Federal Practitioner

Accumulating observational data suggest that metformin use in patients with type 2 diabetes might reduce the risk for death from COVID-19, but the randomized trials needed to prove this are unlikely to be carried out, according to experts.

The latest results, which are not yet peer reviewed, were published online July 31. The study was conducted by Andrew B. Crouse, PhD, of the Hugh Kaul Precision Medicine Institute, University of Alabama at Birmingham, and colleagues.

The researchers found that among more than 600 patients with diabetes and COVID-19, use of metformin was associated with a nearly 70% reduction in mortality after adjustment for multiple confounders.

Data from four previous studies that also show a reduction in mortality among metformin users compared to nonusers were summarized in a “mini review” by André J. Scheen, MD, PhD, published Aug. 1 in Diabetes and Metabolism.

Dr. Scheen, of the division of diabetes, nutrition, and metabolic disorders and the division of clinical pharmacology at Liège (Belgium) University, discussed possible mechanisms behind this observation.

“Because metformin exerts various effects beyond its glucose-lowering action, among which are anti-inflammatory effects, it may be speculated that this biguanide might positively influence the prognosis of patients with [type 2 diabetes] hospitalized for COVID-19,” he said.

“However, given the potential confounders inherently found in observational studies, caution is required before drawing any firm conclusions in the absence of randomized controlled trials,” Dr. Scheen wrote.

Indeed, when asked to comment, endocrinologist Kasia Lipska, MD, of Yale University, New Haven, Conn., said in an interview: “Metformin users tend to do better in many different settings with respect to many different outcomes. To me, it is still unclear whether metformin is truly a miracle drug or whether it is simply used more often among people who are healthier and who do not have contraindications to its use.”

She added, “I don’t think we have enough data to suggest metformin use for COVID-19 mitigation at this point.”

Alabama authors say confounding effects ‘unlikely’

In the retrospective analysis of electronic health records from their institution, Dr. Crouse and colleagues reviewed data from 604 patients who were confirmed to have tested positive for COVID-19 between Feb. 25 and June 22, 2020. Of those individuals, 40% had diabetes.

Death occurred in 11% (n = 67); the odds ratio (OR) for death among those with, vs. without, diabetes was 3.62 (P < .0001).

Individuals with diabetes accounted for >60% of all deaths. In multiple logistic regression, age 50-70 vs. <50, male sex, and diabetes emerged as independent predictors of death.

Of the 42 patients with diabetes who died, 8 (19%) had used metformin, and 34 (81%) had not*, a significant difference (OR, 0.38; P = .0221). Insulin use, on the other hand, had no effect on mortality (P = .5728).

“In fact, with 11% [being] the mortality of metformin users, [this] was comparable to that of the general COVID-19-positive population and dramatically lower than the 23% mortality observed in subjects with diabetes and not on metformin,” the authors said.

The survival benefit observed with metformin remained after exclusion of patients with classic metformin contraindications, such as chronic kidney disease and heart failure (OR, 0.17; P = .0231).

“This makes any potential confounding effects from skewing metformin users toward healthier subjects without these additional comorbidities very unlikely,” Dr. Crouse and colleagues contended.

After further analysis that controlled for other covariates (age, sex, obesity status, and hypertension), age, sex, and metformin use remained independent predictors of mortality.

For metformin, the odds ratio was 0.33 (P = .0210).

But, Dr. Lipska pointed out, “Observational studies can take into account confounders that are measured. However, unmeasured confounders may still affect the conclusions of these studies ... Propensity score matching to account for the likelihood of use of metformin could be used to better account for differences between metformin users and nonusers.”

If metformin does reduce COVID-19 deaths, multiple mechanisms likely

In his article, Dr. Scheen noted that several mechanisms have been proposed for the possible beneficial effect of metformin on COVID-19 outcomes, including direct improvements in glucose control, body weight, and insulin resistance; reduction in inflammation; inhibition of virus penetration via phosphorylation of ACE2; inhibition of an immune hyperactivation pathway; and neutrophil reduction. All remain theoretical, he emphasized.

He noted that some authors have raised concerns about possible harms from the use of metformin by patients with type 2 diabetes who are hospitalized for COVID-19, particularly because of the potential risk for lactic acidosis in cases of multiple organ failure.

In totality, four studies suggest 25% death reduction with metformin

Taken together, the four observational studies that Dr. Scheen reviewed showed that metformin had a positive effect, with an overall 25% reduction in death (P < .00001), albeit with relatively high heterogeneity (I² = 61%).

The largest of these, from the United States, included 6,256 patients hospitalized with COVID-19 and involved propensity matching. A significant reduction in mortality with metformin use was seen in women but not men (odds ratio, 0.759).

The French Coronavirus-SARS-CoV-2 and Diabetes Outcomes (CORONADO) study of 1,317 patients with diabetes and confirmed COVID-19 who were admitted to 53 French hospitals also showed a significant survival benefit for metformin, although the study wasn’t designed to address that issue.

In that study, the odds ratio for death on day 7 in prior metformin users compared to nonusers was 0.59. This finding lost significance but remained a trend after full adjustments (0.80).

Two smaller observational studies produced similar trends toward survival benefit with metformin.

Nonetheless, Dr. Scheen cautioned: “Firm conclusions about the impact of metformin therapy can only be drawn from double-blind randomized controlled trials (RCTs), and such trials are almost impossible in the context of COVID-19.”

He added: “Because metformin is out of patent and very inexpensive, no pharmaceutical company is likely to be interested in planning a study to demonstrate the benefits of metformin on COVID-19-related clinical outcomes.”

Dr. Lipska agreed: “RCTs are unlikely to be conducted to settle these issues. In their absence, metformin use should be based on its safety and effectiveness profile.”

Dr. Scheen concluded, however, that “there are at least no negative safety indications, so there is no reason to stop metformin therapy during COVID-19 infection except in cases of severe gastrointestinal symptoms, hypoxia and/or multiple organ failure.”

Dr. Lipska has received grants from the National Institutes of Health and works under contract for the Centers for Medicare & Medicaid Services to develop publicly reported quality measures. Dr. Scheen has disclosed no relevant financial relationships.
 

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

*A previous version reversed these two outcomes in error. 

Accumulating observational data suggest that metformin use in patients with type 2 diabetes might reduce the risk for death from COVID-19, but the randomized trials needed to prove this are unlikely to be carried out, according to experts.

The latest results, which are not yet peer reviewed, were published online July 31. The study was conducted by Andrew B. Crouse, PhD, of the Hugh Kaul Precision Medicine Institute, University of Alabama at Birmingham, and colleagues.

The researchers found that among more than 600 patients with diabetes and COVID-19, use of metformin was associated with a nearly 70% reduction in mortality after adjustment for multiple confounders.

Data from four previous studies that also show a reduction in mortality among metformin users compared to nonusers were summarized in a “mini review” by André J. Scheen, MD, PhD, published Aug. 1 in Diabetes and Metabolism.

Dr. Scheen, of the division of diabetes, nutrition, and metabolic disorders and the division of clinical pharmacology at Liège (Belgium) University, discussed possible mechanisms behind this observation.

“Because metformin exerts various effects beyond its glucose-lowering action, among which are anti-inflammatory effects, it may be speculated that this biguanide might positively influence the prognosis of patients with [type 2 diabetes] hospitalized for COVID-19,” he said.

“However, given the potential confounders inherently found in observational studies, caution is required before drawing any firm conclusions in the absence of randomized controlled trials,” Dr. Scheen wrote.

Indeed, when asked to comment, endocrinologist Kasia Lipska, MD, of Yale University, New Haven, Conn., said in an interview: “Metformin users tend to do better in many different settings with respect to many different outcomes. To me, it is still unclear whether metformin is truly a miracle drug or whether it is simply used more often among people who are healthier and who do not have contraindications to its use.”

She added, “I don’t think we have enough data to suggest metformin use for COVID-19 mitigation at this point.”

Alabama authors say confounding effects ‘unlikely’

In the retrospective analysis of electronic health records from their institution, Dr. Crouse and colleagues reviewed data from 604 patients who were confirmed to have tested positive for COVID-19 between Feb. 25 and June 22, 2020. Of those individuals, 40% had diabetes.

Death occurred in 11% (n = 67); the odds ratio (OR) for death among those with, vs. without, diabetes was 3.62 (P < .0001).

Individuals with diabetes accounted for >60% of all deaths. In multiple logistic regression, age 50-70 vs. <50, male sex, and diabetes emerged as independent predictors of death.

Of the 42 patients with diabetes who died, 8 (19%) had used metformin, and 34 (81%) had not*, a significant difference (OR, 0.38; P = .0221). Insulin use, on the other hand, had no effect on mortality (P = .5728).

“In fact, with 11% [being] the mortality of metformin users, [this] was comparable to that of the general COVID-19-positive population and dramatically lower than the 23% mortality observed in subjects with diabetes and not on metformin,” the authors said.

The survival benefit observed with metformin remained after exclusion of patients with classic metformin contraindications, such as chronic kidney disease and heart failure (OR, 0.17; P = .0231).

“This makes any potential confounding effects from skewing metformin users toward healthier subjects without these additional comorbidities very unlikely,” Dr. Crouse and colleagues contended.

After further analysis that controlled for other covariates (age, sex, obesity status, and hypertension), age, sex, and metformin use remained independent predictors of mortality.

For metformin, the odds ratio was 0.33 (P = .0210).

But, Dr. Lipska pointed out, “Observational studies can take into account confounders that are measured. However, unmeasured confounders may still affect the conclusions of these studies ... Propensity score matching to account for the likelihood of use of metformin could be used to better account for differences between metformin users and nonusers.”

If metformin does reduce COVID-19 deaths, multiple mechanisms likely

In his article, Dr. Scheen noted that several mechanisms have been proposed for the possible beneficial effect of metformin on COVID-19 outcomes, including direct improvements in glucose control, body weight, and insulin resistance; reduction in inflammation; inhibition of virus penetration via phosphorylation of ACE2; inhibition of an immune hyperactivation pathway; and neutrophil reduction. All remain theoretical, he emphasized.

He noted that some authors have raised concerns about possible harms from the use of metformin by patients with type 2 diabetes who are hospitalized for COVID-19, particularly because of the potential risk for lactic acidosis in cases of multiple organ failure.

In totality, four studies suggest 25% death reduction with metformin

Taken together, the four observational studies that Dr. Scheen reviewed showed that metformin had a positive effect, with an overall 25% reduction in death (P < .00001), albeit with relatively high heterogeneity (I² = 61%).

The largest of these, from the United States, included 6,256 patients hospitalized with COVID-19 and involved propensity matching. A significant reduction in mortality with metformin use was seen in women but not men (odds ratio, 0.759).

The French Coronavirus-SARS-CoV-2 and Diabetes Outcomes (CORONADO) study of 1,317 patients with diabetes and confirmed COVID-19 who were admitted to 53 French hospitals also showed a significant survival benefit for metformin, although the study wasn’t designed to address that issue.

In that study, the odds ratio for death on day 7 in prior metformin users compared to nonusers was 0.59. This finding lost significance but remained a trend after full adjustments (0.80).

Two smaller observational studies produced similar trends toward survival benefit with metformin.

Nonetheless, Dr. Scheen cautioned: “Firm conclusions about the impact of metformin therapy can only be drawn from double-blind randomized controlled trials (RCTs), and such trials are almost impossible in the context of COVID-19.”

He added: “Because metformin is out of patent and very inexpensive, no pharmaceutical company is likely to be interested in planning a study to demonstrate the benefits of metformin on COVID-19-related clinical outcomes.”

Dr. Lipska agreed: “RCTs are unlikely to be conducted to settle these issues. In their absence, metformin use should be based on its safety and effectiveness profile.”

Dr. Scheen concluded, however, that “there are at least no negative safety indications, so there is no reason to stop metformin therapy during COVID-19 infection except in cases of severe gastrointestinal symptoms, hypoxia and/or multiple organ failure.”

Dr. Lipska has received grants from the National Institutes of Health and works under contract for the Centers for Medicare & Medicaid Services to develop publicly reported quality measures. Dr. Scheen has disclosed no relevant financial relationships.
 

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

*A previous version reversed these two outcomes in error. 

Accumulating observational data suggest that metformin use in patients with type 2 diabetes might reduce the risk for death from COVID-19, but the randomized trials needed to prove this are unlikely to be carried out, according to experts.

The latest results, which are not yet peer reviewed, were published online July 31. The study was conducted by Andrew B. Crouse, PhD, of the Hugh Kaul Precision Medicine Institute, University of Alabama at Birmingham, and colleagues.

The researchers found that among more than 600 patients with diabetes and COVID-19, use of metformin was associated with a nearly 70% reduction in mortality after adjustment for multiple confounders.

Data from four previous studies that also show a reduction in mortality among metformin users compared to nonusers were summarized in a “mini review” by André J. Scheen, MD, PhD, published Aug. 1 in Diabetes and Metabolism.

Dr. Scheen, of the division of diabetes, nutrition, and metabolic disorders and the division of clinical pharmacology at Liège (Belgium) University, discussed possible mechanisms behind this observation.

“Because metformin exerts various effects beyond its glucose-lowering action, among which are anti-inflammatory effects, it may be speculated that this biguanide might positively influence the prognosis of patients with [type 2 diabetes] hospitalized for COVID-19,” he said.

“However, given the potential confounders inherently found in observational studies, caution is required before drawing any firm conclusions in the absence of randomized controlled trials,” Dr. Scheen wrote.

Indeed, when asked to comment, endocrinologist Kasia Lipska, MD, of Yale University, New Haven, Conn., said in an interview: “Metformin users tend to do better in many different settings with respect to many different outcomes. To me, it is still unclear whether metformin is truly a miracle drug or whether it is simply used more often among people who are healthier and who do not have contraindications to its use.”

She added, “I don’t think we have enough data to suggest metformin use for COVID-19 mitigation at this point.”

Alabama authors say confounding effects ‘unlikely’

In the retrospective analysis of electronic health records from their institution, Dr. Crouse and colleagues reviewed data from 604 patients who were confirmed to have tested positive for COVID-19 between Feb. 25 and June 22, 2020. Of those individuals, 40% had diabetes.

Death occurred in 11% (n = 67); the odds ratio (OR) for death among those with, vs. without, diabetes was 3.62 (P < .0001).

Individuals with diabetes accounted for >60% of all deaths. In multiple logistic regression, age 50-70 vs. <50, male sex, and diabetes emerged as independent predictors of death.

Of the 42 patients with diabetes who died, 8 (19%) had used metformin, and 34 (81%) had not*, a significant difference (OR, 0.38; P = .0221). Insulin use, on the other hand, had no effect on mortality (P = .5728).

“In fact, with 11% [being] the mortality of metformin users, [this] was comparable to that of the general COVID-19-positive population and dramatically lower than the 23% mortality observed in subjects with diabetes and not on metformin,” the authors said.

The survival benefit observed with metformin remained after exclusion of patients with classic metformin contraindications, such as chronic kidney disease and heart failure (OR, 0.17; P = .0231).

“This makes any potential confounding effects from skewing metformin users toward healthier subjects without these additional comorbidities very unlikely,” Dr. Crouse and colleagues contended.

After further analysis that controlled for other covariates (age, sex, obesity status, and hypertension), age, sex, and metformin use remained independent predictors of mortality.

For metformin, the odds ratio was 0.33 (P = .0210).

But, Dr. Lipska pointed out, “Observational studies can take into account confounders that are measured. However, unmeasured confounders may still affect the conclusions of these studies ... Propensity score matching to account for the likelihood of use of metformin could be used to better account for differences between metformin users and nonusers.”

If metformin does reduce COVID-19 deaths, multiple mechanisms likely

In his article, Dr. Scheen noted that several mechanisms have been proposed for the possible beneficial effect of metformin on COVID-19 outcomes, including direct improvements in glucose control, body weight, and insulin resistance; reduction in inflammation; inhibition of virus penetration via phosphorylation of ACE2; inhibition of an immune hyperactivation pathway; and neutrophil reduction. All remain theoretical, he emphasized.

He noted that some authors have raised concerns about possible harms from the use of metformin by patients with type 2 diabetes who are hospitalized for COVID-19, particularly because of the potential risk for lactic acidosis in cases of multiple organ failure.

In totality, four studies suggest 25% death reduction with metformin

Taken together, the four observational studies that Dr. Scheen reviewed showed that metformin had a positive effect, with an overall 25% reduction in death (P < .00001), albeit with relatively high heterogeneity (I² = 61%).

The largest of these, from the United States, included 6,256 patients hospitalized with COVID-19 and involved propensity matching. A significant reduction in mortality with metformin use was seen in women but not men (odds ratio, 0.759).

The French Coronavirus-SARS-CoV-2 and Diabetes Outcomes (CORONADO) study of 1,317 patients with diabetes and confirmed COVID-19 who were admitted to 53 French hospitals also showed a significant survival benefit for metformin, although the study wasn’t designed to address that issue.

In that study, the odds ratio for death on day 7 in prior metformin users compared to nonusers was 0.59. This finding lost significance but remained a trend after full adjustments (0.80).

