THE CASE

A 20-year-old man presented to our clinic with a 3-day history of nonradiating chest pain located at the center of his chest. Past medical history included idiopathic neonatal giant-cell hepatitis and subsequent liver transplant at 1 month of age; he had been followed by the transplant team without rejection or infection and was in otherwise good health prior to the chest pain.

On the day of symptom onset, he was walking inside his house and fell to his knees with a chest pain described as “a punch” to the center of the chest that lasted for a few seconds. He was able to continue his daily activities without limitation despite a constant, squeezing, centrally located chest pain. The pain worsened with cough and exertion.

A few hours later, he went to an urgent care center for evaluation. There, he reported, his chest radiograph and electrocardiogram (EKG) results were normal and he was given a diagnosis of musculoskeletal chest pain. Over the next 3 days, his chest pain persisted but did not worsen. He was taking 500 mg of naproxen every 8 hours with no improvement. No other acute or chronic medications were being taken. He had no significant family history. A review of systems was otherwise negative.

On physical exam, his vital statistics included a height of 6’4”; weight, 261 lb; body mass index, 31.8; temperature, 98.7 °F; blood pressure, 134/77 mm Hg; heart rate, 92 beats/min; respiratory rate, 18 breaths/min; and oxygen saturation, 96%. Throughout the exam, he demonstrated no acute distress, appeared well, and was talkative; however, he reported having a “constant, squeezing” chest pain that did not worsen with palpation of the chest. The rest of his physical exam was unremarkable.

Although he reported that his EKG and chest radiograph were normal 3 days prior, repeat chest radiograph and EKG were ordered due to his unexplained, active chest pain and the lack of immediate access to the prior results.

THE DIAGNOSIS

The chest radiograph (FIGURE 1A) showed a “mildly ectatic ascending thoracic aorta” that had increased since a chest radiograph from 6 years prior (FIGURE 1B) and “was concerning for an aneurysm.” Computed tomography (CT) angiography (FIGURE 2) then confirmed a 7-cm aneurysm of the ascending aorta, with findings suggestive of a retrograde ascending aortic dissection.

DISCUSSION

The average age of a patient with acute aortic dissection (AAD) is 63 years; only 7% occur in people younger than 40.¹ AAD is often accompanied by a predisposing risk factor such as a connective tissue disease, bicuspid aortic valve, longstanding hypertension, trauma, or larger aortic dimensions.^2,3 Younger patients are more likely to have predisposing risk factors of Marfan syndrome, prior aortic surgery, or a bicuspid aortic valve.³

Continue to: A literature review did not reveal...

A literature review did not reveal any known correlation between the patient’s history of giant-cell hepatitis or antirejection therapy with thoracic aortic dissection. Furthermore, liver transplant is not known to be a specific risk factor for AAD in pediatric patients or outside the immediate postoperative period. Therefore, there were no known predisposing risk factors for AAD in our patient.

The most common clinical feature of AAD is chest pain, which occurs in 75% of patients.¹ Other clinical symptoms include hypertension and diaphoresis.^2,4 However, classic clinical findings are not always displayed, making the diagnosis difficult.^2,4 The classical description of “tearing pain” is seen in only 51% of patients, and 5% to 15% of patients present without any pain.¹

Commonly missed or misdiagnosed. The diagnosis of AAD has been missed during the initial exam in 38% of patients.⁴ As seen in our case, symptoms may be initially diagnosed as musculoskeletal chest pain. Based on symptoms, AAD can be incorrectly diagnosed as an acute myocardial infarction or vascular embolization.^2,4

Every hour after symptom onset, the mortality rate of untreated AAD increases 1% to 2%,with no difference based on age.^3,4 Different reports have shown mortality rates between 7% and 30%.⁴

Effective imaging is crucial to the diagnosis and treatment of AAD, given the occurrence of atypical presentation, missed diagnosis, and high mortality rate.⁴ A chest radiograph will show a widened mediastinum, but the preferred diagnostic tests are a CT or transthoracic echocardiogram.^2,4 Once the diagnosis of AAD is confirmed, an aortic angiogram is the preferred test to determine the extent of the dissection prior to surgical treatment.²

Continue to: Classification dictates treatment

Classification dictates treatment. AAD is classified based on where the dissection of the aorta occurs. If the dissection involves the ascending aorta, it is classified as a type A AAD and should immediately be treated with emergent surgery in order to prevent complications including myocardial infarction, cardiac tamponade, and aortic rupture.^2,4,5 If the dissection is limited to the descending aorta, it is classified as a type B AAD and can be medically managed by controlling pain and lowering blood pressure; if symptoms persist, surgical management may be required.² After hospital discharge, AAD patients are followed closely with medical therapy, serial imaging, and reoperation if necessary.⁴

Our patient underwent emergent surgery for aortic root/ascending aortic replacement with a mechanical valve. He tolerated the procedure well. Surgical tissue pathology of the aortic segment showed a wall of elastic vessel with medial degeneration and dissection, and the tissue pathology of the aorta leaflets showed valvular tissue with myxoid degeneration.

