fishman, MD, director of the Maryland Treatment Centers, Johns Hopkins University, Baltimore, said in an interview.

The findings were presented at the virtual American Academy of Addiction Psychiatry 31st Annual Meeting.
 

Treatment barriers

Young adults with SUD are difficult to reach, which leads to decreased addiction program retention, decreased medication adherence, early drop out, waxing and waning motivation, and worse outcomes, compared with older adults with SUD, Dr. Fishman said.

In July, positive results from a pilot trial conducted by the investigators of YORS were published online in Addiction.

In that study, 41 young adults aged 18-26 years who intended to undergo treatment for SUD with extended-release naltrexone were randomly assigned to also undergo YORS or treatment as usual, which consisted of a standard referral to outpatient care following an inpatient stay.

The primary outcomes were number of medication doses received over 24 weeks and relapse to opioid use, which was defined as 10 or more days of use within 28 days at 24 weeks.

Participants in the YORS group received more doses of extended-release naltrexone (mean, 4.28; standard deviation, 2.3) than participants in the treatment-as-usual group (mean, 0.70; SD, 1.2; P < .01).

In the YORS group, rates of relapse at both 12 and 24 weeks were lower, and there were fewer overall days of opioid use.

For the current study, the investigators wanted to test whether there was a possible effect when patients were given a choice of medication. In the earlier trial, patients did not have a choice – they had to take extended-release naltrexone. In this study, they could opt for it or extended-release buprenorphine.

The researchers recruited 22 young adults (aged 18-26 years) from their inpatient clinic to participate. Half the patients chose to take extended-release naltrexone, and the other half chose extended-release buprenorphine.

The groups were then compared to a historical group of 20 patients who received treatment as usual and served as the control group.
 

Positive outcomes

As in the first study, outcomes in the new study were better with YORS.

All participants who underwent YORS received more outpatient medication doses at 12 weeks and 24 weeks than those who received treatment as usual (1.91 vs. 0.40 and 3.76 vs. 0.70, respectively; P < .001).

For the YORS group, rates of opioid relapse were lower at 12 weeks (27.3% vs. 75.0%) and at 24 weeks (52.9% vs. 95.0%; P < .01.)

All components of YORS work together to improve retention, Dr. Fishman noted. Patients do much better if a relative such as a mother, father, or grandmother is closely involved, he added.

Also important is drug delivery.

“In some ways, this is similar to the assertive community treatment, or ACT, for schizophrenia. Like substance use disorder, schizophrenia requires long-acting injectable antipsychotics. When that is delivered to the patient through an organized delivery service like YORS, it improves outcomes,” said Dr. Fishman.

SUD is a chronic, relapsing illness in which an individual’s judgment is impaired, he added.

“ACT has become a relatively standard feature of treatment in most communities in this country and internationally and is sustainable under public sector funding, so it’s not an impossible leap to say it could be done. But it will not be cheap,” Dr. Fishman said.
 

Removing barriers

In a comment, Serra Akyar, MD, a psychiatry resident at Northwell Health’s Staten Island University Hospital, New York, said that the YORS program may appear to be labor intensive.

“However, the combination of medication-assisted treatment and support are essential to the treatment of opioid use disorder, especially for young adults. Developing effective interventions for young adults is particularly important, given the plasticity of their brains,” said Dr. Akyar, who was not involved with the research.

Inability to access medication and a lack of a supportive environment, both in everyday life and in regards to therapy, are barriers to successful treatment, she noted.

“The YORS intervention aims to remove these barriers to further enhance engagement to care through a combination of medication delivery and family engagement and assertive outreach via text messaging, a modality presumed to be well received by youth,” Dr. Akyar said.

Despite having a limited sample size, the study shows how a comprehensive intervention can have a large impact on the maintenance of medication adherence and reduction of relapse in young adults, she added.

“Its early success is encouraging and warrants further study on a larger scale to determine long-term effectiveness, overall costs and feasibility, generalizability, and whether certain independent factors exist that may predict medication adherence and reduction of relapse,” she said.
 

Wraparound support

The study is also a significant reminder that the opioid crisis has affected the young adult population, who are very vulnerable to OUD, said Jose Vito, MD, child, adolescent, and addiction psychiatrist at New York University.

“The study made me realize the importance of the four components of YORS, which were the outreach, family involvement, home delivery, and monetary incentives,” Dr. Vito said in an interview.

All of these components, in addition to extended-release naltrexone or extended-release buprenorphine, “have contributed to lower rates of opioid relapse, and the relapses are much later in the course of treatment if they do occur,” he said.

Overall, the findings demonstrate the importance of not giving up on these youths, he noted.