Two smaller observational studies produced similar trends toward survival benefit with metformin.

Nonetheless, Dr. Scheen cautioned: “Firm conclusions about the impact of metformin therapy can only be drawn from double-blind randomized controlled trials (RCTs), and such trials are almost impossible in the context of COVID-19.”

He added: “Because metformin is out of patent and very inexpensive, no pharmaceutical company is likely to be interested in planning a study to demonstrate the benefits of metformin on COVID-19-related clinical outcomes.”

Dr. Lipska agreed: “RCTs are unlikely to be conducted to settle these issues. In their absence, metformin use should be based on its safety and effectiveness profile.”

Dr. Scheen concluded, however, that “there are at least no negative safety indications, so there is no reason to stop metformin therapy during COVID-19 infection except in cases of severe gastrointestinal symptoms, hypoxia and/or multiple organ failure.”

Dr. Lipska has received grants from the National Institutes of Health and works under contract for the Centers for Medicare & Medicaid Services to develop publicly reported quality measures. Dr. Scheen has disclosed no relevant financial relationships.
 

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

*A previous version reversed these two outcomes in error. 

The Centers for Disease Control and Prevention reported recently that opioid overdose deaths will increase to a new U.S. record, and more are expected as pandemic-related overdose deaths are yet to be counted.¹

Specifically, according to the CDC, 70,980 people died from fatal overdoses in 2019,² which is record high. Experts such as Bruce A. Goldberger, PhD, fear that the 2020 numbers could rise even higher, exacerbated by the coronavirus pandemic.

Deaths from drug overdoses remain higher than the peak yearly death totals ever recorded for car accidents, guns, or AIDS. Overdose deaths have accelerated further – pushing down overall life expectancy in the United States.³ Headlines purporting to identify good news in drug death figures don’t always get below top-level data. Deaths and despair tied to drug dependence are indeed accelerating. I am concerned about these alarmingly dangerous trends.

Synthetic opioids such as fentanyl accounted for about 3,000 deaths in 2013. By 2019, they accounted for more than 37,137.⁴ In addition, 16,539 deaths involved stimulants such as methamphetamine, and 16,196 deaths involved cocaine, the most recent CDC reporting shows. Opioids continue to play a role in U.S. “deaths of despair,” or rising fatalities from drugs, suicides, and alcohol among Americans without employment, hope of job opportunities, or college degrees.⁵ As the American Medical Association has warned,⁶ more people are dying from overdoses amid the COVID-19 pandemic. Clinicians need to be aware of trends so that we can help our patients navigate these challenges.
 

Fentanyl presents dangers

Experts had predicted that the pandemic, by limiting access to treatment, rescue, or overdose services, and increasing time at home and in the neighborhood, would result in more tragedy. In addition, the shift from prescription opioids to heroin and now to fentanyl has made deaths more common.

Fentanyls – synthetic opioids – are involved in more than half of overdose deaths, and in many of the cocaine and methamphetamine-related deaths, which also are on the rise. Fentanyl is about 100 times more potent than morphine and 50 times more potent than heroin. Breathing can stop after use of just 2 mg of fentanyl, which is about as much as trace amounts of table salt. Fentanyl has replaced heroin in many cities as the pandemic changed the relative ease of importing raw drugs such as heroin.

Another important trend is that fentanyl production and distribution throughout the United States have expanded. The ease of manufacture in unregulated sectors of the Chinese and Mexican economies is difficult for U.S. authorities to curb or eliminate. The Internet promotes novel strategies for synthesizing the substance, spreading its production across many labs; suppliers use the U.S. Postal Service for distribution, and e-commerce helps to get the drug from manufacturers to U.S. consumers for fentanyl transactions.

A recent RAND report observes that, for only $10 through the postal service, suppliers can ship a 1-kg parcel from China to the United States, and private shipments cost about $100.⁷ And with large volumes of legal trade between the two countries making rigorous scrutiny of products difficult, especially given the light weight of fentanyl, suppliers find it relatively easy to hide illicit substances in licit shipments. Opioid users have made the switch to fentanyl, and have seen fentanyl added to cocaine and methamphetamine they buy on the streets.
 

OUD and buprenorphine

Fentanyl is one part of the overdose crisis. Opioid use disorder (OUD) is the other. Both need to be addressed if we are to make any progress in this epidemic of death and dependency.

The OUD crisis continues amid the pandemic – and isn’t going away.⁸ Slips, relapses, and overdoses are all too common. Medication-assisted treatment (MAT) and OUD treatment programs are essential parts of our response to overdose initiatives. After naloxone rescue, the best anti-overdose response is to get the OUD patient into treatment with MATs. Patients with OUD have continuously high risks of overdose. The best outcomes appear to be related to treatment duration of greater than 2 years. But it is common to see patients with OUDs who have been in treatment multiple times, taking MATs, dropping out, overdosing, and dying. Some have been described as treatment resistant.⁹ It is clear that treatment can work, but also that even evidence-based treatments often fail.¹⁰

A recent study compared OUD patients who continued treatment for 6-9 months to those patients who had continued MAT treatment for 15-18 months. The longer the treatment, the fewer emergencies, prescriptions, or hospitalizations.¹¹

But this study reminds us that all OUD patients, whether they are currently buprenorphine treated or not, experience overdoses and emergency department interventions. Short and longer treatment groups have a similar nonfatal overdose rate, about 6%, and went to the emergency department at a high rate, above 40%. Discontinuation of buprenorphine treatment is a major risk factor in opioid relapse, emergency department visits, and overdose. Cures are not common. Whether an OUD patient is being treated or has been treated in the past, carrying naloxone (brand name Narcan), makes sense and can save lives.
 

Methadone still considered most effective

Methadone is a synthetic opioid first studied as a treatment for OUD at Rockefeller University in New York City in the 1960s. Methadone may be the most effective treatment for OUD in promoting treatment retention for years, decreasing intravenous drug use, and decreasing deaths.¹² It has been studied and safely used in treatment programs for decades. Methadone is typically administered in a clinic, daily, and with observation. In addition, methadone patients periodically take urine drug tests, which can distinguish methadone from substances of abuse. They also receive counseling. But methadone can be prescribed and administered only in methadone clinics in the United States. It is available for prescription in primary care clinics in Great Britain, Canada, and Australia.¹³ Numerous experts have suggested passing new legislation aimed at changing how methadone can be prescribed. Allowing primary care to administer methadone, just like buprenorphine, can improve access and benefit OUD patients.¹²

Availability of Narcan is critical

A comprehensive treatment model for OUDs includes prescribing naloxone, encouraging those patients with an OUD and their loved ones to have naloxone with them, and providing MATs and appropriate therapies, such as counseling.

As described by Allison L. Pitt and colleagues at Stanford (Calif.) University,¹⁴ the United States might be on track to have up to 500,000 deaths tied to opioid overdoses that might occur over the next 5 years. They modeled the effect on overdose of a long list of interventions, but only a few had an impact. At the top of the list was naloxone availability. We need to focus on saving lives by increasing naloxone availability, improving initiation, and expanding access to MAT, and increasing psychosocial treatment to improve outcomes, increase life-years and quality-adjusted life-years, and reduce opioid-related deaths. When Ms. Pitt and colleagues looked at what would make the most impact in reducing OUD deaths, it was naloxone. Pain patients on higher doses of opioids, nonprescription opioid users, OUD patients should be given naloxone prescriptions. While many can give a Heimlich to a choking person or CPR, few have naloxone to rescue a person who has overdosed on opioids. If an overdose is suspected, it should be administered by anyone who has it, as soon as possible. Then, the person who is intervening should call 911.
 

What we can do today

At this moment, clinicians can follow the Surgeon General’s advice,¹⁵ and prescribe naloxone.

We should give naloxone to OUD patients and their families, to pain patients at dosages of greater than or equal to 50 MME. Our top priorities should be patients with comorbid pain syndromes, those being treated with benzodiazepines and sleeping medications, and patients with alcohol use disorders. This is also an important intervention for those who binge drink, and have sleep apnea, and heart and respiratory diseases.

Naloxone is available without a prescription in at least 43 states. Naloxone is available in harm reduction programs and in hospitals, and is carried by emergency medical staff, law enforcement, and EMTs. It also is available on the streets, though it does not appear to have a dollar value like opioids or even buprenorphine. Also, the availability of naloxone in pharmacies has made it easier for family members and caregivers of pain patients or those with OUD to have it to administer in an emergency.

An excellent place for MDs to start is to do more to encourage all patients with OUD to carry naloxone, for their loved ones to carry naloxone, and for their homes to have naloxone nearby in the bedroom or bathroom. It is not logical to expect a person with an OUD to rescue themselves. Current and past OUD patients, as well as their loved ones, are at high risk – and should have naloxone nearby at all times.

Naloxone reverses an opioid overdose, but it should be thought about like cardioversion or CPR rather than a treatment for an underlying disease. Increasing access to buprenorphine, buprenorphine + naloxone, and naltrexone treatment for OUDs is an important organizing principle. Initiation of MAT treatment in the emergency setting or most anywhere and any place a patient with an OUD can begin treatment is necessary. Treatment with buprenorphine or methadone reduces opioid overdose and opioid-related acute care use.¹⁶

Reducing racial disparities in OUD treatment is necessary, because buprenorphine treatment is concentrated among White patients who either use private insurance or are self-pay.¹⁷ Reducing barriers to methadone program licenses, expanding sites for distribution,¹⁸ prescribing methadone in an office setting might help. Clinicians can do a better job of explaining the risks associated with opioid prescriptions, including diversion and overdose, and the benefits of OUD treatment. So, while naloxone saves lives and is a wonder drug, it does not replace an intervention such as MAT, a counselor, a good treatment program, and a treatment plan. To reduce opioid overdoses, we must increase physician competencies in addiction medicine.
 

Dr. Gold is professor of psychiatry (adjunct) at Washington University, St. Louis. He is the 17th Distinguished Alumni Professor at the University of Florida, Gainesville. For more than 40 years, Dr. Gold has worked on developing models for understanding the effects of opioid, tobacco, cocaine, and other drugs, as well as food, on the brain and behavior. He disclosed financial ties with ADAPT Pharma and Magstim Ltd.

References

1. Kamp J. Overdose deaths rise, may reach record level, federal data show. Wall Street Journal. 2020 Jul 15.

2. 12 month–ending provisional number of drug overdose drugs. Centers for Disease Control and Prevention. 2020 Jul 5.

3. Katz J et al. In shadow of pandemic, U.S. drug overdose deaths resurge to record. New York Times. 2020 Jul 15.

4. Gold MS. The fentanyl crisis is only getting worse. Addiction Policy Forum. Updated 2020 Mar 12.

5. Gold MS. Mo Med. 2020-Mar-Apr;117(2):99-101.

6. Reports of increases in opioid-related overdoses and other concerns during the COVID-19 pandemic. American Medical Association. Issue brief. Updated 2020 Jul 20.

7. Pardo B et al. The future of fentanyl and other synthetic opioids. RAND report.

8. Gold MS. New challenges in the opioid epidemic. Addiction Policy Forum. 2020 Jun 4.

9. Patterson Silver Wolf DA and Gold MS. J Neurol Sci. 2020;411:116718.

10. Oesterle TS et al. Mayo Clin Proc. 2019;94(10):2072-86.

11. Connery HS and Weiss RD. Am J Psychiatry. 2020;177(2):104-6.

12. Kleber HD. JAMA. 2008;300(19):2303-5.

13. Samet JH et al. N Engl J Med. 2018;379(1):7-8.

14. Pitt AL et al. Am J Public Health. 2018;108(10):1394-1400.

15. U.S. Surgeon General’s Advisory on Naloxone and Opioid Overdose. hhs.gov.

16. Wakeman SE et al. JAMA Netw Open. 2020;3(2):e1920622.

17. Lagisetty PA et al. JAMA Psychiatry. 2019;76(9):979-81.

18. Kleinman RA. JAMA Psychiatry. 2020 Jul 15. doi: 10.1001/jamapsychiatry.2020.1624.

The Centers for Disease Control and Prevention reported recently that opioid overdose deaths will increase to a new U.S. record, and more are expected as pandemic-related overdose deaths are yet to be counted.¹

Specifically, according to the CDC, 70,980 people died from fatal overdoses in 2019,² which is record high. Experts such as Bruce A. Goldberger, PhD, fear that the 2020 numbers could rise even higher, exacerbated by the coronavirus pandemic.

Deaths from drug overdoses remain higher than the peak yearly death totals ever recorded for car accidents, guns, or AIDS. Overdose deaths have accelerated further – pushing down overall life expectancy in the United States.³ Headlines purporting to identify good news in drug death figures don’t always get below top-level data. Deaths and despair tied to drug dependence are indeed accelerating. I am concerned about these alarmingly dangerous trends.

Synthetic opioids such as fentanyl accounted for about 3,000 deaths in 2013. By 2019, they accounted for more than 37,137.⁴ In addition, 16,539 deaths involved stimulants such as methamphetamine, and 16,196 deaths involved cocaine, the most recent CDC reporting shows. Opioids continue to play a role in U.S. “deaths of despair,” or rising fatalities from drugs, suicides, and alcohol among Americans without employment, hope of job opportunities, or college degrees.⁵ As the American Medical Association has warned,⁶ more people are dying from overdoses amid the COVID-19 pandemic. Clinicians need to be aware of trends so that we can help our patients navigate these challenges.
 

Fentanyl presents dangers

Experts had predicted that the pandemic, by limiting access to treatment, rescue, or overdose services, and increasing time at home and in the neighborhood, would result in more tragedy. In addition, the shift from prescription opioids to heroin and now to fentanyl has made deaths more common.

Fentanyls – synthetic opioids – are involved in more than half of overdose deaths, and in many of the cocaine and methamphetamine-related deaths, which also are on the rise. Fentanyl is about 100 times more potent than morphine and 50 times more potent than heroin. Breathing can stop after use of just 2 mg of fentanyl, which is about as much as trace amounts of table salt. Fentanyl has replaced heroin in many cities as the pandemic changed the relative ease of importing raw drugs such as heroin.

Another important trend is that fentanyl production and distribution throughout the United States have expanded. The ease of manufacture in unregulated sectors of the Chinese and Mexican economies is difficult for U.S. authorities to curb or eliminate. The Internet promotes novel strategies for synthesizing the substance, spreading its production across many labs; suppliers use the U.S. Postal Service for distribution, and e-commerce helps to get the drug from manufacturers to U.S. consumers for fentanyl transactions.

A recent RAND report observes that, for only $10 through the postal service, suppliers can ship a 1-kg parcel from China to the United States, and private shipments cost about $100.⁷ And with large volumes of legal trade between the two countries making rigorous scrutiny of products difficult, especially given the light weight of fentanyl, suppliers find it relatively easy to hide illicit substances in licit shipments. Opioid users have made the switch to fentanyl, and have seen fentanyl added to cocaine and methamphetamine they buy on the streets.
 

OUD and buprenorphine

Fentanyl is one part of the overdose crisis. Opioid use disorder (OUD) is the other. Both need to be addressed if we are to make any progress in this epidemic of death and dependency.

The OUD crisis continues amid the pandemic – and isn’t going away.⁸ Slips, relapses, and overdoses are all too common. Medication-assisted treatment (MAT) and OUD treatment programs are essential parts of our response to overdose initiatives. After naloxone rescue, the best anti-overdose response is to get the OUD patient into treatment with MATs. Patients with OUD have continuously high risks of overdose. The best outcomes appear to be related to treatment duration of greater than 2 years. But it is common to see patients with OUDs who have been in treatment multiple times, taking MATs, dropping out, overdosing, and dying. Some have been described as treatment resistant.⁹ It is clear that treatment can work, but also that even evidence-based treatments often fail.¹⁰

A recent study compared OUD patients who continued treatment for 6-9 months to those patients who had continued MAT treatment for 15-18 months. The longer the treatment, the fewer emergencies, prescriptions, or hospitalizations.¹¹

But this study reminds us that all OUD patients, whether they are currently buprenorphine treated or not, experience overdoses and emergency department interventions. Short and longer treatment groups have a similar nonfatal overdose rate, about 6%, and went to the emergency department at a high rate, above 40%. Discontinuation of buprenorphine treatment is a major risk factor in opioid relapse, emergency department visits, and overdose. Cures are not common. Whether an OUD patient is being treated or has been treated in the past, carrying naloxone (brand name Narcan), makes sense and can save lives.
 

Methadone still considered most effective

Methadone is a synthetic opioid first studied as a treatment for OUD at Rockefeller University in New York City in the 1960s. Methadone may be the most effective treatment for OUD in promoting treatment retention for years, decreasing intravenous drug use, and decreasing deaths.¹² It has been studied and safely used in treatment programs for decades. Methadone is typically administered in a clinic, daily, and with observation. In addition, methadone patients periodically take urine drug tests, which can distinguish methadone from substances of abuse. They also receive counseling. But methadone can be prescribed and administered only in methadone clinics in the United States. It is available for prescription in primary care clinics in Great Britain, Canada, and Australia.¹³ Numerous experts have suggested passing new legislation aimed at changing how methadone can be prescribed. Allowing primary care to administer methadone, just like buprenorphine, can improve access and benefit OUD patients.¹²

Availability of Narcan is critical

A comprehensive treatment model for OUDs includes prescribing naloxone, encouraging those patients with an OUD and their loved ones to have naloxone with them, and providing MATs and appropriate therapies, such as counseling.