THE TAKEAWAY

It is critical to keep AAD in the differential diagnosis of a patient presenting with acute onset of chest pain, as AAD often has an atypical presentation and can easily be misdiagnosed. Effective imaging is crucial to diagnosis, and immediate treatment is essential to patient survival.

CORRESPONDENCE
Rachel A. Reedy, PA, University of Florida, Department of General Pediatrics, 7046 SW Archer Road, Gainesville, FL 32608; [email protected]

THE CASE

A 20-year-old man presented to our clinic with a 3-day history of nonradiating chest pain located at the center of his chest. Past medical history included idiopathic neonatal giant-cell hepatitis and subsequent liver transplant at 1 month of age; he had been followed by the transplant team without rejection or infection and was in otherwise good health prior to the chest pain.

On the day of symptom onset, he was walking inside his house and fell to his knees with a chest pain described as “a punch” to the center of the chest that lasted for a few seconds. He was able to continue his daily activities without limitation despite a constant, squeezing, centrally located chest pain. The pain worsened with cough and exertion.

A few hours later, he went to an urgent care center for evaluation. There, he reported, his chest radiograph and electrocardiogram (EKG) results were normal and he was given a diagnosis of musculoskeletal chest pain. Over the next 3 days, his chest pain persisted but did not worsen. He was taking 500 mg of naproxen every 8 hours with no improvement. No other acute or chronic medications were being taken. He had no significant family history. A review of systems was otherwise negative.

On physical exam, his vital statistics included a height of 6’4”; weight, 261 lb; body mass index, 31.8; temperature, 98.7 °F; blood pressure, 134/77 mm Hg; heart rate, 92 beats/min; respiratory rate, 18 breaths/min; and oxygen saturation, 96%. Throughout the exam, he demonstrated no acute distress, appeared well, and was talkative; however, he reported having a “constant, squeezing” chest pain that did not worsen with palpation of the chest. The rest of his physical exam was unremarkable.

Although he reported that his EKG and chest radiograph were normal 3 days prior, repeat chest radiograph and EKG were ordered due to his unexplained, active chest pain and the lack of immediate access to the prior results.

THE DIAGNOSIS

The chest radiograph (FIGURE 1A) showed a “mildly ectatic ascending thoracic aorta” that had increased since a chest radiograph from 6 years prior (FIGURE 1B) and “was concerning for an aneurysm.” Computed tomography (CT) angiography (FIGURE 2) then confirmed a 7-cm aneurysm of the ascending aorta, with findings suggestive of a retrograde ascending aortic dissection.

DISCUSSION

The average age of a patient with acute aortic dissection (AAD) is 63 years; only 7% occur in people younger than 40.¹ AAD is often accompanied by a predisposing risk factor such as a connective tissue disease, bicuspid aortic valve, longstanding hypertension, trauma, or larger aortic dimensions.^2,3 Younger patients are more likely to have predisposing risk factors of Marfan syndrome, prior aortic surgery, or a bicuspid aortic valve.³

Continue to: A literature review did not reveal...

A literature review did not reveal any known correlation between the patient’s history of giant-cell hepatitis or antirejection therapy with thoracic aortic dissection. Furthermore, liver transplant is not known to be a specific risk factor for AAD in pediatric patients or outside the immediate postoperative period. Therefore, there were no known predisposing risk factors for AAD in our patient.

The most common clinical feature of AAD is chest pain, which occurs in 75% of patients.¹ Other clinical symptoms include hypertension and diaphoresis.^2,4 However, classic clinical findings are not always displayed, making the diagnosis difficult.^2,4 The classical description of “tearing pain” is seen in only 51% of patients, and 5% to 15% of patients present without any pain.¹

Commonly missed or misdiagnosed. The diagnosis of AAD has been missed during the initial exam in 38% of patients.⁴ As seen in our case, symptoms may be initially diagnosed as musculoskeletal chest pain. Based on symptoms, AAD can be incorrectly diagnosed as an acute myocardial infarction or vascular embolization.^2,4

Every hour after symptom onset, the mortality rate of untreated AAD increases 1% to 2%,with no difference based on age.^3,4 Different reports have shown mortality rates between 7% and 30%.⁴