“Programs like YORS that provide wraparound support can help alleviate the opioid health care crisis by keeping these young adults in treatment,” Dr. Vito concluded.

The study was funded by the University of Maryland Center for Addiction Research, Education, and Service. Dr. Fishman has a financial relationship with Alkermes.

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

There is a substantial mismatch between patient and physician reports of toxicity during radiotherapy for breast cancer, according to an analysis of nearly 10,000 U.S. patients.

Researchers assessed physician underrecognition of four key symptoms – pain, pruritus, edema, and fatigue – during radiotherapy. Physicians underrecognized one of these four symptoms at least once in 53.2% of patients who reported having at least one substantial symptom.

“Understanding whether physicians detect when their patients are experiencing substantial toxicity is important, not only because recognition of symptoms is necessary for appropriate supportive care, but also because it influences what techniques and treatments we adopt,” said Reshma Jagsi, MD, DPhil, of the University of Michigan, Ann Arbor.

Dr. Jagsi presented the study results at the 2020 San Antonio Breast Cancer Symposium.

The underrecognition of symptoms during radiotherapy may reflect differences in physician or patient behaviors, according to Dr. Jagsi. “It’s absolutely something we need to understand better.”

Ian E. Krop, MD, PhD, of the Dana-Farber Cancer Institute in Boston, moderated the session where this research was presented and called the work “striking,” noting that it “clearly identifies an important area that needs improvement.”

“We need to do a better job. We as physicians need to listen more to our patients,” said Virginia Kaklamani, MD, of the University of Texas Health Science Center, San Antonio, and codirector of the SABCS 2020 meeting.
 

Comparing patient and physician reports

Dr. Jagsi and colleagues analyzed data on patients who had received radiotherapy after lumpectomy for breast cancer and had completed patient-reported outcome measures (PROs) as part of the Michigan Radiation Oncology Quality Consortium (MROQC). The MROQC registry collects data on patients receiving radiation for breast, lung, and prostate cancers, as well as for bone metastases.

Results of the PROs were compared with physician reports of toxicity as assessed using the Common Terminology Criteria for Adverse Events (CTCAE) system.

The researchers evaluated underrecognition of toxicity in 9,868 patients by comparing 37,593 independent paired observations from patients and their doctors. Patient and physician reports were made on the same day (n = 35,797) or within 3 days of each other (n = 1,796).

The comparison showed underrecognition of all four symptoms assessed – pain, pruritus, edema, and fatigue.

Underrecognition of pain was defined as patients reporting moderate pain while physicians graded pain as absent or as patients reporting severe pain while physicians rated pain as grade 1 or lower. Underrecognition of fatigue, bother from pruritus, or bother from edema were defined as physicians grading these symptoms as absent when patients reported fatigue or bother from pruritus/edema often or all of the time.

The percentage of observations with underrecognized symptoms was 30.9% for moderate to severe pain, 36.7% for frequent bother from pruritus, 51.4% for frequent bother from edema, and 18.8% for severe fatigue.

Factors independently associated with symptom underrecognition were younger age (odds ratio, 1.4 for <50 years and 1.2 for 50-59 years), Black or other non-White race (OR, 1.9 and 1.8, respectively), conventional fractionation (OR, 1.2), not having a supraclavicular field (OR, 1.3), and being treated at an academic center (OR, 1.1).
 

Underreporting worse in the time of COVID?

Data collection for this study ended before the start of the COVID-19 pandemic, but Dr. Jagsi expressed concern that the pandemic could lead to underrecognition of toxicity as well.

“We are doing more virtual visits, and I think the relationships between physicians and patients are a bit more strained,” Dr. Jagsi said. While virtual visits mean that patients can be seen safely, they are “not the same as being in the same room as one another.”

On the other hand, in-person visits during the pandemic may pose challenges as well. The need to wear masks during in-person consultations could lead to a lot of nonverbal communication being missed.

“I wouldn’t be surprised at all if underrecognition were worse in this context,” Dr. Jagsi said.
 

Encourage patients to speak up, use PROs

“I think we need to encourage patients that when we’ve told them that certain side effects are expected, it doesn’t mean that they shouldn’t tell us if they’re bothered by those side effects,” Dr. Jagsi said. “They’re not bothering us. They’re not troubling us to bring those symptoms to our attention, because there actually are things that we can do to help support them through the experience.”

Dr. Jagsi also said PROs should be included in clinical trials. Trials tend to rely on physician assessment of possible toxicity using the CTCAE system, but this can miss important symptoms that patients experience during radiotherapy.