As described by Allison L. Pitt and colleagues at Stanford (Calif.) University,¹⁴ the United States might be on track to have up to 500,000 deaths tied to opioid overdoses that might occur over the next 5 years. They modeled the effect on overdose of a long list of interventions, but only a few had an impact. At the top of the list was naloxone availability. We need to focus on saving lives by increasing naloxone availability, improving initiation, and expanding access to MAT, and increasing psychosocial treatment to improve outcomes, increase life-years and quality-adjusted life-years, and reduce opioid-related deaths. When Ms. Pitt and colleagues looked at what would make the most impact in reducing OUD deaths, it was naloxone. Pain patients on higher doses of opioids, nonprescription opioid users, OUD patients should be given naloxone prescriptions. While many can give a Heimlich to a choking person or CPR, few have naloxone to rescue a person who has overdosed on opioids. If an overdose is suspected, it should be administered by anyone who has it, as soon as possible. Then, the person who is intervening should call 911.
 

What we can do today

At this moment, clinicians can follow the Surgeon General’s advice,¹⁵ and prescribe naloxone.

We should give naloxone to OUD patients and their families, to pain patients at dosages of greater than or equal to 50 MME. Our top priorities should be patients with comorbid pain syndromes, those being treated with benzodiazepines and sleeping medications, and patients with alcohol use disorders. This is also an important intervention for those who binge drink, and have sleep apnea, and heart and respiratory diseases.

Naloxone is available without a prescription in at least 43 states. Naloxone is available in harm reduction programs and in hospitals, and is carried by emergency medical staff, law enforcement, and EMTs. It also is available on the streets, though it does not appear to have a dollar value like opioids or even buprenorphine. Also, the availability of naloxone in pharmacies has made it easier for family members and caregivers of pain patients or those with OUD to have it to administer in an emergency.

An excellent place for MDs to start is to do more to encourage all patients with OUD to carry naloxone, for their loved ones to carry naloxone, and for their homes to have naloxone nearby in the bedroom or bathroom. It is not logical to expect a person with an OUD to rescue themselves. Current and past OUD patients, as well as their loved ones, are at high risk – and should have naloxone nearby at all times.

Naloxone reverses an opioid overdose, but it should be thought about like cardioversion or CPR rather than a treatment for an underlying disease. Increasing access to buprenorphine, buprenorphine + naloxone, and naltrexone treatment for OUDs is an important organizing principle. Initiation of MAT treatment in the emergency setting or most anywhere and any place a patient with an OUD can begin treatment is necessary. Treatment with buprenorphine or methadone reduces opioid overdose and opioid-related acute care use.¹⁶

Reducing racial disparities in OUD treatment is necessary, because buprenorphine treatment is concentrated among White patients who either use private insurance or are self-pay.¹⁷ Reducing barriers to methadone program licenses, expanding sites for distribution,¹⁸ prescribing methadone in an office setting might help. Clinicians can do a better job of explaining the risks associated with opioid prescriptions, including diversion and overdose, and the benefits of OUD treatment. So, while naloxone saves lives and is a wonder drug, it does not replace an intervention such as MAT, a counselor, a good treatment program, and a treatment plan. To reduce opioid overdoses, we must increase physician competencies in addiction medicine.
 

Dr. Gold is professor of psychiatry (adjunct) at Washington University, St. Louis. He is the 17th Distinguished Alumni Professor at the University of Florida, Gainesville. For more than 40 years, Dr. Gold has worked on developing models for understanding the effects of opioid, tobacco, cocaine, and other drugs, as well as food, on the brain and behavior. He disclosed financial ties with ADAPT Pharma and Magstim Ltd.

References

1. Kamp J. Overdose deaths rise, may reach record level, federal data show. Wall Street Journal. 2020 Jul 15.

2. 12 month–ending provisional number of drug overdose drugs. Centers for Disease Control and Prevention. 2020 Jul 5.

3. Katz J et al. In shadow of pandemic, U.S. drug overdose deaths resurge to record. New York Times. 2020 Jul 15.

4. Gold MS. The fentanyl crisis is only getting worse. Addiction Policy Forum. Updated 2020 Mar 12.

5. Gold MS. Mo Med. 2020-Mar-Apr;117(2):99-101.

6. Reports of increases in opioid-related overdoses and other concerns during the COVID-19 pandemic. American Medical Association. Issue brief. Updated 2020 Jul 20.

7. Pardo B et al. The future of fentanyl and other synthetic opioids. RAND report.

8. Gold MS. New challenges in the opioid epidemic. Addiction Policy Forum. 2020 Jun 4.

9. Patterson Silver Wolf DA and Gold MS. J Neurol Sci. 2020;411:116718.

10. Oesterle TS et al. Mayo Clin Proc. 2019;94(10):2072-86.

11. Connery HS and Weiss RD. Am J Psychiatry. 2020;177(2):104-6.

12. Kleber HD. JAMA. 2008;300(19):2303-5.

13. Samet JH et al. N Engl J Med. 2018;379(1):7-8.

14. Pitt AL et al. Am J Public Health. 2018;108(10):1394-1400.

15. U.S. Surgeon General’s Advisory on Naloxone and Opioid Overdose. hhs.gov.

16. Wakeman SE et al. JAMA Netw Open. 2020;3(2):e1920622.

17. Lagisetty PA et al. JAMA Psychiatry. 2019;76(9):979-81.

18. Kleinman RA. JAMA Psychiatry. 2020 Jul 15. doi: 10.1001/jamapsychiatry.2020.1624.

The Centers for Disease Control and Prevention reported recently that opioid overdose deaths will increase to a new U.S. record, and more are expected as pandemic-related overdose deaths are yet to be counted.¹

Specifically, according to the CDC, 70,980 people died from fatal overdoses in 2019,² which is record high. Experts such as Bruce A. Goldberger, PhD, fear that the 2020 numbers could rise even higher, exacerbated by the coronavirus pandemic.

Deaths from drug overdoses remain higher than the peak yearly death totals ever recorded for car accidents, guns, or AIDS. Overdose deaths have accelerated further – pushing down overall life expectancy in the United States.³ Headlines purporting to identify good news in drug death figures don’t always get below top-level data. Deaths and despair tied to drug dependence are indeed accelerating. I am concerned about these alarmingly dangerous trends.

Synthetic opioids such as fentanyl accounted for about 3,000 deaths in 2013. By 2019, they accounted for more than 37,137.⁴ In addition, 16,539 deaths involved stimulants such as methamphetamine, and 16,196 deaths involved cocaine, the most recent CDC reporting shows. Opioids continue to play a role in U.S. “deaths of despair,” or rising fatalities from drugs, suicides, and alcohol among Americans without employment, hope of job opportunities, or college degrees.⁵ As the American Medical Association has warned,⁶ more people are dying from overdoses amid the COVID-19 pandemic. Clinicians need to be aware of trends so that we can help our patients navigate these challenges.
 

Fentanyl presents dangers

Experts had predicted that the pandemic, by limiting access to treatment, rescue, or overdose services, and increasing time at home and in the neighborhood, would result in more tragedy. In addition, the shift from prescription opioids to heroin and now to fentanyl has made deaths more common.

Fentanyls – synthetic opioids – are involved in more than half of overdose deaths, and in many of the cocaine and methamphetamine-related deaths, which also are on the rise. Fentanyl is about 100 times more potent than morphine and 50 times more potent than heroin. Breathing can stop after use of just 2 mg of fentanyl, which is about as much as trace amounts of table salt. Fentanyl has replaced heroin in many cities as the pandemic changed the relative ease of importing raw drugs such as heroin.

Another important trend is that fentanyl production and distribution throughout the United States have expanded. The ease of manufacture in unregulated sectors of the Chinese and Mexican economies is difficult for U.S. authorities to curb or eliminate. The Internet promotes novel strategies for synthesizing the substance, spreading its production across many labs; suppliers use the U.S. Postal Service for distribution, and e-commerce helps to get the drug from manufacturers to U.S. consumers for fentanyl transactions.

A recent RAND report observes that, for only $10 through the postal service, suppliers can ship a 1-kg parcel from China to the United States, and private shipments cost about $100.⁷ And with large volumes of legal trade between the two countries making rigorous scrutiny of products difficult, especially given the light weight of fentanyl, suppliers find it relatively easy to hide illicit substances in licit shipments. Opioid users have made the switch to fentanyl, and have seen fentanyl added to cocaine and methamphetamine they buy on the streets.
 

OUD and buprenorphine

Fentanyl is one part of the overdose crisis. Opioid use disorder (OUD) is the other. Both need to be addressed if we are to make any progress in this epidemic of death and dependency.

The OUD crisis continues amid the pandemic – and isn’t going away.⁸ Slips, relapses, and overdoses are all too common. Medication-assisted treatment (MAT) and OUD treatment programs are essential parts of our response to overdose initiatives. After naloxone rescue, the best anti-overdose response is to get the OUD patient into treatment with MATs. Patients with OUD have continuously high risks of overdose. The best outcomes appear to be related to treatment duration of greater than 2 years. But it is common to see patients with OUDs who have been in treatment multiple times, taking MATs, dropping out, overdosing, and dying. Some have been described as treatment resistant.⁹ It is clear that treatment can work, but also that even evidence-based treatments often fail.¹⁰

A recent study compared OUD patients who continued treatment for 6-9 months to those patients who had continued MAT treatment for 15-18 months. The longer the treatment, the fewer emergencies, prescriptions, or hospitalizations.¹¹

But this study reminds us that all OUD patients, whether they are currently buprenorphine treated or not, experience overdoses and emergency department interventions. Short and longer treatment groups have a similar nonfatal overdose rate, about 6%, and went to the emergency department at a high rate, above 40%. Discontinuation of buprenorphine treatment is a major risk factor in opioid relapse, emergency department visits, and overdose. Cures are not common. Whether an OUD patient is being treated or has been treated in the past, carrying naloxone (brand name Narcan), makes sense and can save lives.
 

Methadone still considered most effective

Methadone is a synthetic opioid first studied as a treatment for OUD at Rockefeller University in New York City in the 1960s. Methadone may be the most effective treatment for OUD in promoting treatment retention for years, decreasing intravenous drug use, and decreasing deaths.¹² It has been studied and safely used in treatment programs for decades. Methadone is typically administered in a clinic, daily, and with observation. In addition, methadone patients periodically take urine drug tests, which can distinguish methadone from substances of abuse. They also receive counseling. But methadone can be prescribed and administered only in methadone clinics in the United States. It is available for prescription in primary care clinics in Great Britain, Canada, and Australia.¹³ Numerous experts have suggested passing new legislation aimed at changing how methadone can be prescribed. Allowing primary care to administer methadone, just like buprenorphine, can improve access and benefit OUD patients.¹²

Availability of Narcan is critical

A comprehensive treatment model for OUDs includes prescribing naloxone, encouraging those patients with an OUD and their loved ones to have naloxone with them, and providing MATs and appropriate therapies, such as counseling.

As described by Allison L. Pitt and colleagues at Stanford (Calif.) University,¹⁴ the United States might be on track to have up to 500,000 deaths tied to opioid overdoses that might occur over the next 5 years. They modeled the effect on overdose of a long list of interventions, but only a few had an impact. At the top of the list was naloxone availability. We need to focus on saving lives by increasing naloxone availability, improving initiation, and expanding access to MAT, and increasing psychosocial treatment to improve outcomes, increase life-years and quality-adjusted life-years, and reduce opioid-related deaths. When Ms. Pitt and colleagues looked at what would make the most impact in reducing OUD deaths, it was naloxone. Pain patients on higher doses of opioids, nonprescription opioid users, OUD patients should be given naloxone prescriptions. While many can give a Heimlich to a choking person or CPR, few have naloxone to rescue a person who has overdosed on opioids. If an overdose is suspected, it should be administered by anyone who has it, as soon as possible. Then, the person who is intervening should call 911.
 

What we can do today

At this moment, clinicians can follow the Surgeon General’s advice,¹⁵ and prescribe naloxone.

We should give naloxone to OUD patients and their families, to pain patients at dosages of greater than or equal to 50 MME. Our top priorities should be patients with comorbid pain syndromes, those being treated with benzodiazepines and sleeping medications, and patients with alcohol use disorders. This is also an important intervention for those who binge drink, and have sleep apnea, and heart and respiratory diseases.

Naloxone is available without a prescription in at least 43 states. Naloxone is available in harm reduction programs and in hospitals, and is carried by emergency medical staff, law enforcement, and EMTs. It also is available on the streets, though it does not appear to have a dollar value like opioids or even buprenorphine. Also, the availability of naloxone in pharmacies has made it easier for family members and caregivers of pain patients or those with OUD to have it to administer in an emergency.

An excellent place for MDs to start is to do more to encourage all patients with OUD to carry naloxone, for their loved ones to carry naloxone, and for their homes to have naloxone nearby in the bedroom or bathroom. It is not logical to expect a person with an OUD to rescue themselves. Current and past OUD patients, as well as their loved ones, are at high risk – and should have naloxone nearby at all times.

Naloxone reverses an opioid overdose, but it should be thought about like cardioversion or CPR rather than a treatment for an underlying disease. Increasing access to buprenorphine, buprenorphine + naloxone, and naltrexone treatment for OUDs is an important organizing principle. Initiation of MAT treatment in the emergency setting or most anywhere and any place a patient with an OUD can begin treatment is necessary. Treatment with buprenorphine or methadone reduces opioid overdose and opioid-related acute care use.¹⁶

Reducing racial disparities in OUD treatment is necessary, because buprenorphine treatment is concentrated among White patients who either use private insurance or are self-pay.¹⁷ Reducing barriers to methadone program licenses, expanding sites for distribution,¹⁸ prescribing methadone in an office setting might help. Clinicians can do a better job of explaining the risks associated with opioid prescriptions, including diversion and overdose, and the benefits of OUD treatment. So, while naloxone saves lives and is a wonder drug, it does not replace an intervention such as MAT, a counselor, a good treatment program, and a treatment plan. To reduce opioid overdoses, we must increase physician competencies in addiction medicine.
 

Dr. Gold is professor of psychiatry (adjunct) at Washington University, St. Louis. He is the 17th Distinguished Alumni Professor at the University of Florida, Gainesville. For more than 40 years, Dr. Gold has worked on developing models for understanding the effects of opioid, tobacco, cocaine, and other drugs, as well as food, on the brain and behavior. He disclosed financial ties with ADAPT Pharma and Magstim Ltd.

References

1. Kamp J. Overdose deaths rise, may reach record level, federal data show. Wall Street Journal. 2020 Jul 15.

2. 12 month–ending provisional number of drug overdose drugs. Centers for Disease Control and Prevention. 2020 Jul 5.

3. Katz J et al. In shadow of pandemic, U.S. drug overdose deaths resurge to record. New York Times. 2020 Jul 15.

4. Gold MS. The fentanyl crisis is only getting worse. Addiction Policy Forum. Updated 2020 Mar 12.

5. Gold MS. Mo Med. 2020-Mar-Apr;117(2):99-101.

6. Reports of increases in opioid-related overdoses and other concerns during the COVID-19 pandemic. American Medical Association. Issue brief. Updated 2020 Jul 20.

7. Pardo B et al. The future of fentanyl and other synthetic opioids. RAND report.

8. Gold MS. New challenges in the opioid epidemic. Addiction Policy Forum. 2020 Jun 4.

9. Patterson Silver Wolf DA and Gold MS. J Neurol Sci. 2020;411:116718.

10. Oesterle TS et al. Mayo Clin Proc. 2019;94(10):2072-86.

11. Connery HS and Weiss RD. Am J Psychiatry. 2020;177(2):104-6.

12. Kleber HD. JAMA. 2008;300(19):2303-5.

13. Samet JH et al. N Engl J Med. 2018;379(1):7-8.

14. Pitt AL et al. Am J Public Health. 2018;108(10):1394-1400.

15. U.S. Surgeon General’s Advisory on Naloxone and Opioid Overdose. hhs.gov.

16. Wakeman SE et al. JAMA Netw Open. 2020;3(2):e1920622.

17. Lagisetty PA et al. JAMA Psychiatry. 2019;76(9):979-81.

18. Kleinman RA. JAMA Psychiatry. 2020 Jul 15. doi: 10.1001/jamapsychiatry.2020.1624.

A poor combined score on tests of hearing, vision, smell, and touch is associated with a higher risk for dementia and cognitive decline among older adults, new research suggests. The study, which included almost 1,800 participants, adds to emerging evidence that even mild levels of multisensory impairment are associated with accelerated cognitive aging, the researchers noted.