Effective imaging is crucial to the diagnosis and treatment of AAD, given the occurrence of atypical presentation, missed diagnosis, and high mortality rate.⁴ A chest radiograph will show a widened mediastinum, but the preferred diagnostic tests are a CT or transthoracic echocardiogram.^2,4 Once the diagnosis of AAD is confirmed, an aortic angiogram is the preferred test to determine the extent of the dissection prior to surgical treatment.²

Continue to: Classification dictates treatment

Classification dictates treatment. AAD is classified based on where the dissection of the aorta occurs. If the dissection involves the ascending aorta, it is classified as a type A AAD and should immediately be treated with emergent surgery in order to prevent complications including myocardial infarction, cardiac tamponade, and aortic rupture.^2,4,5 If the dissection is limited to the descending aorta, it is classified as a type B AAD and can be medically managed by controlling pain and lowering blood pressure; if symptoms persist, surgical management may be required.² After hospital discharge, AAD patients are followed closely with medical therapy, serial imaging, and reoperation if necessary.⁴

Our patient underwent emergent surgery for aortic root/ascending aortic replacement with a mechanical valve. He tolerated the procedure well. Surgical tissue pathology of the aortic segment showed a wall of elastic vessel with medial degeneration and dissection, and the tissue pathology of the aorta leaflets showed valvular tissue with myxoid degeneration.

THE TAKEAWAY

It is critical to keep AAD in the differential diagnosis of a patient presenting with acute onset of chest pain, as AAD often has an atypical presentation and can easily be misdiagnosed. Effective imaging is crucial to diagnosis, and immediate treatment is essential to patient survival.

CORRESPONDENCE
Rachel A. Reedy, PA, University of Florida, Department of General Pediatrics, 7046 SW Archer Road, Gainesville, FL 32608; [email protected]

THE CASE

A 20-year-old man presented to our clinic with a 3-day history of nonradiating chest pain located at the center of his chest. Past medical history included idiopathic neonatal giant-cell hepatitis and subsequent liver transplant at 1 month of age; he had been followed by the transplant team without rejection or infection and was in otherwise good health prior to the chest pain.

On the day of symptom onset, he was walking inside his house and fell to his knees with a chest pain described as “a punch” to the center of the chest that lasted for a few seconds. He was able to continue his daily activities without limitation despite a constant, squeezing, centrally located chest pain. The pain worsened with cough and exertion.

A few hours later, he went to an urgent care center for evaluation. There, he reported, his chest radiograph and electrocardiogram (EKG) results were normal and he was given a diagnosis of musculoskeletal chest pain. Over the next 3 days, his chest pain persisted but did not worsen. He was taking 500 mg of naproxen every 8 hours with no improvement. No other acute or chronic medications were being taken. He had no significant family history. A review of systems was otherwise negative.

On physical exam, his vital statistics included a height of 6’4”; weight, 261 lb; body mass index, 31.8; temperature, 98.7 °F; blood pressure, 134/77 mm Hg; heart rate, 92 beats/min; respiratory rate, 18 breaths/min; and oxygen saturation, 96%. Throughout the exam, he demonstrated no acute distress, appeared well, and was talkative; however, he reported having a “constant, squeezing” chest pain that did not worsen with palpation of the chest. The rest of his physical exam was unremarkable.

Although he reported that his EKG and chest radiograph were normal 3 days prior, repeat chest radiograph and EKG were ordered due to his unexplained, active chest pain and the lack of immediate access to the prior results.

THE DIAGNOSIS

The chest radiograph (FIGURE 1A) showed a “mildly ectatic ascending thoracic aorta” that had increased since a chest radiograph from 6 years prior (FIGURE 1B) and “was concerning for an aneurysm.” Computed tomography (CT) angiography (FIGURE 2) then confirmed a 7-cm aneurysm of the ascending aorta, with findings suggestive of a retrograde ascending aortic dissection.

DISCUSSION

The average age of a patient with acute aortic dissection (AAD) is 63 years; only 7% occur in people younger than 40.¹ AAD is often accompanied by a predisposing risk factor such as a connective tissue disease, bicuspid aortic valve, longstanding hypertension, trauma, or larger aortic dimensions.^2,3 Younger patients are more likely to have predisposing risk factors of Marfan syndrome, prior aortic surgery, or a bicuspid aortic valve.³

Continue to: A literature review did not reveal...

A literature review did not reveal any known correlation between the patient’s history of giant-cell hepatitis or antirejection therapy with thoracic aortic dissection. Furthermore, liver transplant is not known to be a specific risk factor for AAD in pediatric patients or outside the immediate postoperative period. Therefore, there were no known predisposing risk factors for AAD in our patient.