The current study and MROQC were sponsored by Blue Cross Blue Shield of Michigan and the Blue Care Network as part of the BCBSM Value Partnership program. Dr. Jagsi disclosed financial relationships with Amgen, Equity Quotient, Genentech, Vizient, law firms, various foundations, the National Institutes of Health, and BCBSM for the MROQC. Dr. Kaklamani and Dr. Krop disclosed relationships with many pharmaceutical companies.

SOURCE: Jagsi R J et al. SABCS 2020, Abstract GS3-07.

There is a substantial mismatch between patient and physician reports of toxicity during radiotherapy for breast cancer, according to an analysis of nearly 10,000 U.S. patients.

Researchers assessed physician underrecognition of four key symptoms – pain, pruritus, edema, and fatigue – during radiotherapy. Physicians underrecognized one of these four symptoms at least once in 53.2% of patients who reported having at least one substantial symptom.

“Understanding whether physicians detect when their patients are experiencing substantial toxicity is important, not only because recognition of symptoms is necessary for appropriate supportive care, but also because it influences what techniques and treatments we adopt,” said Reshma Jagsi, MD, DPhil, of the University of Michigan, Ann Arbor.

Dr. Jagsi presented the study results at the 2020 San Antonio Breast Cancer Symposium.

The underrecognition of symptoms during radiotherapy may reflect differences in physician or patient behaviors, according to Dr. Jagsi. “It’s absolutely something we need to understand better.”

Ian E. Krop, MD, PhD, of the Dana-Farber Cancer Institute in Boston, moderated the session where this research was presented and called the work “striking,” noting that it “clearly identifies an important area that needs improvement.”

“We need to do a better job. We as physicians need to listen more to our patients,” said Virginia Kaklamani, MD, of the University of Texas Health Science Center, San Antonio, and codirector of the SABCS 2020 meeting.
 

Comparing patient and physician reports

Dr. Jagsi and colleagues analyzed data on patients who had received radiotherapy after lumpectomy for breast cancer and had completed patient-reported outcome measures (PROs) as part of the Michigan Radiation Oncology Quality Consortium (MROQC). The MROQC registry collects data on patients receiving radiation for breast, lung, and prostate cancers, as well as for bone metastases.

Results of the PROs were compared with physician reports of toxicity as assessed using the Common Terminology Criteria for Adverse Events (CTCAE) system.

The researchers evaluated underrecognition of toxicity in 9,868 patients by comparing 37,593 independent paired observations from patients and their doctors. Patient and physician reports were made on the same day (n = 35,797) or within 3 days of each other (n = 1,796).

The comparison showed underrecognition of all four symptoms assessed – pain, pruritus, edema, and fatigue.

Underrecognition of pain was defined as patients reporting moderate pain while physicians graded pain as absent or as patients reporting severe pain while physicians rated pain as grade 1 or lower. Underrecognition of fatigue, bother from pruritus, or bother from edema were defined as physicians grading these symptoms as absent when patients reported fatigue or bother from pruritus/edema often or all of the time.

The percentage of observations with underrecognized symptoms was 30.9% for moderate to severe pain, 36.7% for frequent bother from pruritus, 51.4% for frequent bother from edema, and 18.8% for severe fatigue.

Factors independently associated with symptom underrecognition were younger age (odds ratio, 1.4 for <50 years and 1.2 for 50-59 years), Black or other non-White race (OR, 1.9 and 1.8, respectively), conventional fractionation (OR, 1.2), not having a supraclavicular field (OR, 1.3), and being treated at an academic center (OR, 1.1).
 

Underreporting worse in the time of COVID?

Data collection for this study ended before the start of the COVID-19 pandemic, but Dr. Jagsi expressed concern that the pandemic could lead to underrecognition of toxicity as well.

“We are doing more virtual visits, and I think the relationships between physicians and patients are a bit more strained,” Dr. Jagsi said. While virtual visits mean that patients can be seen safely, they are “not the same as being in the same room as one another.”

On the other hand, in-person visits during the pandemic may pose challenges as well. The need to wear masks during in-person consultations could lead to a lot of nonverbal communication being missed.

“I wouldn’t be surprised at all if underrecognition were worse in this context,” Dr. Jagsi said.
 

Encourage patients to speak up, use PROs

“I think we need to encourage patients that when we’ve told them that certain side effects are expected, it doesn’t mean that they shouldn’t tell us if they’re bothered by those side effects,” Dr. Jagsi said. “They’re not bothering us. They’re not troubling us to bring those symptoms to our attention, because there actually are things that we can do to help support them through the experience.”

Dr. Jagsi also said PROs should be included in clinical trials. Trials tend to rely on physician assessment of possible toxicity using the CTCAE system, but this can miss important symptoms that patients experience during radiotherapy.