Clinicians should be aware of this link between sensory impairment and dementia risk, said lead author Willa Brenowitz, PhD, assistant professor, department of psychiatry and behavioral sciences, University of California, San Francisco. “Many of these impairments are treatable, or at least physicians can monitor them; and this can improve quality of life, even if it doesn’t improve dementia risk.”

The findings were published online July 12 in Alzheimer’s and Dementia.
 

Additive effects

Previous research has focused on the link between dementia and individual senses, but this new work is unique in that it focuses on the additive effects of multiple impairments in sensory function, said Dr. Brenowitz. The study included 1,794 dementia-free participants in their 70s from the Health, Aging and Body Composition study, a prospective cohort study of healthy Black and White men and women.

Researchers tested participants’ hearing using a pure tone average without hearing aids and vision using contrast sensitivity with glasses permitted. They also measured vibrations in the big toe to assess touch and had participants identify distinctive odors such as paint thinner, roses, lemons, and onions to assess smell.

A score of 0-3 was assigned based on sample quartiles for each of the four sensory functions. Individuals with the best quartile were assigned a score of 0 and those with the worst were assigned a score of 3.

The investigators added scores across all senses to create a summary score of multisensory function (0-12) and classified the participants into tertiles of good, medium, and poor. Individuals with a score of 0 would have good function in all senses, whereas those with 12 would have poor function in all senses. Those with medium scores could have a mix of impairments.

Participants with good multisensory function were more likely to be healthier than those with poor function. They were also significantly more likely to have completed high school (85.0% vs. 72.1%), were significantly less likely to have diabetes (16.9% vs. 27.9%), and were marginally less likely to have cardiovascular disease, high blood pressure, and history of stroke.

Investigators measured cognition using the Modified Mini-Mental State (3MS) examination, a test of global cognitive function, and the Digit Symbol Substitution Test (DSST), a measure of cognitive processing speed. Cognitive testing was carried out at the beginning of the study and repeated every other year.

Dementia was defined as the use of dementia medication, being hospitalized with dementia as a primary or secondary diagnosis, or having a 3MS score 1.5 standard deviations lower than the race-stratified Health ABC study baseline mean.

Over an average follow-up of 6.3 years, 18% of participants developed dementia.
 

Dose-response increase

Results showed that, with worsening multisensory function score, the risk for dementia increased in a dose-response manner. In models adjusted for demographics and health conditions, participants with a poor multisensory function score were more than twice as likely to develop dementia than those with a good score (hazard ratio, 2.05; 95% confidence interval, 1.50-2.81; P < .001). Those with a middle multisensory function score were 1.45 times more likely to develop dementia (HR, 1.45; 95% CI, 1.09-1.91; P < .001).

Even a 1-point worse multisensory function score was associated with a 14% higher risk for dementia (95% CI, 8%-21%), while a 4-point worse score was associated with 71% higher risk for dementia (95% CI, 38%-211%).

Smell was the sensory function most strongly associated with dementia risk. Participants whose sense of smell declined by 10% had a 19% higher risk for dementia versus a 1%-3% higher risk for declines in vision, hearing, and touch.

It is not clear why smell was a stronger determinant of dementia risk. However, loss of this sense is often considered to be a marker for Alzheimer’s disease “because it is closely linked with brain regions that are affected” in that disease, said Dr. Brenowitz.

However, that does not necessarily mean smell is more important than vision or hearing, she added. “Even if hearing and vision have a smaller contribution to dementia, they have a stronger potential for intervention.” The findings suggest “some additive or cumulative” effects for loss of the different senses. “There’s an association above and beyond those which can be attributed to individual sensory domains,” she said.
 

Frailty link

After including mobility, which is a potential mediator, estimates for the multisensory function score were slightly lower. “Walking speed is pretty strongly associated with dementia risk,” Dr. Brenowitz noted. Physical frailty might help explain the link between sensory impairment and dementia risk. “It’s not clear if that’s because people with dementia are declining or because people with frailty are especially vulnerable to dementia,” she said.

The researchers also assessed the role of social support, another potential mechanism by which sensory decline, especially in hearing and vision, could influence dementia risk. Although the study did not find substantial differences in social support measures, the investigators noted that questions assessing social support were limited in scope.

Interactions between multisensory function score and race, APOE e4 allele status, and sex were not significant.

Worsening multisensory function was also linked to faster annual rates of cognitive decline as measured by both the 3MS and DSST. Each 1-point worse score was associated with faster decline (P < .05), even after adjustment for demographics and health conditions.
 

Possible mechanisms

A number of possible mechanisms may explain the link between poor sensory function and dementia. It could be that neurodegeneration underlying dementia affects the senses, or vision and/or hearing loss leads to social isolation and poor mental health, which in turn could affect dementia risk, the researchers wrote. It also is possible that cardiovascular disease or diabetes affect both dementia risk and sensory impairment.

Dr. Brenowitz noted that, because cognitive tests rely on a certain degree of vision and hearing, impairment of these senses may complicate such tests. Still to be determined is whether correcting sensory impairments, such as wearing corrective lenses or hearing aids, affects dementia risk.

Meanwhile, it might be a good idea to more regularly check sensory function, especially vision and hearing, the researchers suggested. These functions affect various aspects of health and can be assessed rather easily. However, because smell is so strongly associated with dementia risk, Dr. Brenowitz said she would like to see it also become “part of a screening tool.”

A possible study limitation cited was that the researchers checked sensory function only once. “Most likely, some of these would change over time, but at least it captured sensory function at one point,” Dr. Brenowitz said.
 

“Sheds further light”

Commenting on the study, Jo V. Rushworth, PhD, associate professor and national teaching fellow, De Montfort University Leicester (England), said it “sheds further light on the emerging links” between multisensory impairment and cognitive decline leading to dementia. “The authors show that people with even mild loss of function in various senses are more likely to develop cognitive impairment.”

Dr. Rushworth was not involved with the study but has done research in the area.

The current results suggest that measuring patients’ hearing, vision, sense of smell, and touch might “flag at-risk groups” who could be targeted for dementia prevention strategies, Dr. Rushworth noted. Such tests are noninvasive and potentially less distressing than other methods of diagnosing dementia. “Importantly, the relatively low cost and simplicity of sensory tests offer the potential for more frequent testing and the use of these methods in areas of the world where medical facilities and resources are limited.”

This new study raises the question of whether the observed sensory impairments are a cause or an effect of dementia, Dr. Rushworth noted. “As the authors suggest, decreased sensory function can lead to a decrease in social engagement, mobility, and other factors which would usually contribute to counteracting cognitive decline.”

The study raises other questions, too, said Dr. Rushworth. She noted that the participants who experienced more severe sensory impairments were, on average, 2 years older than those with the least impairments. “To what degree were the observed sensory deficits linked to normal aging rather than dementia?”

As well, Dr. Rushworth pointed out that the molecular mechanisms that “kick-start” dementia are believed to occur in midlife – so possibly at an age younger than the study participants. “Do younger people of a ‘predementia’ age range display multisensory impairments?”

Because study participants could wear glasses during vision tests but were not allowed to wear hearing aids for the hearing tests, further standardization of sensory impairment is required, Dr. Rushworth said.

“Future studies will be essential in determining the value of clinical measurement of multisensory impairment as a possible dementia indicator and prevention strategy,” she concluded.

The study was funded by the National Institute on Aging, the National Institute of Nursing Research, and the Alzheimer’s Association. Dr. Brenowitz and Dr. Rushworth have reported no relevant financial relationships.

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

A poor combined score on tests of hearing, vision, smell, and touch is associated with a higher risk for dementia and cognitive decline among older adults, new research suggests. The study, which included almost 1,800 participants, adds to emerging evidence that even mild levels of multisensory impairment are associated with accelerated cognitive aging, the researchers noted.

Clinicians should be aware of this link between sensory impairment and dementia risk, said lead author Willa Brenowitz, PhD, assistant professor, department of psychiatry and behavioral sciences, University of California, San Francisco. “Many of these impairments are treatable, or at least physicians can monitor them; and this can improve quality of life, even if it doesn’t improve dementia risk.”

The findings were published online July 12 in Alzheimer’s and Dementia.
 

Additive effects

Previous research has focused on the link between dementia and individual senses, but this new work is unique in that it focuses on the additive effects of multiple impairments in sensory function, said Dr. Brenowitz. The study included 1,794 dementia-free participants in their 70s from the Health, Aging and Body Composition study, a prospective cohort study of healthy Black and White men and women.

Researchers tested participants’ hearing using a pure tone average without hearing aids and vision using contrast sensitivity with glasses permitted. They also measured vibrations in the big toe to assess touch and had participants identify distinctive odors such as paint thinner, roses, lemons, and onions to assess smell.

A score of 0-3 was assigned based on sample quartiles for each of the four sensory functions. Individuals with the best quartile were assigned a score of 0 and those with the worst were assigned a score of 3.

The investigators added scores across all senses to create a summary score of multisensory function (0-12) and classified the participants into tertiles of good, medium, and poor. Individuals with a score of 0 would have good function in all senses, whereas those with 12 would have poor function in all senses. Those with medium scores could have a mix of impairments.

Participants with good multisensory function were more likely to be healthier than those with poor function. They were also significantly more likely to have completed high school (85.0% vs. 72.1%), were significantly less likely to have diabetes (16.9% vs. 27.9%), and were marginally less likely to have cardiovascular disease, high blood pressure, and history of stroke.

Investigators measured cognition using the Modified Mini-Mental State (3MS) examination, a test of global cognitive function, and the Digit Symbol Substitution Test (DSST), a measure of cognitive processing speed. Cognitive testing was carried out at the beginning of the study and repeated every other year.

Dementia was defined as the use of dementia medication, being hospitalized with dementia as a primary or secondary diagnosis, or having a 3MS score 1.5 standard deviations lower than the race-stratified Health ABC study baseline mean.

Over an average follow-up of 6.3 years, 18% of participants developed dementia.
 

Dose-response increase

Results showed that, with worsening multisensory function score, the risk for dementia increased in a dose-response manner. In models adjusted for demographics and health conditions, participants with a poor multisensory function score were more than twice as likely to develop dementia than those with a good score (hazard ratio, 2.05; 95% confidence interval, 1.50-2.81; P < .001). Those with a middle multisensory function score were 1.45 times more likely to develop dementia (HR, 1.45; 95% CI, 1.09-1.91; P < .001).

Even a 1-point worse multisensory function score was associated with a 14% higher risk for dementia (95% CI, 8%-21%), while a 4-point worse score was associated with 71% higher risk for dementia (95% CI, 38%-211%).

Smell was the sensory function most strongly associated with dementia risk. Participants whose sense of smell declined by 10% had a 19% higher risk for dementia versus a 1%-3% higher risk for declines in vision, hearing, and touch.

It is not clear why smell was a stronger determinant of dementia risk. However, loss of this sense is often considered to be a marker for Alzheimer’s disease “because it is closely linked with brain regions that are affected” in that disease, said Dr. Brenowitz.

However, that does not necessarily mean smell is more important than vision or hearing, she added. “Even if hearing and vision have a smaller contribution to dementia, they have a stronger potential for intervention.” The findings suggest “some additive or cumulative” effects for loss of the different senses. “There’s an association above and beyond those which can be attributed to individual sensory domains,” she said.
 

Frailty link

After including mobility, which is a potential mediator, estimates for the multisensory function score were slightly lower. “Walking speed is pretty strongly associated with dementia risk,” Dr. Brenowitz noted. Physical frailty might help explain the link between sensory impairment and dementia risk. “It’s not clear if that’s because people with dementia are declining or because people with frailty are especially vulnerable to dementia,” she said.

The researchers also assessed the role of social support, another potential mechanism by which sensory decline, especially in hearing and vision, could influence dementia risk. Although the study did not find substantial differences in social support measures, the investigators noted that questions assessing social support were limited in scope.

Interactions between multisensory function score and race, APOE e4 allele status, and sex were not significant.

Worsening multisensory function was also linked to faster annual rates of cognitive decline as measured by both the 3MS and DSST. Each 1-point worse score was associated with faster decline (P < .05), even after adjustment for demographics and health conditions.
 

Possible mechanisms

A number of possible mechanisms may explain the link between poor sensory function and dementia. It could be that neurodegeneration underlying dementia affects the senses, or vision and/or hearing loss leads to social isolation and poor mental health, which in turn could affect dementia risk, the researchers wrote. It also is possible that cardiovascular disease or diabetes affect both dementia risk and sensory impairment.

Dr. Brenowitz noted that, because cognitive tests rely on a certain degree of vision and hearing, impairment of these senses may complicate such tests. Still to be determined is whether correcting sensory impairments, such as wearing corrective lenses or hearing aids, affects dementia risk.

Meanwhile, it might be a good idea to more regularly check sensory function, especially vision and hearing, the researchers suggested. These functions affect various aspects of health and can be assessed rather easily. However, because smell is so strongly associated with dementia risk, Dr. Brenowitz said she would like to see it also become “part of a screening tool.”

A possible study limitation cited was that the researchers checked sensory function only once. “Most likely, some of these would change over time, but at least it captured sensory function at one point,” Dr. Brenowitz said.
 

“Sheds further light”

Commenting on the study, Jo V. Rushworth, PhD, associate professor and national teaching fellow, De Montfort University Leicester (England), said it “sheds further light on the emerging links” between multisensory impairment and cognitive decline leading to dementia. “The authors show that people with even mild loss of function in various senses are more likely to develop cognitive impairment.”

Dr. Rushworth was not involved with the study but has done research in the area.

The current results suggest that measuring patients’ hearing, vision, sense of smell, and touch might “flag at-risk groups” who could be targeted for dementia prevention strategies, Dr. Rushworth noted. Such tests are noninvasive and potentially less distressing than other methods of diagnosing dementia. “Importantly, the relatively low cost and simplicity of sensory tests offer the potential for more frequent testing and the use of these methods in areas of the world where medical facilities and resources are limited.”

This new study raises the question of whether the observed sensory impairments are a cause or an effect of dementia, Dr. Rushworth noted. “As the authors suggest, decreased sensory function can lead to a decrease in social engagement, mobility, and other factors which would usually contribute to counteracting cognitive decline.”

The study raises other questions, too, said Dr. Rushworth. She noted that the participants who experienced more severe sensory impairments were, on average, 2 years older than those with the least impairments. “To what degree were the observed sensory deficits linked to normal aging rather than dementia?”

As well, Dr. Rushworth pointed out that the molecular mechanisms that “kick-start” dementia are believed to occur in midlife – so possibly at an age younger than the study participants. “Do younger people of a ‘predementia’ age range display multisensory impairments?”

Because study participants could wear glasses during vision tests but were not allowed to wear hearing aids for the hearing tests, further standardization of sensory impairment is required, Dr. Rushworth said.

“Future studies will be essential in determining the value of clinical measurement of multisensory impairment as a possible dementia indicator and prevention strategy,” she concluded.

The study was funded by the National Institute on Aging, the National Institute of Nursing Research, and the Alzheimer’s Association. Dr. Brenowitz and Dr. Rushworth have reported no relevant financial relationships.

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

A poor combined score on tests of hearing, vision, smell, and touch is associated with a higher risk for dementia and cognitive decline among older adults, new research suggests. The study, which included almost 1,800 participants, adds to emerging evidence that even mild levels of multisensory impairment are associated with accelerated cognitive aging, the researchers noted.

Clinicians should be aware of this link between sensory impairment and dementia risk, said lead author Willa Brenowitz, PhD, assistant professor, department of psychiatry and behavioral sciences, University of California, San Francisco. “Many of these impairments are treatable, or at least physicians can monitor them; and this can improve quality of life, even if it doesn’t improve dementia risk.”

The findings were published online July 12 in Alzheimer’s and Dementia.
 

Additive effects

Previous research has focused on the link between dementia and individual senses, but this new work is unique in that it focuses on the additive effects of multiple impairments in sensory function, said Dr. Brenowitz. The study included 1,794 dementia-free participants in their 70s from the Health, Aging and Body Composition study, a prospective cohort study of healthy Black and White men and women.

Researchers tested participants’ hearing using a pure tone average without hearing aids and vision using contrast sensitivity with glasses permitted. They also measured vibrations in the big toe to assess touch and had participants identify distinctive odors such as paint thinner, roses, lemons, and onions to assess smell.

A score of 0-3 was assigned based on sample quartiles for each of the four sensory functions. Individuals with the best quartile were assigned a score of 0 and those with the worst were assigned a score of 3.

The investigators added scores across all senses to create a summary score of multisensory function (0-12) and classified the participants into tertiles of good, medium, and poor. Individuals with a score of 0 would have good function in all senses, whereas those with 12 would have poor function in all senses. Those with medium scores could have a mix of impairments.

Participants with good multisensory function were more likely to be healthier than those with poor function. They were also significantly more likely to have completed high school (85.0% vs. 72.1%), were significantly less likely to have diabetes (16.9% vs. 27.9%), and were marginally less likely to have cardiovascular disease, high blood pressure, and history of stroke.