The most common clinical feature of AAD is chest pain, which occurs in 75% of patients.¹ Other clinical symptoms include hypertension and diaphoresis.^2,4 However, classic clinical findings are not always displayed, making the diagnosis difficult.^2,4 The classical description of “tearing pain” is seen in only 51% of patients, and 5% to 15% of patients present without any pain.¹

Commonly missed or misdiagnosed. The diagnosis of AAD has been missed during the initial exam in 38% of patients.⁴ As seen in our case, symptoms may be initially diagnosed as musculoskeletal chest pain. Based on symptoms, AAD can be incorrectly diagnosed as an acute myocardial infarction or vascular embolization.^2,4

Every hour after symptom onset, the mortality rate of untreated AAD increases 1% to 2%,with no difference based on age.^3,4 Different reports have shown mortality rates between 7% and 30%.⁴

Effective imaging is crucial to the diagnosis and treatment of AAD, given the occurrence of atypical presentation, missed diagnosis, and high mortality rate.⁴ A chest radiograph will show a widened mediastinum, but the preferred diagnostic tests are a CT or transthoracic echocardiogram.^2,4 Once the diagnosis of AAD is confirmed, an aortic angiogram is the preferred test to determine the extent of the dissection prior to surgical treatment.²

Continue to: Classification dictates treatment

Classification dictates treatment. AAD is classified based on where the dissection of the aorta occurs. If the dissection involves the ascending aorta, it is classified as a type A AAD and should immediately be treated with emergent surgery in order to prevent complications including myocardial infarction, cardiac tamponade, and aortic rupture.^2,4,5 If the dissection is limited to the descending aorta, it is classified as a type B AAD and can be medically managed by controlling pain and lowering blood pressure; if symptoms persist, surgical management may be required.² After hospital discharge, AAD patients are followed closely with medical therapy, serial imaging, and reoperation if necessary.⁴

Our patient underwent emergent surgery for aortic root/ascending aortic replacement with a mechanical valve. He tolerated the procedure well. Surgical tissue pathology of the aortic segment showed a wall of elastic vessel with medial degeneration and dissection, and the tissue pathology of the aorta leaflets showed valvular tissue with myxoid degeneration.

THE TAKEAWAY

It is critical to keep AAD in the differential diagnosis of a patient presenting with acute onset of chest pain, as AAD often has an atypical presentation and can easily be misdiagnosed. Effective imaging is crucial to diagnosis, and immediate treatment is essential to patient survival.

CORRESPONDENCE
Rachel A. Reedy, PA, University of Florida, Department of General Pediatrics, 7046 SW Archer Road, Gainesville, FL 32608; [email protected]

Across this period of the pandemic, we’ve spent considerable attention focusing on adaptations to clinical care for pregnant and postpartum women across the board. From the start, this has included a shift to telemedicine for the majority of our patients who come to see us with psychiatric disorders either before, during, or after pregnancy.

Specific issues for perinatal patients since the early days of COVID-19 have included the shifts in women’s plans with respect to delivery as well as the limitation on women’s ability to configure the types of support that they had originally planned on with family, friends, and others during delivery. Telemedicine again helped, at least in part, to fill that void by having online digital support by individuals or groups for both pregnant and postpartum women. These supports were always available, but quickly scaled up during the first 6-9 months of the pandemic and have likely seen their greatest increase in participation in the history of support groups for pregnant and postpartum women.

Similarly, at our own center, we have seen a dramatic increase across the last 10 months in requests for consultation by women with psychiatric disorders who have hopes and plans to conceive, to those who are pregnant or post partum and who are trying to sustain emotional well-being despite the added burden of the pandemic. As we heard similar stories regarding interactions with perinatal patients from reproductive psychiatrists across the country, my colleagues and I had to set up an additional resource, Virtual Rounds at the Center for Women’s Mental Health at Massachusetts General Hospital, Boston, which has been mentioned in previous columns, which has only grown during the last 6 months of the pandemic. We have colleagues across the country joining us from 2 p.m. to 3 p.m. on Wednesdays after our own faculty rounds, where we perform case reviews of our own patients, and invite our colleagues to share cases that are then reviewed with expert panelists together with our own faculty in a collaborative environment. Feedback from the community of clinicians has indicated that these virtual rounds have been invaluable to their efforts in taking care of women with perinatal psychiatric issues, particularly during the pandemic.

Of particular note during consultations on our service is the number of women coming to see us for questions about the reproductive safety of the medications on which they are maintained. Hundreds of women present to the center each year for the most up-to-date information regarding the reproductive safety of the most commonly used psychiatric medications in reproductive-age women, including antidepressants (SSRIs, serotonin norepinephrine reuptake inhibitor), mood stabilizers, lithium, lamotrigine, and atypical antipsychotics, as well as other medicines used to treat symptoms that have been a particular issue during the pandemic, such as insomnia and anxiety (benzodiazepines, nonbenzodiazepines, sedative hypnotics, and medicines such as gabapentin).