The current study and MROQC were sponsored by Blue Cross Blue Shield of Michigan and the Blue Care Network as part of the BCBSM Value Partnership program. Dr. Jagsi disclosed financial relationships with Amgen, Equity Quotient, Genentech, Vizient, law firms, various foundations, the National Institutes of Health, and BCBSM for the MROQC. Dr. Kaklamani and Dr. Krop disclosed relationships with many pharmaceutical companies.

SOURCE: Jagsi R J et al. SABCS 2020, Abstract GS3-07.

There is a substantial mismatch between patient and physician reports of toxicity during radiotherapy for breast cancer, according to an analysis of nearly 10,000 U.S. patients.

Researchers assessed physician underrecognition of four key symptoms – pain, pruritus, edema, and fatigue – during radiotherapy. Physicians underrecognized one of these four symptoms at least once in 53.2% of patients who reported having at least one substantial symptom.

“Understanding whether physicians detect when their patients are experiencing substantial toxicity is important, not only because recognition of symptoms is necessary for appropriate supportive care, but also because it influences what techniques and treatments we adopt,” said Reshma Jagsi, MD, DPhil, of the University of Michigan, Ann Arbor.

Dr. Jagsi presented the study results at the 2020 San Antonio Breast Cancer Symposium.

The underrecognition of symptoms during radiotherapy may reflect differences in physician or patient behaviors, according to Dr. Jagsi. “It’s absolutely something we need to understand better.”

Ian E. Krop, MD, PhD, of the Dana-Farber Cancer Institute in Boston, moderated the session where this research was presented and called the work “striking,” noting that it “clearly identifies an important area that needs improvement.”

“We need to do a better job. We as physicians need to listen more to our patients,” said Virginia Kaklamani, MD, of the University of Texas Health Science Center, San Antonio, and codirector of the SABCS 2020 meeting.
 

Comparing patient and physician reports

Dr. Jagsi and colleagues analyzed data on patients who had received radiotherapy after lumpectomy for breast cancer and had completed patient-reported outcome measures (PROs) as part of the Michigan Radiation Oncology Quality Consortium (MROQC). The MROQC registry collects data on patients receiving radiation for breast, lung, and prostate cancers, as well as for bone metastases.

Results of the PROs were compared with physician reports of toxicity as assessed using the Common Terminology Criteria for Adverse Events (CTCAE) system.

The researchers evaluated underrecognition of toxicity in 9,868 patients by comparing 37,593 independent paired observations from patients and their doctors. Patient and physician reports were made on the same day (n = 35,797) or within 3 days of each other (n = 1,796).

The comparison showed underrecognition of all four symptoms assessed – pain, pruritus, edema, and fatigue.

Underrecognition of pain was defined as patients reporting moderate pain while physicians graded pain as absent or as patients reporting severe pain while physicians rated pain as grade 1 or lower. Underrecognition of fatigue, bother from pruritus, or bother from edema were defined as physicians grading these symptoms as absent when patients reported fatigue or bother from pruritus/edema often or all of the time.

The percentage of observations with underrecognized symptoms was 30.9% for moderate to severe pain, 36.7% for frequent bother from pruritus, 51.4% for frequent bother from edema, and 18.8% for severe fatigue.

Factors independently associated with symptom underrecognition were younger age (odds ratio, 1.4 for <50 years and 1.2 for 50-59 years), Black or other non-White race (OR, 1.9 and 1.8, respectively), conventional fractionation (OR, 1.2), not having a supraclavicular field (OR, 1.3), and being treated at an academic center (OR, 1.1).
 

Underreporting worse in the time of COVID?

Data collection for this study ended before the start of the COVID-19 pandemic, but Dr. Jagsi expressed concern that the pandemic could lead to underrecognition of toxicity as well.

“We are doing more virtual visits, and I think the relationships between physicians and patients are a bit more strained,” Dr. Jagsi said. While virtual visits mean that patients can be seen safely, they are “not the same as being in the same room as one another.”

On the other hand, in-person visits during the pandemic may pose challenges as well. The need to wear masks during in-person consultations could lead to a lot of nonverbal communication being missed.

“I wouldn’t be surprised at all if underrecognition were worse in this context,” Dr. Jagsi said.
 

Encourage patients to speak up, use PROs

“I think we need to encourage patients that when we’ve told them that certain side effects are expected, it doesn’t mean that they shouldn’t tell us if they’re bothered by those side effects,” Dr. Jagsi said. “They’re not bothering us. They’re not troubling us to bring those symptoms to our attention, because there actually are things that we can do to help support them through the experience.”