Investigators measured cognition using the Modified Mini-Mental State (3MS) examination, a test of global cognitive function, and the Digit Symbol Substitution Test (DSST), a measure of cognitive processing speed. Cognitive testing was carried out at the beginning of the study and repeated every other year.

Dementia was defined as the use of dementia medication, being hospitalized with dementia as a primary or secondary diagnosis, or having a 3MS score 1.5 standard deviations lower than the race-stratified Health ABC study baseline mean.

Over an average follow-up of 6.3 years, 18% of participants developed dementia.
 

Dose-response increase

Results showed that, with worsening multisensory function score, the risk for dementia increased in a dose-response manner. In models adjusted for demographics and health conditions, participants with a poor multisensory function score were more than twice as likely to develop dementia than those with a good score (hazard ratio, 2.05; 95% confidence interval, 1.50-2.81; P < .001). Those with a middle multisensory function score were 1.45 times more likely to develop dementia (HR, 1.45; 95% CI, 1.09-1.91; P < .001).

Even a 1-point worse multisensory function score was associated with a 14% higher risk for dementia (95% CI, 8%-21%), while a 4-point worse score was associated with 71% higher risk for dementia (95% CI, 38%-211%).

Smell was the sensory function most strongly associated with dementia risk. Participants whose sense of smell declined by 10% had a 19% higher risk for dementia versus a 1%-3% higher risk for declines in vision, hearing, and touch.

It is not clear why smell was a stronger determinant of dementia risk. However, loss of this sense is often considered to be a marker for Alzheimer’s disease “because it is closely linked with brain regions that are affected” in that disease, said Dr. Brenowitz.

However, that does not necessarily mean smell is more important than vision or hearing, she added. “Even if hearing and vision have a smaller contribution to dementia, they have a stronger potential for intervention.” The findings suggest “some additive or cumulative” effects for loss of the different senses. “There’s an association above and beyond those which can be attributed to individual sensory domains,” she said.
 

Frailty link

After including mobility, which is a potential mediator, estimates for the multisensory function score were slightly lower. “Walking speed is pretty strongly associated with dementia risk,” Dr. Brenowitz noted. Physical frailty might help explain the link between sensory impairment and dementia risk. “It’s not clear if that’s because people with dementia are declining or because people with frailty are especially vulnerable to dementia,” she said.

The researchers also assessed the role of social support, another potential mechanism by which sensory decline, especially in hearing and vision, could influence dementia risk. Although the study did not find substantial differences in social support measures, the investigators noted that questions assessing social support were limited in scope.

Interactions between multisensory function score and race, APOE e4 allele status, and sex were not significant.

Worsening multisensory function was also linked to faster annual rates of cognitive decline as measured by both the 3MS and DSST. Each 1-point worse score was associated with faster decline (P < .05), even after adjustment for demographics and health conditions.
 

Possible mechanisms

A number of possible mechanisms may explain the link between poor sensory function and dementia. It could be that neurodegeneration underlying dementia affects the senses, or vision and/or hearing loss leads to social isolation and poor mental health, which in turn could affect dementia risk, the researchers wrote. It also is possible that cardiovascular disease or diabetes affect both dementia risk and sensory impairment.

Dr. Brenowitz noted that, because cognitive tests rely on a certain degree of vision and hearing, impairment of these senses may complicate such tests. Still to be determined is whether correcting sensory impairments, such as wearing corrective lenses or hearing aids, affects dementia risk.

Meanwhile, it might be a good idea to more regularly check sensory function, especially vision and hearing, the researchers suggested. These functions affect various aspects of health and can be assessed rather easily. However, because smell is so strongly associated with dementia risk, Dr. Brenowitz said she would like to see it also become “part of a screening tool.”

A possible study limitation cited was that the researchers checked sensory function only once. “Most likely, some of these would change over time, but at least it captured sensory function at one point,” Dr. Brenowitz said.
 

“Sheds further light”

Commenting on the study, Jo V. Rushworth, PhD, associate professor and national teaching fellow, De Montfort University Leicester (England), said it “sheds further light on the emerging links” between multisensory impairment and cognitive decline leading to dementia. “The authors show that people with even mild loss of function in various senses are more likely to develop cognitive impairment.”

Dr. Rushworth was not involved with the study but has done research in the area.

The current results suggest that measuring patients’ hearing, vision, sense of smell, and touch might “flag at-risk groups” who could be targeted for dementia prevention strategies, Dr. Rushworth noted. Such tests are noninvasive and potentially less distressing than other methods of diagnosing dementia. “Importantly, the relatively low cost and simplicity of sensory tests offer the potential for more frequent testing and the use of these methods in areas of the world where medical facilities and resources are limited.”

This new study raises the question of whether the observed sensory impairments are a cause or an effect of dementia, Dr. Rushworth noted. “As the authors suggest, decreased sensory function can lead to a decrease in social engagement, mobility, and other factors which would usually contribute to counteracting cognitive decline.”

The study raises other questions, too, said Dr. Rushworth. She noted that the participants who experienced more severe sensory impairments were, on average, 2 years older than those with the least impairments. “To what degree were the observed sensory deficits linked to normal aging rather than dementia?”

As well, Dr. Rushworth pointed out that the molecular mechanisms that “kick-start” dementia are believed to occur in midlife – so possibly at an age younger than the study participants. “Do younger people of a ‘predementia’ age range display multisensory impairments?”

Because study participants could wear glasses during vision tests but were not allowed to wear hearing aids for the hearing tests, further standardization of sensory impairment is required, Dr. Rushworth said.

“Future studies will be essential in determining the value of clinical measurement of multisensory impairment as a possible dementia indicator and prevention strategy,” she concluded.

The study was funded by the National Institute on Aging, the National Institute of Nursing Research, and the Alzheimer’s Association. Dr. Brenowitz and Dr. Rushworth have reported no relevant financial relationships.

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

August was National Immunization Awareness Month. ... just in time to address the precipitous drop in immunization delivered during the early months of the pandemic.

FatCamera/Getty Images

In May, the Centers for Disease Control and Prevention reported substantial reductions in vaccine doses ordered through the Vaccines for Children program after the declaration of national emergency because of COVID-19 on March 13. Approximately 2.5 million fewer doses of routine, noninfluenza vaccines were administered between Jan. 6 and April 2020, compared with a similar period last year (MMWR Morb Mortal Wkly Rep. 2020 May 15;69[19]:591-3). Declines in immunization rates were echoed by states and municipalities across the United States. Last month, the health system in which I work reported 40,000 children behind on at least one vaccine.

We all know that, when immunization rates drop, outbreaks of vaccine-preventable diseases follow. In order to avert another public health crisis, we need action as well as awareness to catch up with childhood immunizations, and that is going to take more than a single month.
 

Identify patients who’ve missed vaccinations

Simply being open and ready to vaccinate is not enough. The Centers for Disease Control and Prevention urges providers to identify patients who have missed vaccines, and call them to schedule in-person visits. Proactively let parents know about strategies implemented in your office to ensure a safe environment.

Pediatricians are accustomed to an influx of patients in the summer, as parents make sure their children have all of the vaccines required for school attendance. As noted in a Washington Post article from Aug. 4, 2020, schools have traditionally served as a backstop for immunization rates. But as many school districts opt to take education online this fall, the implications for vaccine requirements are unclear. District of Columbia public schools continue to require immunization for virtual school attendance, but it is not clear how easily this can be enforced. To read about how other school districts have chosen to address – or not address – immunization requirements for school, visit the the Immunization Action Coalition’s Repository of Resources for Maintaining Immunization during the COVID-19 Pandemic. The repository links to international, national, and state-level policies and guidance and advocacy materials, including talking points, webinars, press releases, media articles from around the United States and social media posts, as well as telehealth resources.
 

Get some inspiration to talk about vaccination

Need a little inspiration for talking to parents about vaccines? Check out the CDC’s #HowIRecommend video series. These are short videos, most under a minute in length, that explain the importance of vaccination, how to effectively address questions from parents about vaccine safety, and how clinicians routinely recommend same day vaccination to their patients. These videos are part of the CDC’s National Immunization Awareness Month (NIAM) toolkit for communication with health care professionals. A companion toolkit for communicating with parents and patients contains sample social media messages with graphics, along with educational resources to share with parents.

The “Comprehensive Vaccine Education Program – From Training to Practice,” a free online program offered by the Pediatric Infectious Diseases Society, takes a deeper dive into strategies to combat vaccine misinformation and address vaccine hesitancy. Available modules cover vaccine fundamentals, vaccine safety, clinical manifestations of vaccine-preventable diseases, and communication skills that lead to more effective conversations with patients and parents. The curriculum also includes the newest edition of The Vaccine Handbook app, a comprehensive source of practical information for vaccine providers.
 

Educate young children about vaccines

Don’t leave young children out of the conversation. Vax-Force is a children’s book that explores how vaccination works inside the human body. Dr. Vaxson the pediatrician explains how trusted doctors and scientists made Vicky the Vaccine. Her mission is to tell Willy the White Blood Cell and his Antibuddies how to find and fight bad-guy germs like measles, tetanus, and polio. The book was written by Kelsey Rowe, MD, while she was a medical student at Saint Louis University School of Medicine. Dr. Rowe, now a pediatric resident, notes, “In a world where anti-vaccination rhetoric threatens the health of our global community, this book’s mission is to teach children and adults alike that getting vaccinations is a safe, effective, and even exciting thing to do.” The book is available for purchase at https://www.vax-force.com/, and a small part of every sale is donated to Unicef USA.
 

Consider vaccination advocacy in your communities

Vaccinate Your Family, a national, nonprofit organization dedicated to protecting people of all ages from vaccine-preventable diseases, suggests that health care providers need to take an active role in raising immunization rates, not just in their own practices, but in their communities. One way to do this is to submit an opinion piece or letter to the editor to a local newspaper describing why it’s important for parents to make sure their child’s immunizations are current. Those who have never written an opinion-editorial should look at the guidance developed by Voices for Vaccines.
 

How are we doing?

Early data suggest a rebound in immunization rates in May and June, but that is unlikely to close the gap created by disruptions in health care delivery earlier in the year. Collectively, we need to set ambitious goals. Are we just trying to reach prepandemic immunization levels? In Kentucky, where I practice, only 71% of kids aged 19-45 months had received all doses of seven routinely recommended vaccines (≥4 DTaP doses, ≥3 polio doses, ≥1 MMR dose, Hib full series, ≥3 HepB doses, ≥1 varicella dose, and ≥4 PCV doses) based on 2017 National Immunization Survey data. The Healthy People 2020 target goal is 80%. Only 55% of Kentucky girls aged 13-17 years received at least one dose of HPV vaccine, and rates in boys were even lower. Flu vaccine coverage in children 6 months to 17 years also was 55%. The status quo sets the bar too low. To see how your state is doing, check out the interactive map developed by the American Academy of Pediatrics.

Are we attempting to avoid disaster or can we seize the opportunity to protect more children than ever from vaccine-preventable diseases? The latter would really be something to celebrate.
 

Dr. Bryant is a pediatrician specializing in infectious diseases at the University of Louisville (Ky.) and Norton Children’s Hospital, also in Louisville. She said she had no relevant financial disclosures. Email her at [email protected].

August was National Immunization Awareness Month. ... just in time to address the precipitous drop in immunization delivered during the early months of the pandemic.

FatCamera/Getty Images

In May, the Centers for Disease Control and Prevention reported substantial reductions in vaccine doses ordered through the Vaccines for Children program after the declaration of national emergency because of COVID-19 on March 13. Approximately 2.5 million fewer doses of routine, noninfluenza vaccines were administered between Jan. 6 and April 2020, compared with a similar period last year (MMWR Morb Mortal Wkly Rep. 2020 May 15;69[19]:591-3). Declines in immunization rates were echoed by states and municipalities across the United States. Last month, the health system in which I work reported 40,000 children behind on at least one vaccine.

We all know that, when immunization rates drop, outbreaks of vaccine-preventable diseases follow. In order to avert another public health crisis, we need action as well as awareness to catch up with childhood immunizations, and that is going to take more than a single month.
 

Identify patients who’ve missed vaccinations

Simply being open and ready to vaccinate is not enough. The Centers for Disease Control and Prevention urges providers to identify patients who have missed vaccines, and call them to schedule in-person visits. Proactively let parents know about strategies implemented in your office to ensure a safe environment.

Pediatricians are accustomed to an influx of patients in the summer, as parents make sure their children have all of the vaccines required for school attendance. As noted in a Washington Post article from Aug. 4, 2020, schools have traditionally served as a backstop for immunization rates. But as many school districts opt to take education online this fall, the implications for vaccine requirements are unclear. District of Columbia public schools continue to require immunization for virtual school attendance, but it is not clear how easily this can be enforced. To read about how other school districts have chosen to address – or not address – immunization requirements for school, visit the the Immunization Action Coalition’s Repository of Resources for Maintaining Immunization during the COVID-19 Pandemic. The repository links to international, national, and state-level policies and guidance and advocacy materials, including talking points, webinars, press releases, media articles from around the United States and social media posts, as well as telehealth resources.
 

Get some inspiration to talk about vaccination

Need a little inspiration for talking to parents about vaccines? Check out the CDC’s #HowIRecommend video series. These are short videos, most under a minute in length, that explain the importance of vaccination, how to effectively address questions from parents about vaccine safety, and how clinicians routinely recommend same day vaccination to their patients. These videos are part of the CDC’s National Immunization Awareness Month (NIAM) toolkit for communication with health care professionals. A companion toolkit for communicating with parents and patients contains sample social media messages with graphics, along with educational resources to share with parents.

The “Comprehensive Vaccine Education Program – From Training to Practice,” a free online program offered by the Pediatric Infectious Diseases Society, takes a deeper dive into strategies to combat vaccine misinformation and address vaccine hesitancy. Available modules cover vaccine fundamentals, vaccine safety, clinical manifestations of vaccine-preventable diseases, and communication skills that lead to more effective conversations with patients and parents. The curriculum also includes the newest edition of The Vaccine Handbook app, a comprehensive source of practical information for vaccine providers.
 

Educate young children about vaccines

Don’t leave young children out of the conversation. Vax-Force is a children’s book that explores how vaccination works inside the human body. Dr. Vaxson the pediatrician explains how trusted doctors and scientists made Vicky the Vaccine. Her mission is to tell Willy the White Blood Cell and his Antibuddies how to find and fight bad-guy germs like measles, tetanus, and polio. The book was written by Kelsey Rowe, MD, while she was a medical student at Saint Louis University School of Medicine. Dr. Rowe, now a pediatric resident, notes, “In a world where anti-vaccination rhetoric threatens the health of our global community, this book’s mission is to teach children and adults alike that getting vaccinations is a safe, effective, and even exciting thing to do.” The book is available for purchase at https://www.vax-force.com/, and a small part of every sale is donated to Unicef USA.
 

Consider vaccination advocacy in your communities

Vaccinate Your Family, a national, nonprofit organization dedicated to protecting people of all ages from vaccine-preventable diseases, suggests that health care providers need to take an active role in raising immunization rates, not just in their own practices, but in their communities. One way to do this is to submit an opinion piece or letter to the editor to a local newspaper describing why it’s important for parents to make sure their child’s immunizations are current. Those who have never written an opinion-editorial should look at the guidance developed by Voices for Vaccines.
 

How are we doing?

Early data suggest a rebound in immunization rates in May and June, but that is unlikely to close the gap created by disruptions in health care delivery earlier in the year. Collectively, we need to set ambitious goals. Are we just trying to reach prepandemic immunization levels? In Kentucky, where I practice, only 71% of kids aged 19-45 months had received all doses of seven routinely recommended vaccines (≥4 DTaP doses, ≥3 polio doses, ≥1 MMR dose, Hib full series, ≥3 HepB doses, ≥1 varicella dose, and ≥4 PCV doses) based on 2017 National Immunization Survey data. The Healthy People 2020 target goal is 80%. Only 55% of Kentucky girls aged 13-17 years received at least one dose of HPV vaccine, and rates in boys were even lower. Flu vaccine coverage in children 6 months to 17 years also was 55%. The status quo sets the bar too low. To see how your state is doing, check out the interactive map developed by the American Academy of Pediatrics.

Are we attempting to avoid disaster or can we seize the opportunity to protect more children than ever from vaccine-preventable diseases? The latter would really be something to celebrate.
 

Dr. Bryant is a pediatrician specializing in infectious diseases at the University of Louisville (Ky.) and Norton Children’s Hospital, also in Louisville. She said she had no relevant financial disclosures. Email her at [email protected].

August was National Immunization Awareness Month. ... just in time to address the precipitous drop in immunization delivered during the early months of the pandemic.

FatCamera/Getty Images

In May, the Centers for Disease Control and Prevention reported substantial reductions in vaccine doses ordered through the Vaccines for Children program after the declaration of national emergency because of COVID-19 on March 13. Approximately 2.5 million fewer doses of routine, noninfluenza vaccines were administered between Jan. 6 and April 2020, compared with a similar period last year (MMWR Morb Mortal Wkly Rep. 2020 May 15;69[19]:591-3). Declines in immunization rates were echoed by states and municipalities across the United States. Last month, the health system in which I work reported 40,000 children behind on at least one vaccine.