While consultation regarding risk of fetal exposure to psychotropics has been the cornerstone of our clinical work for 25 years, it has taken on a particularly critical dimension during the pandemic given the wish that women stay euthymic during the pandemic to limit the possibility of patients needing to present in a clinical space that would increase their risk for COVID-19, and to also minimize their risk for postpartum depression. (Psychiatric disorder during pregnancy remains the strongest predictor of emergence or worsening of underlying illness during the postpartum period.)

It is also noteworthy that, during a pandemic year, publications in reproductive psychiatry have been numerous, and we continue to make an effort at our own center to keep up with this and to share with our colleagues our impression of that literature using the weekly blog at womensmentalhealth.org. Last year brought the largest audience to the blog and visits to womensmentalhealth.org in the history of our center.

A case recently at our center presents a unique opportunity to review a confusing question in reproductive psychiatry over the last 15 years. A woman with a longstanding history of mixed anxiety and depression recently came to see us on a regimen of escitalopram and low-dose benzodiazepine. She was doing well, and she and her husband of 4 years were hopeful about starting to try to conceive despite the pandemic. We reviewed the reproductive safety data of the medicines on which she was maintained and made plans to follow-up as her plans galvanized. She notified me several months later that she had become pregnant but had experienced an early miscarriage. The patient was obviously upset and, as she reflected on her decision to maintain treatment with SSRI during her attempts to conceive and across a very early pregnancy, she queried about the extent to which her SSRI use might have contributed to her miscarriage.

The question about the possible association of antidepressant use during pregnancy and increased risk for miscarriage goes back at least 15 years when there were reports of an increased risk of miscarriage in women taking SSRIs during pregnancy. In that early work, there was an apparent increase in miscarriage in women taking SSRIs relative to a control group, but the rate did not exceed the prevalence of miscarriage in the general population. Since those early reports, we are lucky to have had multiple investigators look very closely at this issue, including one meta-analysis of 11 studies done approximately 8 years ago that failed to show an increased risk of miscarriage in the setting of first trimester exposure to SSRIs.

What has been most problematic methodologically, however, has been the failure to account for the potential role of depression in models that predict risk. A subsequent large epidemiologic study from Denmark evaluating over a million women has looked at this question further. The authors found a slightly increased risk of spontaneous abortion associated with the use of antidepressants (12.0% in women with antidepressant exposure vs. 11.1% in women with no exposure). However, looking only at women with a diagnosis of depression, the adjusted risk ratio for spontaneous abortion after any antidepressant exposure was 1.00 (95% confidence interval, 0.80-1.24). Thus, the researchers concluded that exposure to depression – but not exposure to antidepressant – is associated with a slightly higher risk of miscarriage.

Even more recently, a follow-up study examining this question supports the large epidemiologic study by Kjaersgaard and colleagues. For most readers, this effectively answers this very important question for women about rates of miscarriage associated with fetal exposure to SSRIs.

For the patient who presented at the center, reassuring her with this information felt particularly good, especially within the context of the pandemic. After several months of trying to conceive, she again became pregnant and delivered without difficulty. What was palpable in that clinical scenario, as it relates to the practice of reproductive psychiatry during the pandemic, is the even-greater emotional valence that questions about using psychiatric medications during pregnancy has taken on across these past months. While attention and thoughtful consideration about the relative risks of using psychiatric medications during pregnancy should be standard clinical practice, the level of anxiety associated with decisions to sustain or to discontinue treatment during pregnancy seems to have increased for some patients during the pandemic.

Even as the COVID-19 vaccine initiative across the United States is rolled out, 2021 will continue to be a complicated time for women and families. We still need to be vigilant. In addition to screening for perinatal depression during pregnancy and the postpartum period, we should be equally mindful of screening and treating perinatal anxiety, particularly during this challenging time. The challenge to keep pregnant and postpartum women well is perhaps even greater now, 10 months into the pandemic, than it was when we were in crisis mode in March 2020. As clinicians, we need to mobilize the spectrum of both pharmacologic and nonpharmacologic treatment options to sustain emotional well-being among women planning to conceive as well as those who are pregnant or postpartum as we navigate our way to safer times.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].

Across this period of the pandemic, we’ve spent considerable attention focusing on adaptations to clinical care for pregnant and postpartum women across the board. From the start, this has included a shift to telemedicine for the majority of our patients who come to see us with psychiatric disorders either before, during, or after pregnancy.