Dr. Jagsi also said PROs should be included in clinical trials. Trials tend to rely on physician assessment of possible toxicity using the CTCAE system, but this can miss important symptoms that patients experience during radiotherapy.

The current study and MROQC were sponsored by Blue Cross Blue Shield of Michigan and the Blue Care Network as part of the BCBSM Value Partnership program. Dr. Jagsi disclosed financial relationships with Amgen, Equity Quotient, Genentech, Vizient, law firms, various foundations, the National Institutes of Health, and BCBSM for the MROQC. Dr. Kaklamani and Dr. Krop disclosed relationships with many pharmaceutical companies.

SOURCE: Jagsi R J et al. SABCS 2020, Abstract GS3-07.

Joshua Brody, MD, Director of the Lymphoma Immunotherapy Program at Icahn School of Medicine at Mount Sinai, highlights some of the exciting findings on classical Hodgkin lymphoma from the 62nd ASH Annual Meeting and Exposition, held virtually from December 5 to 8, 2020.

The efficacy of brentuximab vedotin (BV) as monotherapy or in combination was evaluated in patients aged 60 and older. Although all regimens appear to be effective, BV plus dacarbazine and BV plus nivolumab were shown to be the most promising combinations.

A 5-year update from the ECHELON-1 trial demonstrated that treatment with BV, doxorubicin, vinblastine, and dacarbazine (A+AVD) maintained reported initial efficacy findings. Many patients with peripheral neuropathy showed improvement or complete resolution at follow up, and most with persisting symptoms had low-grade (grade 1 or 2) neuropathy.

Advanced immune monitoring techniques have revealed details about the T cells in Hodgkin tumors at single-cell resolution. Cytotoxic CD8+ T cells might be antitumor T cells that mediate response to anti-PD1 antibody therapies.

--

Joshua Brody, MD, is the director of the Lymphoma Immunotherapy Program, Icahn School of Medicine at Mount Sinai, Hess Center for Science and Medicine

Dr. Brody has no relevant disclosures.

Joshua Brody, MD, Director of the Lymphoma Immunotherapy Program at Icahn School of Medicine at Mount Sinai, highlights some of the exciting findings on classical Hodgkin lymphoma from the 62nd ASH Annual Meeting and Exposition, held virtually from December 5 to 8, 2020.

The efficacy of brentuximab vedotin (BV) as monotherapy or in combination was evaluated in patients aged 60 and older. Although all regimens appear to be effective, BV plus dacarbazine and BV plus nivolumab were shown to be the most promising combinations.

A 5-year update from the ECHELON-1 trial demonstrated that treatment with BV, doxorubicin, vinblastine, and dacarbazine (A+AVD) maintained reported initial efficacy findings. Many patients with peripheral neuropathy showed improvement or complete resolution at follow up, and most with persisting symptoms had low-grade (grade 1 or 2) neuropathy.

Advanced immune monitoring techniques have revealed details about the T cells in Hodgkin tumors at single-cell resolution. Cytotoxic CD8+ T cells might be antitumor T cells that mediate response to anti-PD1 antibody therapies.

--

Joshua Brody, MD, is the director of the Lymphoma Immunotherapy Program, Icahn School of Medicine at Mount Sinai, Hess Center for Science and Medicine

Dr. Brody has no relevant disclosures.

Joshua Brody, MD, Director of the Lymphoma Immunotherapy Program at Icahn School of Medicine at Mount Sinai, highlights some of the exciting findings on classical Hodgkin lymphoma from the 62nd ASH Annual Meeting and Exposition, held virtually from December 5 to 8, 2020.

The efficacy of brentuximab vedotin (BV) as monotherapy or in combination was evaluated in patients aged 60 and older. Although all regimens appear to be effective, BV plus dacarbazine and BV plus nivolumab were shown to be the most promising combinations.

A 5-year update from the ECHELON-1 trial demonstrated that treatment with BV, doxorubicin, vinblastine, and dacarbazine (A+AVD) maintained reported initial efficacy findings. Many patients with peripheral neuropathy showed improvement or complete resolution at follow up, and most with persisting symptoms had low-grade (grade 1 or 2) neuropathy.

Advanced immune monitoring techniques have revealed details about the T cells in Hodgkin tumors at single-cell resolution. Cytotoxic CD8+ T cells might be antitumor T cells that mediate response to anti-PD1 antibody therapies.

--

Joshua Brody, MD, is the director of the Lymphoma Immunotherapy Program, Icahn School of Medicine at Mount Sinai, Hess Center for Science and Medicine

Dr. Brody has no relevant disclosures.