We all know that, when immunization rates drop, outbreaks of vaccine-preventable diseases follow. In order to avert another public health crisis, we need action as well as awareness to catch up with childhood immunizations, and that is going to take more than a single month.
 

Identify patients who’ve missed vaccinations

Simply being open and ready to vaccinate is not enough. The Centers for Disease Control and Prevention urges providers to identify patients who have missed vaccines, and call them to schedule in-person visits. Proactively let parents know about strategies implemented in your office to ensure a safe environment.

Pediatricians are accustomed to an influx of patients in the summer, as parents make sure their children have all of the vaccines required for school attendance. As noted in a Washington Post article from Aug. 4, 2020, schools have traditionally served as a backstop for immunization rates. But as many school districts opt to take education online this fall, the implications for vaccine requirements are unclear. District of Columbia public schools continue to require immunization for virtual school attendance, but it is not clear how easily this can be enforced. To read about how other school districts have chosen to address – or not address – immunization requirements for school, visit the the Immunization Action Coalition’s Repository of Resources for Maintaining Immunization during the COVID-19 Pandemic. The repository links to international, national, and state-level policies and guidance and advocacy materials, including talking points, webinars, press releases, media articles from around the United States and social media posts, as well as telehealth resources.
 

Get some inspiration to talk about vaccination

Need a little inspiration for talking to parents about vaccines? Check out the CDC’s #HowIRecommend video series. These are short videos, most under a minute in length, that explain the importance of vaccination, how to effectively address questions from parents about vaccine safety, and how clinicians routinely recommend same day vaccination to their patients. These videos are part of the CDC’s National Immunization Awareness Month (NIAM) toolkit for communication with health care professionals. A companion toolkit for communicating with parents and patients contains sample social media messages with graphics, along with educational resources to share with parents.

The “Comprehensive Vaccine Education Program – From Training to Practice,” a free online program offered by the Pediatric Infectious Diseases Society, takes a deeper dive into strategies to combat vaccine misinformation and address vaccine hesitancy. Available modules cover vaccine fundamentals, vaccine safety, clinical manifestations of vaccine-preventable diseases, and communication skills that lead to more effective conversations with patients and parents. The curriculum also includes the newest edition of The Vaccine Handbook app, a comprehensive source of practical information for vaccine providers.
 

Educate young children about vaccines

Don’t leave young children out of the conversation. Vax-Force is a children’s book that explores how vaccination works inside the human body. Dr. Vaxson the pediatrician explains how trusted doctors and scientists made Vicky the Vaccine. Her mission is to tell Willy the White Blood Cell and his Antibuddies how to find and fight bad-guy germs like measles, tetanus, and polio. The book was written by Kelsey Rowe, MD, while she was a medical student at Saint Louis University School of Medicine. Dr. Rowe, now a pediatric resident, notes, “In a world where anti-vaccination rhetoric threatens the health of our global community, this book’s mission is to teach children and adults alike that getting vaccinations is a safe, effective, and even exciting thing to do.” The book is available for purchase at https://www.vax-force.com/, and a small part of every sale is donated to Unicef USA.
 

Consider vaccination advocacy in your communities

Vaccinate Your Family, a national, nonprofit organization dedicated to protecting people of all ages from vaccine-preventable diseases, suggests that health care providers need to take an active role in raising immunization rates, not just in their own practices, but in their communities. One way to do this is to submit an opinion piece or letter to the editor to a local newspaper describing why it’s important for parents to make sure their child’s immunizations are current. Those who have never written an opinion-editorial should look at the guidance developed by Voices for Vaccines.
 

How are we doing?

Early data suggest a rebound in immunization rates in May and June, but that is unlikely to close the gap created by disruptions in health care delivery earlier in the year. Collectively, we need to set ambitious goals. Are we just trying to reach prepandemic immunization levels? In Kentucky, where I practice, only 71% of kids aged 19-45 months had received all doses of seven routinely recommended vaccines (≥4 DTaP doses, ≥3 polio doses, ≥1 MMR dose, Hib full series, ≥3 HepB doses, ≥1 varicella dose, and ≥4 PCV doses) based on 2017 National Immunization Survey data. The Healthy People 2020 target goal is 80%. Only 55% of Kentucky girls aged 13-17 years received at least one dose of HPV vaccine, and rates in boys were even lower. Flu vaccine coverage in children 6 months to 17 years also was 55%. The status quo sets the bar too low. To see how your state is doing, check out the interactive map developed by the American Academy of Pediatrics.

Are we attempting to avoid disaster or can we seize the opportunity to protect more children than ever from vaccine-preventable diseases? The latter would really be something to celebrate.
 

Dr. Bryant is a pediatrician specializing in infectious diseases at the University of Louisville (Ky.) and Norton Children’s Hospital, also in Louisville. She said she had no relevant financial disclosures. Email her at [email protected].

Many COVID-19 treatments, in addition to the infection, may be associated with adverse skin reactions and should be considered in a differential diagnosis, according to a review published in the Journal of the American Academy of Dermatology.

SARS-CoV-2 infection has been associated with a range of skin conditions, wrote Antonio Martinez-Lopez, MD, of Virgen de las Nieves University Hospital, Granada, Spain, and colleagues, who provided an overview of the cutaneous side effects associated with drugs used to treat COVID-19 infection.

“Cutaneous manifestations have recently been described in patients with the new coronavirus infection, similar to cutaneous involvement occurring in common viral infections,” they said. Infected individuals have experienced maculopapular eruption, pseudo-chilblain lesions, urticaria, monomorphic disseminated vesicular lesions, acral vesicular-pustulous lesions, and livedo or necrosis, they noted.

Diagnosing skin manifestations in patients with COVID-19 remains a challenge, because it is unclear whether the skin lesions are related to the virus, the authors said. “Skin diseases not related to coronavirus, other seasonal viral infections, and drug reactions should be considered in the differential diagnosis, especially in those patients suffering from nonspecific manifestations such as urticaria or maculopapular eruptions,” they wrote.

However, “urticarial lesions and maculopapular eruptions in SARS-CoV-2 infections usually appear at the same time as the systemic symptoms, while drug adverse reactions are likely to arise hours to days after the start of the treatment,” they said.

The reviewers noted several cutaneous side effects associated with several of the often-prescribed drugs for COVID-19 infection. The antimalarials hydroxychloroquine and chloroquine had been authorized for COVID-19 treatment by the Food and Drug Administration, but this emergency authorization was rescinded in June. They noted that up to 11.5% of patients on these drugs may experience cutaneous adverse effects, including some that “can be mistaken for skin manifestations of SARS-CoV-2, especially those with maculopapular rash or exanthematous reactions.” Another side effect is exacerbation of psoriasis, which has been described in patients with COVID-19, the authors said.

The oral antiretroviral combination lopinavir/ritonavir, under investigation in clinical trials for COVID-19, has been associated with skin rashes in as many as 5% of adults in HIV studies. Usually appearing after treatment is started, the maculopapular pruritic rash is “usually well tolerated,” they said, although there have been reports of Stevens-Johnson syndrome. Alopecia areata is among the other side effects reported.

Remdesivir also has been authorized for emergency treatment of COVID-19, and the small amount of data available suggest that cutaneous manifestations may be infrequent, the reviewers said. In a recent study of 53 patients treated with remdesivir for 10 days, approximately 8% developed a rash, but the study did not include any information “about rash morphology, distribution, or timeline in relation to remdesivir that may help clinicians differentiate from cutaneous manifestations of COVID-19,” they said.

Other potential treatments for complications of COVID-19 include imatinib, tocilizumab, anakinra, immunoglobulins, corticosteroids, colchicine, and low molecular weight heparins; all have the potential for association with skin reactions, but data on skin manifestations associated with COVID-19 are limited, the authors wrote.

Notably, data on the use of systemic corticosteroids for COVID-19 patients are controversial, although preliminary data showed some reduced mortality in COVID-19 patients who were on respiratory support, they noted. “With regard to differential diagnosis of cutaneous manifestations of COVID-19, the vascular fragility associated with corticosteroid use, especially in elderly patients, may be similar to the thrombotic complications of COVID-19 infection.”

Knowledge about the virology of COVID-19 continues to evolve rapidly, and the number of drugs being studied as treatments continues to expand, the authors pointed out.

“By considering adverse drug reactions in the differential diagnosis, dermatologists can be useful in assisting in the care of these patients,” they wrote. Drugs, rather than the infection, may be the cause of skin reactions in some COVID-19 patients, and “management is often symptomatic, but it is sometimes necessary to modify or discontinue the treatment, and some conditions can even be life-threatening,” they concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

SOURCE: Martinez-Lopez A et al. J Am Acad Dermatol. 2020 doi: 10.1016/j.jaad.2020.08.006.

Many COVID-19 treatments, in addition to the infection, may be associated with adverse skin reactions and should be considered in a differential diagnosis, according to a review published in the Journal of the American Academy of Dermatology.

SARS-CoV-2 infection has been associated with a range of skin conditions, wrote Antonio Martinez-Lopez, MD, of Virgen de las Nieves University Hospital, Granada, Spain, and colleagues, who provided an overview of the cutaneous side effects associated with drugs used to treat COVID-19 infection.

“Cutaneous manifestations have recently been described in patients with the new coronavirus infection, similar to cutaneous involvement occurring in common viral infections,” they said. Infected individuals have experienced maculopapular eruption, pseudo-chilblain lesions, urticaria, monomorphic disseminated vesicular lesions, acral vesicular-pustulous lesions, and livedo or necrosis, they noted.

Diagnosing skin manifestations in patients with COVID-19 remains a challenge, because it is unclear whether the skin lesions are related to the virus, the authors said. “Skin diseases not related to coronavirus, other seasonal viral infections, and drug reactions should be considered in the differential diagnosis, especially in those patients suffering from nonspecific manifestations such as urticaria or maculopapular eruptions,” they wrote.

However, “urticarial lesions and maculopapular eruptions in SARS-CoV-2 infections usually appear at the same time as the systemic symptoms, while drug adverse reactions are likely to arise hours to days after the start of the treatment,” they said.

The reviewers noted several cutaneous side effects associated with several of the often-prescribed drugs for COVID-19 infection. The antimalarials hydroxychloroquine and chloroquine had been authorized for COVID-19 treatment by the Food and Drug Administration, but this emergency authorization was rescinded in June. They noted that up to 11.5% of patients on these drugs may experience cutaneous adverse effects, including some that “can be mistaken for skin manifestations of SARS-CoV-2, especially those with maculopapular rash or exanthematous reactions.” Another side effect is exacerbation of psoriasis, which has been described in patients with COVID-19, the authors said.

The oral antiretroviral combination lopinavir/ritonavir, under investigation in clinical trials for COVID-19, has been associated with skin rashes in as many as 5% of adults in HIV studies. Usually appearing after treatment is started, the maculopapular pruritic rash is “usually well tolerated,” they said, although there have been reports of Stevens-Johnson syndrome. Alopecia areata is among the other side effects reported.

Remdesivir also has been authorized for emergency treatment of COVID-19, and the small amount of data available suggest that cutaneous manifestations may be infrequent, the reviewers said. In a recent study of 53 patients treated with remdesivir for 10 days, approximately 8% developed a rash, but the study did not include any information “about rash morphology, distribution, or timeline in relation to remdesivir that may help clinicians differentiate from cutaneous manifestations of COVID-19,” they said.

Other potential treatments for complications of COVID-19 include imatinib, tocilizumab, anakinra, immunoglobulins, corticosteroids, colchicine, and low molecular weight heparins; all have the potential for association with skin reactions, but data on skin manifestations associated with COVID-19 are limited, the authors wrote.

Notably, data on the use of systemic corticosteroids for COVID-19 patients are controversial, although preliminary data showed some reduced mortality in COVID-19 patients who were on respiratory support, they noted. “With regard to differential diagnosis of cutaneous manifestations of COVID-19, the vascular fragility associated with corticosteroid use, especially in elderly patients, may be similar to the thrombotic complications of COVID-19 infection.”

Knowledge about the virology of COVID-19 continues to evolve rapidly, and the number of drugs being studied as treatments continues to expand, the authors pointed out.

“By considering adverse drug reactions in the differential diagnosis, dermatologists can be useful in assisting in the care of these patients,” they wrote. Drugs, rather than the infection, may be the cause of skin reactions in some COVID-19 patients, and “management is often symptomatic, but it is sometimes necessary to modify or discontinue the treatment, and some conditions can even be life-threatening,” they concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

SOURCE: Martinez-Lopez A et al. J Am Acad Dermatol. 2020 doi: 10.1016/j.jaad.2020.08.006.

Many COVID-19 treatments, in addition to the infection, may be associated with adverse skin reactions and should be considered in a differential diagnosis, according to a review published in the Journal of the American Academy of Dermatology.

SARS-CoV-2 infection has been associated with a range of skin conditions, wrote Antonio Martinez-Lopez, MD, of Virgen de las Nieves University Hospital, Granada, Spain, and colleagues, who provided an overview of the cutaneous side effects associated with drugs used to treat COVID-19 infection.

“Cutaneous manifestations have recently been described in patients with the new coronavirus infection, similar to cutaneous involvement occurring in common viral infections,” they said. Infected individuals have experienced maculopapular eruption, pseudo-chilblain lesions, urticaria, monomorphic disseminated vesicular lesions, acral vesicular-pustulous lesions, and livedo or necrosis, they noted.

Diagnosing skin manifestations in patients with COVID-19 remains a challenge, because it is unclear whether the skin lesions are related to the virus, the authors said. “Skin diseases not related to coronavirus, other seasonal viral infections, and drug reactions should be considered in the differential diagnosis, especially in those patients suffering from nonspecific manifestations such as urticaria or maculopapular eruptions,” they wrote.

However, “urticarial lesions and maculopapular eruptions in SARS-CoV-2 infections usually appear at the same time as the systemic symptoms, while drug adverse reactions are likely to arise hours to days after the start of the treatment,” they said.

The reviewers noted several cutaneous side effects associated with several of the often-prescribed drugs for COVID-19 infection. The antimalarials hydroxychloroquine and chloroquine had been authorized for COVID-19 treatment by the Food and Drug Administration, but this emergency authorization was rescinded in June. They noted that up to 11.5% of patients on these drugs may experience cutaneous adverse effects, including some that “can be mistaken for skin manifestations of SARS-CoV-2, especially those with maculopapular rash or exanthematous reactions.” Another side effect is exacerbation of psoriasis, which has been described in patients with COVID-19, the authors said.

The oral antiretroviral combination lopinavir/ritonavir, under investigation in clinical trials for COVID-19, has been associated with skin rashes in as many as 5% of adults in HIV studies. Usually appearing after treatment is started, the maculopapular pruritic rash is “usually well tolerated,” they said, although there have been reports of Stevens-Johnson syndrome. Alopecia areata is among the other side effects reported.

Remdesivir also has been authorized for emergency treatment of COVID-19, and the small amount of data available suggest that cutaneous manifestations may be infrequent, the reviewers said. In a recent study of 53 patients treated with remdesivir for 10 days, approximately 8% developed a rash, but the study did not include any information “about rash morphology, distribution, or timeline in relation to remdesivir that may help clinicians differentiate from cutaneous manifestations of COVID-19,” they said.

Other potential treatments for complications of COVID-19 include imatinib, tocilizumab, anakinra, immunoglobulins, corticosteroids, colchicine, and low molecular weight heparins; all have the potential for association with skin reactions, but data on skin manifestations associated with COVID-19 are limited, the authors wrote.

Notably, data on the use of systemic corticosteroids for COVID-19 patients are controversial, although preliminary data showed some reduced mortality in COVID-19 patients who were on respiratory support, they noted. “With regard to differential diagnosis of cutaneous manifestations of COVID-19, the vascular fragility associated with corticosteroid use, especially in elderly patients, may be similar to the thrombotic complications of COVID-19 infection.”

Knowledge about the virology of COVID-19 continues to evolve rapidly, and the number of drugs being studied as treatments continues to expand, the authors pointed out.

“By considering adverse drug reactions in the differential diagnosis, dermatologists can be useful in assisting in the care of these patients,” they wrote. Drugs, rather than the infection, may be the cause of skin reactions in some COVID-19 patients, and “management is often symptomatic, but it is sometimes necessary to modify or discontinue the treatment, and some conditions can even be life-threatening,” they concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

SOURCE: Martinez-Lopez A et al. J Am Acad Dermatol. 2020 doi: 10.1016/j.jaad.2020.08.006.

Patients with RA were at lower risk for developing incident type 2 diabetes mellitus (T2DM) in comparison with patients with hypertension, psoriatic arthritis (PsA), or osteoarthritis, as well as the general population without RA in a retrospective cohort study of a large, nationwide, commercial health insurance claims database.

This result goes against what the study researchers from the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, initially hypothesized: The “risk of incident T2DM in RA patients would be similar to or less than PsA and [hypertension] patients, but higher, compared to general non-RA and OA patients.”