Specific issues for perinatal patients since the early days of COVID-19 have included the shifts in women’s plans with respect to delivery as well as the limitation on women’s ability to configure the types of support that they had originally planned on with family, friends, and others during delivery. Telemedicine again helped, at least in part, to fill that void by having online digital support by individuals or groups for both pregnant and postpartum women. These supports were always available, but quickly scaled up during the first 6-9 months of the pandemic and have likely seen their greatest increase in participation in the history of support groups for pregnant and postpartum women.

Similarly, at our own center, we have seen a dramatic increase across the last 10 months in requests for consultation by women with psychiatric disorders who have hopes and plans to conceive, to those who are pregnant or post partum and who are trying to sustain emotional well-being despite the added burden of the pandemic. As we heard similar stories regarding interactions with perinatal patients from reproductive psychiatrists across the country, my colleagues and I had to set up an additional resource, Virtual Rounds at the Center for Women’s Mental Health at Massachusetts General Hospital, Boston, which has been mentioned in previous columns, which has only grown during the last 6 months of the pandemic. We have colleagues across the country joining us from 2 p.m. to 3 p.m. on Wednesdays after our own faculty rounds, where we perform case reviews of our own patients, and invite our colleagues to share cases that are then reviewed with expert panelists together with our own faculty in a collaborative environment. Feedback from the community of clinicians has indicated that these virtual rounds have been invaluable to their efforts in taking care of women with perinatal psychiatric issues, particularly during the pandemic.

Of particular note during consultations on our service is the number of women coming to see us for questions about the reproductive safety of the medications on which they are maintained. Hundreds of women present to the center each year for the most up-to-date information regarding the reproductive safety of the most commonly used psychiatric medications in reproductive-age women, including antidepressants (SSRIs, serotonin norepinephrine reuptake inhibitor), mood stabilizers, lithium, lamotrigine, and atypical antipsychotics, as well as other medicines used to treat symptoms that have been a particular issue during the pandemic, such as insomnia and anxiety (benzodiazepines, nonbenzodiazepines, sedative hypnotics, and medicines such as gabapentin).

While consultation regarding risk of fetal exposure to psychotropics has been the cornerstone of our clinical work for 25 years, it has taken on a particularly critical dimension during the pandemic given the wish that women stay euthymic during the pandemic to limit the possibility of patients needing to present in a clinical space that would increase their risk for COVID-19, and to also minimize their risk for postpartum depression. (Psychiatric disorder during pregnancy remains the strongest predictor of emergence or worsening of underlying illness during the postpartum period.)

It is also noteworthy that, during a pandemic year, publications in reproductive psychiatry have been numerous, and we continue to make an effort at our own center to keep up with this and to share with our colleagues our impression of that literature using the weekly blog at womensmentalhealth.org. Last year brought the largest audience to the blog and visits to womensmentalhealth.org in the history of our center.

A case recently at our center presents a unique opportunity to review a confusing question in reproductive psychiatry over the last 15 years. A woman with a longstanding history of mixed anxiety and depression recently came to see us on a regimen of escitalopram and low-dose benzodiazepine. She was doing well, and she and her husband of 4 years were hopeful about starting to try to conceive despite the pandemic. We reviewed the reproductive safety data of the medicines on which she was maintained and made plans to follow-up as her plans galvanized. She notified me several months later that she had become pregnant but had experienced an early miscarriage. The patient was obviously upset and, as she reflected on her decision to maintain treatment with SSRI during her attempts to conceive and across a very early pregnancy, she queried about the extent to which her SSRI use might have contributed to her miscarriage.

The question about the possible association of antidepressant use during pregnancy and increased risk for miscarriage goes back at least 15 years when there were reports of an increased risk of miscarriage in women taking SSRIs during pregnancy. In that early work, there was an apparent increase in miscarriage in women taking SSRIs relative to a control group, but the rate did not exceed the prevalence of miscarriage in the general population. Since those early reports, we are lucky to have had multiple investigators look very closely at this issue, including one meta-analysis of 11 studies done approximately 8 years ago that failed to show an increased risk of miscarriage in the setting of first trimester exposure to SSRIs.

What has been most problematic methodologically, however, has been the failure to account for the potential role of depression in models that predict risk. A subsequent large epidemiologic study from Denmark evaluating over a million women has looked at this question further. The authors found a slightly increased risk of spontaneous abortion associated with the use of antidepressants (12.0% in women with antidepressant exposure vs. 11.1% in women with no exposure). However, looking only at women with a diagnosis of depression, the adjusted risk ratio for spontaneous abortion after any antidepressant exposure was 1.00 (95% confidence interval, 0.80-1.24). Thus, the researchers concluded that exposure to depression – but not exposure to antidepressant – is associated with a slightly higher risk of miscarriage.

Even more recently, a follow-up study examining this question supports the large epidemiologic study by Kjaersgaard and colleagues. For most readers, this effectively answers this very important question for women about rates of miscarriage associated with fetal exposure to SSRIs.