Prior epidemiologic studies of the relationship between RA and incident diabetes have yielded inconclusive results suggesting a small increase or no increase in risk of T2DM in patients with RA, possibly because of differences in the risk of T2DM in comparison groups used by previous studies to calculate relative risk, first author Yinzhu Jin and colleagues noted in their report published in Arthritis Care & Research.

After mining a nationwide U.S. commercial health insurance claims database, the Optum Clinformatics Data Mart, for claims data from Jan. 1, 2005, to Dec. 31, 2017, the researchers matched a total of 108,568 patients in RA, general population non-RA, hypertension, and OA cohorts based on age, sex, and index date (the date of disease-specific medication dispensing). Overall, 77% of those patients were female and had a mean age of nearly 56 years, whereas 48% of patients with PsA were female and their mean age was nearly 49 years. (PsA patients were not matched because of smaller numbers.)

During a median follow-up period of 1.4-1.8 years across the comparison groups, the crude incidence rate for diabetes per 1,000 person-years in the cohorts was 7.0 for RA, 7.4 for general non-RA, 12.3 for hypertension, 7.8 for OA, and 9.9 for PsA. The hazard ratios and 95% confidence interval for risk of diabetes in patients with RA – after adjustment for more than 40 baseline covariates that included demographics, comorbidities, medication use, and health care utilization – was 0.72 (0.66-0.78) in comparison withh the general non-RA cohort, 0.65 (0.60-0.71) in comparison with the hypertension cohort, 0.75 (0.69-0.81) in comparison with the OA cohort, and 0.76 (0.67-0.86) in comparison with the PsA cohort. These values correspond to RA patients having a 24%-35% lower risk of incident diabetes versus the comparison groups, the researchers noted. They observed results consistent to these when they conducted a sensitivity analysis using a 1-year lag time from the index date before starting follow-up.

The lower risk of T2DM in patients with RA in comparison with patients in the non-RA cohort “may be, in part, due to the effect of biologic DMARD [disease-modifying antirheumatic drug] treatment in RA which likely modifies the risk of DM,” the researchers wrote. “Both the increasing use of biologic DMARDs for RA in the U.S. over the last decade and our cohort entry criteria for the RA cohort (i.e., at least one dispensing of a DMARD) may explain the finding of the lower risk of DM in RA.”

The results found with the other three cohorts did not surprise the researchers. The reduced risk of diabetes among RA patients versus those with OA jibes with “higher rates of obesity and other comorbidities in patients with OA” as well as findings from a recent study that found a higher incidence rate of diabetes in OA, compared with RA. Ms. Jin and colleagues also acknowledged it is well known that “hypertension and PsA are associated with metabolic dysregulation and increase the risk of diabetes.”

The researchers defined patients with RA as having at least twoinpatient or outpatient ICD-9 or ICD-10 diagnosis codes of RA, separated by 7-365 days and having at least one dispensing for DMARDs within 1 year from the first RA diagnosis date, and defined the primary outcome of incident T2DM as at least one inpatient or outpatient diagnosis of T2DM plus at least one dispensing of an antidiabetic drug. They set the general non-RA cohort by selecting patients with any inpatient or outpatient diagnosis codes and a dispensing of any medications, and the hypertension, PsA, and OA comparator groups as having at least two inpatient or outpatient disease-specific ICD-9/ICD-10 codes separated by 7-365 days and at least one dispensing of disease-specific medication within 1 year from the first diagnosis date. They excluded patients with RA, PsA, or psoriasis diagnosis or disease-specific medication dispensing any time prior to or on the index date (the date of disease-specific medication dispensing).

The researchers recognized that the conclusions that can be drawn from the study are limited by the “potential misclassification of cohorts and covariates” because they “mainly used diagnosis codes and pharmacy dispensing records in claims data,” and some “important covariates such as baseline obesity are likely underreported and not adequately captured in claims data.” The level of covariate misclassification also may have been different across the study cohorts on “unmeasured covariates such as body mass index, diet, and physical activity, as well as disease specific measures,” thus introducing residual confounding. They also could not “examine potential difference in the risk of T2DM in untreated or undertreated RA patients” because “RA and all the non-RA comparator cohorts were required to use a disease-specific drug,” they wrote.

“While systemic inflammation in RA is thought to increase the risk of [cardiovascular disease] and cardiovascular risk factors such as DM, our findings suggest having RA itself does not confer an increased risk of DM. Future study should determine whether untreated RA or undertreated RA is associated with a greater risk of developing DM,” the researchers concluded.

The study was supported by a research grant from Bristol-Myers Squibb, which “played no role in the study design, data analysis or interpretation of data or presentation of results,” the researchers said. The company was “given the opportunity to make nonbinding comments on a draft of the manuscript, but the authors retained the right of publication and to determine the final wording.” One author reported receiving research grants from Brigham and Women’s Hospital from Pfizer, AbbVie, Bristol-Myers Squibb, and Roche for unrelated topics.

[email protected]

SOURCE: Jin Y et al. Arthritis Care Res. 2020 Aug 4. doi: 10.1002/acr.24343.

Patients with RA were at lower risk for developing incident type 2 diabetes mellitus (T2DM) in comparison with patients with hypertension, psoriatic arthritis (PsA), or osteoarthritis, as well as the general population without RA in a retrospective cohort study of a large, nationwide, commercial health insurance claims database.

This result goes against what the study researchers from the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, initially hypothesized: The “risk of incident T2DM in RA patients would be similar to or less than PsA and [hypertension] patients, but higher, compared to general non-RA and OA patients.”

Prior epidemiologic studies of the relationship between RA and incident diabetes have yielded inconclusive results suggesting a small increase or no increase in risk of T2DM in patients with RA, possibly because of differences in the risk of T2DM in comparison groups used by previous studies to calculate relative risk, first author Yinzhu Jin and colleagues noted in their report published in Arthritis Care & Research.

After mining a nationwide U.S. commercial health insurance claims database, the Optum Clinformatics Data Mart, for claims data from Jan. 1, 2005, to Dec. 31, 2017, the researchers matched a total of 108,568 patients in RA, general population non-RA, hypertension, and OA cohorts based on age, sex, and index date (the date of disease-specific medication dispensing). Overall, 77% of those patients were female and had a mean age of nearly 56 years, whereas 48% of patients with PsA were female and their mean age was nearly 49 years. (PsA patients were not matched because of smaller numbers.)

During a median follow-up period of 1.4-1.8 years across the comparison groups, the crude incidence rate for diabetes per 1,000 person-years in the cohorts was 7.0 for RA, 7.4 for general non-RA, 12.3 for hypertension, 7.8 for OA, and 9.9 for PsA. The hazard ratios and 95% confidence interval for risk of diabetes in patients with RA – after adjustment for more than 40 baseline covariates that included demographics, comorbidities, medication use, and health care utilization – was 0.72 (0.66-0.78) in comparison withh the general non-RA cohort, 0.65 (0.60-0.71) in comparison with the hypertension cohort, 0.75 (0.69-0.81) in comparison with the OA cohort, and 0.76 (0.67-0.86) in comparison with the PsA cohort. These values correspond to RA patients having a 24%-35% lower risk of incident diabetes versus the comparison groups, the researchers noted. They observed results consistent to these when they conducted a sensitivity analysis using a 1-year lag time from the index date before starting follow-up.

The lower risk of T2DM in patients with RA in comparison with patients in the non-RA cohort “may be, in part, due to the effect of biologic DMARD [disease-modifying antirheumatic drug] treatment in RA which likely modifies the risk of DM,” the researchers wrote. “Both the increasing use of biologic DMARDs for RA in the U.S. over the last decade and our cohort entry criteria for the RA cohort (i.e., at least one dispensing of a DMARD) may explain the finding of the lower risk of DM in RA.”

The results found with the other three cohorts did not surprise the researchers. The reduced risk of diabetes among RA patients versus those with OA jibes with “higher rates of obesity and other comorbidities in patients with OA” as well as findings from a recent study that found a higher incidence rate of diabetes in OA, compared with RA. Ms. Jin and colleagues also acknowledged it is well known that “hypertension and PsA are associated with metabolic dysregulation and increase the risk of diabetes.”

The researchers defined patients with RA as having at least twoinpatient or outpatient ICD-9 or ICD-10 diagnosis codes of RA, separated by 7-365 days and having at least one dispensing for DMARDs within 1 year from the first RA diagnosis date, and defined the primary outcome of incident T2DM as at least one inpatient or outpatient diagnosis of T2DM plus at least one dispensing of an antidiabetic drug. They set the general non-RA cohort by selecting patients with any inpatient or outpatient diagnosis codes and a dispensing of any medications, and the hypertension, PsA, and OA comparator groups as having at least two inpatient or outpatient disease-specific ICD-9/ICD-10 codes separated by 7-365 days and at least one dispensing of disease-specific medication within 1 year from the first diagnosis date. They excluded patients with RA, PsA, or psoriasis diagnosis or disease-specific medication dispensing any time prior to or on the index date (the date of disease-specific medication dispensing).

The researchers recognized that the conclusions that can be drawn from the study are limited by the “potential misclassification of cohorts and covariates” because they “mainly used diagnosis codes and pharmacy dispensing records in claims data,” and some “important covariates such as baseline obesity are likely underreported and not adequately captured in claims data.” The level of covariate misclassification also may have been different across the study cohorts on “unmeasured covariates such as body mass index, diet, and physical activity, as well as disease specific measures,” thus introducing residual confounding. They also could not “examine potential difference in the risk of T2DM in untreated or undertreated RA patients” because “RA and all the non-RA comparator cohorts were required to use a disease-specific drug,” they wrote.

“While systemic inflammation in RA is thought to increase the risk of [cardiovascular disease] and cardiovascular risk factors such as DM, our findings suggest having RA itself does not confer an increased risk of DM. Future study should determine whether untreated RA or undertreated RA is associated with a greater risk of developing DM,” the researchers concluded.

The study was supported by a research grant from Bristol-Myers Squibb, which “played no role in the study design, data analysis or interpretation of data or presentation of results,” the researchers said. The company was “given the opportunity to make nonbinding comments on a draft of the manuscript, but the authors retained the right of publication and to determine the final wording.” One author reported receiving research grants from Brigham and Women’s Hospital from Pfizer, AbbVie, Bristol-Myers Squibb, and Roche for unrelated topics.

[email protected]

SOURCE: Jin Y et al. Arthritis Care Res. 2020 Aug 4. doi: 10.1002/acr.24343.

Patients with RA were at lower risk for developing incident type 2 diabetes mellitus (T2DM) in comparison with patients with hypertension, psoriatic arthritis (PsA), or osteoarthritis, as well as the general population without RA in a retrospective cohort study of a large, nationwide, commercial health insurance claims database.

This result goes against what the study researchers from the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, initially hypothesized: The “risk of incident T2DM in RA patients would be similar to or less than PsA and [hypertension] patients, but higher, compared to general non-RA and OA patients.”

Prior epidemiologic studies of the relationship between RA and incident diabetes have yielded inconclusive results suggesting a small increase or no increase in risk of T2DM in patients with RA, possibly because of differences in the risk of T2DM in comparison groups used by previous studies to calculate relative risk, first author Yinzhu Jin and colleagues noted in their report published in Arthritis Care & Research.

After mining a nationwide U.S. commercial health insurance claims database, the Optum Clinformatics Data Mart, for claims data from Jan. 1, 2005, to Dec. 31, 2017, the researchers matched a total of 108,568 patients in RA, general population non-RA, hypertension, and OA cohorts based on age, sex, and index date (the date of disease-specific medication dispensing). Overall, 77% of those patients were female and had a mean age of nearly 56 years, whereas 48% of patients with PsA were female and their mean age was nearly 49 years. (PsA patients were not matched because of smaller numbers.)

During a median follow-up period of 1.4-1.8 years across the comparison groups, the crude incidence rate for diabetes per 1,000 person-years in the cohorts was 7.0 for RA, 7.4 for general non-RA, 12.3 for hypertension, 7.8 for OA, and 9.9 for PsA. The hazard ratios and 95% confidence interval for risk of diabetes in patients with RA – after adjustment for more than 40 baseline covariates that included demographics, comorbidities, medication use, and health care utilization – was 0.72 (0.66-0.78) in comparison withh the general non-RA cohort, 0.65 (0.60-0.71) in comparison with the hypertension cohort, 0.75 (0.69-0.81) in comparison with the OA cohort, and 0.76 (0.67-0.86) in comparison with the PsA cohort. These values correspond to RA patients having a 24%-35% lower risk of incident diabetes versus the comparison groups, the researchers noted. They observed results consistent to these when they conducted a sensitivity analysis using a 1-year lag time from the index date before starting follow-up.

The lower risk of T2DM in patients with RA in comparison with patients in the non-RA cohort “may be, in part, due to the effect of biologic DMARD [disease-modifying antirheumatic drug] treatment in RA which likely modifies the risk of DM,” the researchers wrote. “Both the increasing use of biologic DMARDs for RA in the U.S. over the last decade and our cohort entry criteria for the RA cohort (i.e., at least one dispensing of a DMARD) may explain the finding of the lower risk of DM in RA.”

The results found with the other three cohorts did not surprise the researchers. The reduced risk of diabetes among RA patients versus those with OA jibes with “higher rates of obesity and other comorbidities in patients with OA” as well as findings from a recent study that found a higher incidence rate of diabetes in OA, compared with RA. Ms. Jin and colleagues also acknowledged it is well known that “hypertension and PsA are associated with metabolic dysregulation and increase the risk of diabetes.”

The researchers defined patients with RA as having at least twoinpatient or outpatient ICD-9 or ICD-10 diagnosis codes of RA, separated by 7-365 days and having at least one dispensing for DMARDs within 1 year from the first RA diagnosis date, and defined the primary outcome of incident T2DM as at least one inpatient or outpatient diagnosis of T2DM plus at least one dispensing of an antidiabetic drug. They set the general non-RA cohort by selecting patients with any inpatient or outpatient diagnosis codes and a dispensing of any medications, and the hypertension, PsA, and OA comparator groups as having at least two inpatient or outpatient disease-specific ICD-9/ICD-10 codes separated by 7-365 days and at least one dispensing of disease-specific medication within 1 year from the first diagnosis date. They excluded patients with RA, PsA, or psoriasis diagnosis or disease-specific medication dispensing any time prior to or on the index date (the date of disease-specific medication dispensing).

The researchers recognized that the conclusions that can be drawn from the study are limited by the “potential misclassification of cohorts and covariates” because they “mainly used diagnosis codes and pharmacy dispensing records in claims data,” and some “important covariates such as baseline obesity are likely underreported and not adequately captured in claims data.” The level of covariate misclassification also may have been different across the study cohorts on “unmeasured covariates such as body mass index, diet, and physical activity, as well as disease specific measures,” thus introducing residual confounding. They also could not “examine potential difference in the risk of T2DM in untreated or undertreated RA patients” because “RA and all the non-RA comparator cohorts were required to use a disease-specific drug,” they wrote.

“While systemic inflammation in RA is thought to increase the risk of [cardiovascular disease] and cardiovascular risk factors such as DM, our findings suggest having RA itself does not confer an increased risk of DM. Future study should determine whether untreated RA or undertreated RA is associated with a greater risk of developing DM,” the researchers concluded.

The study was supported by a research grant from Bristol-Myers Squibb, which “played no role in the study design, data analysis or interpretation of data or presentation of results,” the researchers said. The company was “given the opportunity to make nonbinding comments on a draft of the manuscript, but the authors retained the right of publication and to determine the final wording.” One author reported receiving research grants from Brigham and Women’s Hospital from Pfizer, AbbVie, Bristol-Myers Squibb, and Roche for unrelated topics.

[email protected]

SOURCE: Jin Y et al. Arthritis Care Res. 2020 Aug 4. doi: 10.1002/acr.24343.

Bilateral lower extremity edema is a common condition with a broad differential diagnosis. New, severe peripheral edema implies a more nefarious underlying etiology than chronic venous insufficiency and should prompt a thorough evaluation for underlying conditions, such as congestive heart failure (CHF), cirrhosis, nephrotic syndrome, hypoalbuminemia, or lymphatic or venous obstruction. We present a case of a patient with sudden onset new bilateral lower extremity edema due to a rare adverse drug reaction (ADR) from valproate.

Case Presentation

A 63-year-old male with a history of seizures, bipolar disorder type I, and memory impairment due to traumatic brain injury (TBI) from a gunshot wound 24 years prior presented to the emergency department for witnessed seizure activity in the community. The patient had been incarcerated for the past 20 years, throughout which he had been taking the antiepileptic drugs (AEDs) phenytoin and divalproex and did not have any seizure activity. No records prior to his incarceration were available for review.

The patient recently had been released from prison and was nonadherent with his AEDs, leading to a witnessed seizure. This episode was described as preceded by an electric sensation, followed by rhythmic shaking of the right upper extremity without loss of consciousness. His regimen prior to admission included divalproex 1,000 mg daily and phenytoin 200 mg daily. His only other medication was folic acid.