For the patient who presented at the center, reassuring her with this information felt particularly good, especially within the context of the pandemic. After several months of trying to conceive, she again became pregnant and delivered without difficulty. What was palpable in that clinical scenario, as it relates to the practice of reproductive psychiatry during the pandemic, is the even-greater emotional valence that questions about using psychiatric medications during pregnancy has taken on across these past months. While attention and thoughtful consideration about the relative risks of using psychiatric medications during pregnancy should be standard clinical practice, the level of anxiety associated with decisions to sustain or to discontinue treatment during pregnancy seems to have increased for some patients during the pandemic.

Even as the COVID-19 vaccine initiative across the United States is rolled out, 2021 will continue to be a complicated time for women and families. We still need to be vigilant. In addition to screening for perinatal depression during pregnancy and the postpartum period, we should be equally mindful of screening and treating perinatal anxiety, particularly during this challenging time. The challenge to keep pregnant and postpartum women well is perhaps even greater now, 10 months into the pandemic, than it was when we were in crisis mode in March 2020. As clinicians, we need to mobilize the spectrum of both pharmacologic and nonpharmacologic treatment options to sustain emotional well-being among women planning to conceive as well as those who are pregnant or postpartum as we navigate our way to safer times.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].

Across this period of the pandemic, we’ve spent considerable attention focusing on adaptations to clinical care for pregnant and postpartum women across the board. From the start, this has included a shift to telemedicine for the majority of our patients who come to see us with psychiatric disorders either before, during, or after pregnancy.

Specific issues for perinatal patients since the early days of COVID-19 have included the shifts in women’s plans with respect to delivery as well as the limitation on women’s ability to configure the types of support that they had originally planned on with family, friends, and others during delivery. Telemedicine again helped, at least in part, to fill that void by having online digital support by individuals or groups for both pregnant and postpartum women. These supports were always available, but quickly scaled up during the first 6-9 months of the pandemic and have likely seen their greatest increase in participation in the history of support groups for pregnant and postpartum women.

Similarly, at our own center, we have seen a dramatic increase across the last 10 months in requests for consultation by women with psychiatric disorders who have hopes and plans to conceive, to those who are pregnant or post partum and who are trying to sustain emotional well-being despite the added burden of the pandemic. As we heard similar stories regarding interactions with perinatal patients from reproductive psychiatrists across the country, my colleagues and I had to set up an additional resource, Virtual Rounds at the Center for Women’s Mental Health at Massachusetts General Hospital, Boston, which has been mentioned in previous columns, which has only grown during the last 6 months of the pandemic. We have colleagues across the country joining us from 2 p.m. to 3 p.m. on Wednesdays after our own faculty rounds, where we perform case reviews of our own patients, and invite our colleagues to share cases that are then reviewed with expert panelists together with our own faculty in a collaborative environment. Feedback from the community of clinicians has indicated that these virtual rounds have been invaluable to their efforts in taking care of women with perinatal psychiatric issues, particularly during the pandemic.

Of particular note during consultations on our service is the number of women coming to see us for questions about the reproductive safety of the medications on which they are maintained. Hundreds of women present to the center each year for the most up-to-date information regarding the reproductive safety of the most commonly used psychiatric medications in reproductive-age women, including antidepressants (SSRIs, serotonin norepinephrine reuptake inhibitor), mood stabilizers, lithium, lamotrigine, and atypical antipsychotics, as well as other medicines used to treat symptoms that have been a particular issue during the pandemic, such as insomnia and anxiety (benzodiazepines, nonbenzodiazepines, sedative hypnotics, and medicines such as gabapentin).

While consultation regarding risk of fetal exposure to psychotropics has been the cornerstone of our clinical work for 25 years, it has taken on a particularly critical dimension during the pandemic given the wish that women stay euthymic during the pandemic to limit the possibility of patients needing to present in a clinical space that would increase their risk for COVID-19, and to also minimize their risk for postpartum depression. (Psychiatric disorder during pregnancy remains the strongest predictor of emergence or worsening of underlying illness during the postpartum period.)

It is also noteworthy that, during a pandemic year, publications in reproductive psychiatry have been numerous, and we continue to make an effort at our own center to keep up with this and to share with our colleagues our impression of that literature using the weekly blog at womensmentalhealth.org. Last year brought the largest audience to the blog and visits to womensmentalhealth.org in the history of our center.