Neurology was consulted on admission. An awake and asleep 4-hour electroencephalogram showed intermittent focal slowing of the right frontocentral region and frequent epileptiform discharges in the right prefrontal region during sleep, corresponding to areas of chronic right anterior frontal and temporal encephalomalacia seen on brain imaging. His seizures were thought likely to be secondary to prior head trauma. While the described seizure activity involving the right upper extremity was not consistent with the location of his prior TBI, neurology considered that he might have simple partial seizures with multiple foci or that his seizure event prior to admission was not accurately described. The neurology consult recommended switching from phenytoin 200 mg daily to lacosamide 100 mg twice daily on admission. His prior dose of divalproex 1,000 mg daily also was resumed for its antiepileptic effect and the added benefit of mood stabilization, as the patient reported elevated mood and decreased need for sleep on admission.

Eight days after changing his AED regimen, the patient was found to have new onset bilateral grade 1+ pitting edema to the level of his shins. He had no history of dyspnea, orthopnea, paroxysmal nocturnal dyspnea, dysuria, or changes in his urination. Although medical records from his incarceration were not available for review, the patient reported that he had never had peripheral edema.

On physical examination, the patient had no periorbital edema, jugular venous pressure of 8 cm H₂O, negative hepatojugular reflex, unremarkable cardiac and lung examination, and grade 2+ posterior tibial and dorsalis pedis pulses bilaterally. He underwent extensive laboratory evaluation for potential underlying causes, including nephrotic syndrome, cirrhosis, hypothyroidism, and CHF (Table). Valproate levels were initially subtherapeutic on admission (< 10 µg/mL, reference range 50-125 µg/mL) then rose to within therapeutic range (54 µg/mL-80 µg/mL throughout admission) after neurology recommended increasing the dose from 1,000 mg daily to 1,500 mg daily. His measured valproate levels were never supratherapeutic.

An electrocardiogram showed normal sinus rhythm unchanged from admission. Transthoracic echocardiogram showed normal left ventricular (LV) size and estimated LV ejection fraction of 55 to 60%. Abdominal ultrasound showed no evidence of cirrhosis and normal portal vein flow. Ultrasound of the lower extremities showed no deep venous thrombosis or valvular insufficiency. The patient was prescribed compression stockings. However, due to memory impairment, he was relatively nonadherent, and his lower extremity edema worsened to grade 3+ over several days. Due to the progressive swelling with no identified cause, a computed tomographic venogram of the abdomen and pelvis was performed to determine whether an inferior vena cava (IVC) thrombus was present. This study was unremarkable and did not show any external IVC compression.

After extensive evaluation did not reveal any other cause, the temporal course of events suggested an association between the patient’s peripheral edema and resumption of divalproex. His swelling remained stable. Discontinuation of divalproex was considered, but the patient’s mood remained euthymic, and he had no further seizure activity while on this medication, so the benefit of continuation was felt to outweigh any risks of switching to another agent.

Discussion

Valproate and its related forms, such as divalproex, often are used in the treatment of generalized or partial seizures, psychiatric disorders, and the prophylaxis of migraine headaches. Common ADRs include gastrointestinal symptoms, sedation, and dose-related thrombocytopenia, among many others. Rare ADRs include fulminant hepatitis, pancreatitis, hyperammonemia, and peripheral edema.¹ There have been case reports of valproate-induced peripheral edema, which seems to be an idiosyncratic ADR that occurs after long-term administration of the medication.^2,3 Early studies reported valproate-related edema in the context of valproate-induced hepatic injury.⁴ However, in more recent case reports, valproate-related edema has been found in patients without hepatotoxicity or supratherapeutic drug levels.^1,2

The exact mechanism by which valproate causes peripheral edema is unknown. It has been reported that medications affecting the γ-aminobutyric acid (GABA) system such as benzodiazepines, for example, can cause this rare ADR.⁵ Unlike benzodiazepines, valproate has an indirect effect on the GABA system, through increasing availability of GABA.⁶ GABA receptors have been identified on peripheral tissues, suggesting that GABAergic medications also may have an effect on regional vascular resistance.⁷ This mechanism was proposed by prior case reports but has yet to be proven in studies.²

In this case, initiation of lacosamide temporally coinciding with development of the patient’s edema leads one to question whether lacosamide may have caused this ADR. Other medications commonly used in seizure management (such as benzodiazepines and gabapentin) have been reported to cause new onset peripheral edema.^5,8 To date, however, there are no reported cases of peripheral edema due to lacosamide. While there are known interactions between various AEDs that may impact drug levels of valproate, there are no reported drug-drug interactions between lacosamide and valproate.⁹

Conclusions

Our case adds to the small but growing body of literature that suggests peripheral edema is a rare but clinically significant ADR of valproate. With its broad differential diagnosis, new onset peripheral edema is a concern that often warrants an extensive evaluation for underlying causes. Clinicians should be aware of this ADR as use of valproate becomes increasingly common so that an extensive workup is not always performed on patients with peripheral edema.

Bilateral lower extremity edema is a common condition with a broad differential diagnosis. New, severe peripheral edema implies a more nefarious underlying etiology than chronic venous insufficiency and should prompt a thorough evaluation for underlying conditions, such as congestive heart failure (CHF), cirrhosis, nephrotic syndrome, hypoalbuminemia, or lymphatic or venous obstruction. We present a case of a patient with sudden onset new bilateral lower extremity edema due to a rare adverse drug reaction (ADR) from valproate.

Case Presentation

A 63-year-old male with a history of seizures, bipolar disorder type I, and memory impairment due to traumatic brain injury (TBI) from a gunshot wound 24 years prior presented to the emergency department for witnessed seizure activity in the community. The patient had been incarcerated for the past 20 years, throughout which he had been taking the antiepileptic drugs (AEDs) phenytoin and divalproex and did not have any seizure activity. No records prior to his incarceration were available for review.

The patient recently had been released from prison and was nonadherent with his AEDs, leading to a witnessed seizure. This episode was described as preceded by an electric sensation, followed by rhythmic shaking of the right upper extremity without loss of consciousness. His regimen prior to admission included divalproex 1,000 mg daily and phenytoin 200 mg daily. His only other medication was folic acid.

Neurology was consulted on admission. An awake and asleep 4-hour electroencephalogram showed intermittent focal slowing of the right frontocentral region and frequent epileptiform discharges in the right prefrontal region during sleep, corresponding to areas of chronic right anterior frontal and temporal encephalomalacia seen on brain imaging. His seizures were thought likely to be secondary to prior head trauma. While the described seizure activity involving the right upper extremity was not consistent with the location of his prior TBI, neurology considered that he might have simple partial seizures with multiple foci or that his seizure event prior to admission was not accurately described. The neurology consult recommended switching from phenytoin 200 mg daily to lacosamide 100 mg twice daily on admission. His prior dose of divalproex 1,000 mg daily also was resumed for its antiepileptic effect and the added benefit of mood stabilization, as the patient reported elevated mood and decreased need for sleep on admission.

Eight days after changing his AED regimen, the patient was found to have new onset bilateral grade 1+ pitting edema to the level of his shins. He had no history of dyspnea, orthopnea, paroxysmal nocturnal dyspnea, dysuria, or changes in his urination. Although medical records from his incarceration were not available for review, the patient reported that he had never had peripheral edema.

On physical examination, the patient had no periorbital edema, jugular venous pressure of 8 cm H₂O, negative hepatojugular reflex, unremarkable cardiac and lung examination, and grade 2+ posterior tibial and dorsalis pedis pulses bilaterally. He underwent extensive laboratory evaluation for potential underlying causes, including nephrotic syndrome, cirrhosis, hypothyroidism, and CHF (Table). Valproate levels were initially subtherapeutic on admission (< 10 µg/mL, reference range 50-125 µg/mL) then rose to within therapeutic range (54 µg/mL-80 µg/mL throughout admission) after neurology recommended increasing the dose from 1,000 mg daily to 1,500 mg daily. His measured valproate levels were never supratherapeutic.

An electrocardiogram showed normal sinus rhythm unchanged from admission. Transthoracic echocardiogram showed normal left ventricular (LV) size and estimated LV ejection fraction of 55 to 60%. Abdominal ultrasound showed no evidence of cirrhosis and normal portal vein flow. Ultrasound of the lower extremities showed no deep venous thrombosis or valvular insufficiency. The patient was prescribed compression stockings. However, due to memory impairment, he was relatively nonadherent, and his lower extremity edema worsened to grade 3+ over several days. Due to the progressive swelling with no identified cause, a computed tomographic venogram of the abdomen and pelvis was performed to determine whether an inferior vena cava (IVC) thrombus was present. This study was unremarkable and did not show any external IVC compression.

After extensive evaluation did not reveal any other cause, the temporal course of events suggested an association between the patient’s peripheral edema and resumption of divalproex. His swelling remained stable. Discontinuation of divalproex was considered, but the patient’s mood remained euthymic, and he had no further seizure activity while on this medication, so the benefit of continuation was felt to outweigh any risks of switching to another agent.

Discussion

Valproate and its related forms, such as divalproex, often are used in the treatment of generalized or partial seizures, psychiatric disorders, and the prophylaxis of migraine headaches. Common ADRs include gastrointestinal symptoms, sedation, and dose-related thrombocytopenia, among many others. Rare ADRs include fulminant hepatitis, pancreatitis, hyperammonemia, and peripheral edema.¹ There have been case reports of valproate-induced peripheral edema, which seems to be an idiosyncratic ADR that occurs after long-term administration of the medication.^2,3 Early studies reported valproate-related edema in the context of valproate-induced hepatic injury.⁴ However, in more recent case reports, valproate-related edema has been found in patients without hepatotoxicity or supratherapeutic drug levels.^1,2

The exact mechanism by which valproate causes peripheral edema is unknown. It has been reported that medications affecting the γ-aminobutyric acid (GABA) system such as benzodiazepines, for example, can cause this rare ADR.⁵ Unlike benzodiazepines, valproate has an indirect effect on the GABA system, through increasing availability of GABA.⁶ GABA receptors have been identified on peripheral tissues, suggesting that GABAergic medications also may have an effect on regional vascular resistance.⁷ This mechanism was proposed by prior case reports but has yet to be proven in studies.²

In this case, initiation of lacosamide temporally coinciding with development of the patient’s edema leads one to question whether lacosamide may have caused this ADR. Other medications commonly used in seizure management (such as benzodiazepines and gabapentin) have been reported to cause new onset peripheral edema.^5,8 To date, however, there are no reported cases of peripheral edema due to lacosamide. While there are known interactions between various AEDs that may impact drug levels of valproate, there are no reported drug-drug interactions between lacosamide and valproate.⁹

Conclusions

Our case adds to the small but growing body of literature that suggests peripheral edema is a rare but clinically significant ADR of valproate. With its broad differential diagnosis, new onset peripheral edema is a concern that often warrants an extensive evaluation for underlying causes. Clinicians should be aware of this ADR as use of valproate becomes increasingly common so that an extensive workup is not always performed on patients with peripheral edema.

Bilateral lower extremity edema is a common condition with a broad differential diagnosis. New, severe peripheral edema implies a more nefarious underlying etiology than chronic venous insufficiency and should prompt a thorough evaluation for underlying conditions, such as congestive heart failure (CHF), cirrhosis, nephrotic syndrome, hypoalbuminemia, or lymphatic or venous obstruction. We present a case of a patient with sudden onset new bilateral lower extremity edema due to a rare adverse drug reaction (ADR) from valproate.

Case Presentation

A 63-year-old male with a history of seizures, bipolar disorder type I, and memory impairment due to traumatic brain injury (TBI) from a gunshot wound 24 years prior presented to the emergency department for witnessed seizure activity in the community. The patient had been incarcerated for the past 20 years, throughout which he had been taking the antiepileptic drugs (AEDs) phenytoin and divalproex and did not have any seizure activity. No records prior to his incarceration were available for review.

The patient recently had been released from prison and was nonadherent with his AEDs, leading to a witnessed seizure. This episode was described as preceded by an electric sensation, followed by rhythmic shaking of the right upper extremity without loss of consciousness. His regimen prior to admission included divalproex 1,000 mg daily and phenytoin 200 mg daily. His only other medication was folic acid.

Neurology was consulted on admission. An awake and asleep 4-hour electroencephalogram showed intermittent focal slowing of the right frontocentral region and frequent epileptiform discharges in the right prefrontal region during sleep, corresponding to areas of chronic right anterior frontal and temporal encephalomalacia seen on brain imaging. His seizures were thought likely to be secondary to prior head trauma. While the described seizure activity involving the right upper extremity was not consistent with the location of his prior TBI, neurology considered that he might have simple partial seizures with multiple foci or that his seizure event prior to admission was not accurately described. The neurology consult recommended switching from phenytoin 200 mg daily to lacosamide 100 mg twice daily on admission. His prior dose of divalproex 1,000 mg daily also was resumed for its antiepileptic effect and the added benefit of mood stabilization, as the patient reported elevated mood and decreased need for sleep on admission.

Eight days after changing his AED regimen, the patient was found to have new onset bilateral grade 1+ pitting edema to the level of his shins. He had no history of dyspnea, orthopnea, paroxysmal nocturnal dyspnea, dysuria, or changes in his urination. Although medical records from his incarceration were not available for review, the patient reported that he had never had peripheral edema.

On physical examination, the patient had no periorbital edema, jugular venous pressure of 8 cm H₂O, negative hepatojugular reflex, unremarkable cardiac and lung examination, and grade 2+ posterior tibial and dorsalis pedis pulses bilaterally. He underwent extensive laboratory evaluation for potential underlying causes, including nephrotic syndrome, cirrhosis, hypothyroidism, and CHF (Table). Valproate levels were initially subtherapeutic on admission (< 10 µg/mL, reference range 50-125 µg/mL) then rose to within therapeutic range (54 µg/mL-80 µg/mL throughout admission) after neurology recommended increasing the dose from 1,000 mg daily to 1,500 mg daily. His measured valproate levels were never supratherapeutic.

An electrocardiogram showed normal sinus rhythm unchanged from admission. Transthoracic echocardiogram showed normal left ventricular (LV) size and estimated LV ejection fraction of 55 to 60%. Abdominal ultrasound showed no evidence of cirrhosis and normal portal vein flow. Ultrasound of the lower extremities showed no deep venous thrombosis or valvular insufficiency. The patient was prescribed compression stockings. However, due to memory impairment, he was relatively nonadherent, and his lower extremity edema worsened to grade 3+ over several days. Due to the progressive swelling with no identified cause, a computed tomographic venogram of the abdomen and pelvis was performed to determine whether an inferior vena cava (IVC) thrombus was present. This study was unremarkable and did not show any external IVC compression.

After extensive evaluation did not reveal any other cause, the temporal course of events suggested an association between the patient’s peripheral edema and resumption of divalproex. His swelling remained stable. Discontinuation of divalproex was considered, but the patient’s mood remained euthymic, and he had no further seizure activity while on this medication, so the benefit of continuation was felt to outweigh any risks of switching to another agent.

Discussion

Valproate and its related forms, such as divalproex, often are used in the treatment of generalized or partial seizures, psychiatric disorders, and the prophylaxis of migraine headaches. Common ADRs include gastrointestinal symptoms, sedation, and dose-related thrombocytopenia, among many others. Rare ADRs include fulminant hepatitis, pancreatitis, hyperammonemia, and peripheral edema.¹ There have been case reports of valproate-induced peripheral edema, which seems to be an idiosyncratic ADR that occurs after long-term administration of the medication.^2,3 Early studies reported valproate-related edema in the context of valproate-induced hepatic injury.⁴ However, in more recent case reports, valproate-related edema has been found in patients without hepatotoxicity or supratherapeutic drug levels.^1,2

The exact mechanism by which valproate causes peripheral edema is unknown. It has been reported that medications affecting the γ-aminobutyric acid (GABA) system such as benzodiazepines, for example, can cause this rare ADR.⁵ Unlike benzodiazepines, valproate has an indirect effect on the GABA system, through increasing availability of GABA.⁶ GABA receptors have been identified on peripheral tissues, suggesting that GABAergic medications also may have an effect on regional vascular resistance.⁷ This mechanism was proposed by prior case reports but has yet to be proven in studies.²

In this case, initiation of lacosamide temporally coinciding with development of the patient’s edema leads one to question whether lacosamide may have caused this ADR. Other medications commonly used in seizure management (such as benzodiazepines and gabapentin) have been reported to cause new onset peripheral edema.^5,8 To date, however, there are no reported cases of peripheral edema due to lacosamide. While there are known interactions between various AEDs that may impact drug levels of valproate, there are no reported drug-drug interactions between lacosamide and valproate.⁹

Conclusions

Our case adds to the small but growing body of literature that suggests peripheral edema is a rare but clinically significant ADR of valproate. With its broad differential diagnosis, new onset peripheral edema is a concern that often warrants an extensive evaluation for underlying causes. Clinicians should be aware of this ADR as use of valproate becomes increasingly common so that an extensive workup is not always performed on patients with peripheral edema.