A case recently at our center presents a unique opportunity to review a confusing question in reproductive psychiatry over the last 15 years. A woman with a longstanding history of mixed anxiety and depression recently came to see us on a regimen of escitalopram and low-dose benzodiazepine. She was doing well, and she and her husband of 4 years were hopeful about starting to try to conceive despite the pandemic. We reviewed the reproductive safety data of the medicines on which she was maintained and made plans to follow-up as her plans galvanized. She notified me several months later that she had become pregnant but had experienced an early miscarriage. The patient was obviously upset and, as she reflected on her decision to maintain treatment with SSRI during her attempts to conceive and across a very early pregnancy, she queried about the extent to which her SSRI use might have contributed to her miscarriage.

The question about the possible association of antidepressant use during pregnancy and increased risk for miscarriage goes back at least 15 years when there were reports of an increased risk of miscarriage in women taking SSRIs during pregnancy. In that early work, there was an apparent increase in miscarriage in women taking SSRIs relative to a control group, but the rate did not exceed the prevalence of miscarriage in the general population. Since those early reports, we are lucky to have had multiple investigators look very closely at this issue, including one meta-analysis of 11 studies done approximately 8 years ago that failed to show an increased risk of miscarriage in the setting of first trimester exposure to SSRIs.

What has been most problematic methodologically, however, has been the failure to account for the potential role of depression in models that predict risk. A subsequent large epidemiologic study from Denmark evaluating over a million women has looked at this question further. The authors found a slightly increased risk of spontaneous abortion associated with the use of antidepressants (12.0% in women with antidepressant exposure vs. 11.1% in women with no exposure). However, looking only at women with a diagnosis of depression, the adjusted risk ratio for spontaneous abortion after any antidepressant exposure was 1.00 (95% confidence interval, 0.80-1.24). Thus, the researchers concluded that exposure to depression – but not exposure to antidepressant – is associated with a slightly higher risk of miscarriage.

Even more recently, a follow-up study examining this question supports the large epidemiologic study by Kjaersgaard and colleagues. For most readers, this effectively answers this very important question for women about rates of miscarriage associated with fetal exposure to SSRIs.

For the patient who presented at the center, reassuring her with this information felt particularly good, especially within the context of the pandemic. After several months of trying to conceive, she again became pregnant and delivered without difficulty. What was palpable in that clinical scenario, as it relates to the practice of reproductive psychiatry during the pandemic, is the even-greater emotional valence that questions about using psychiatric medications during pregnancy has taken on across these past months. While attention and thoughtful consideration about the relative risks of using psychiatric medications during pregnancy should be standard clinical practice, the level of anxiety associated with decisions to sustain or to discontinue treatment during pregnancy seems to have increased for some patients during the pandemic.

Even as the COVID-19 vaccine initiative across the United States is rolled out, 2021 will continue to be a complicated time for women and families. We still need to be vigilant. In addition to screening for perinatal depression during pregnancy and the postpartum period, we should be equally mindful of screening and treating perinatal anxiety, particularly during this challenging time. The challenge to keep pregnant and postpartum women well is perhaps even greater now, 10 months into the pandemic, than it was when we were in crisis mode in March 2020. As clinicians, we need to mobilize the spectrum of both pharmacologic and nonpharmacologic treatment options to sustain emotional well-being among women planning to conceive as well as those who are pregnant or postpartum as we navigate our way to safer times.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].

This moment, for which I am so grateful and fortunate, represents a link in a remarkable chain of events that spans decades and represents the acme of human achievement.

Courtesy Barry Aaronson, MD

My gratitude starts with scientists who years before this pandemic, perfected the ability to extract DNA from viruses, sequence it, and transcribe it to RNA. From there my gratitude goes to scientists who years ago developed an ingenious animal model for mRNA vaccines. The next link of gratitude is for scientists who at the start of this year quickly identified a deadly novel coronavirus and to scientists who rapidly sequenced its villainous DNA.

Next, I give thanks to scientists who promptly identified the segment of that DNA that codes for the spike proteins that the virus uses to invade our cells. And then I am grateful to the scientists who made the mRNA that corresponds to that specific DNA sequence, and to the scientists who figured out how create a lipid womb to protect that precious mRNA payload during its perilous journey from factory floor to the depths of our deltoid musculature.

I am no less grateful to the brave people who volunteered for the Pfizer trial, taking the risk of being the first humans ever to participate in an mRNA trial with stakes so high, and to the investigators who ran that trial and the scientists at Pfizer, the Food and Drug Administration, and the Western Coalition who reviewed the data and approved the vaccine without bowing to political pressure.

My gratitude extends to the factory workers who manufactured the vaccine in mass quantities, and the workers who manufactured the equipment that those factories rely on, and the pilots of planes and drivers of trucks who transported the vaccine to my hospital in Seattle, and to the workers who made those planes and trucks that carried that precious cargo. And the workers who devised super-cold storage systems and the workers who built those systems, and the people who fed them and clothed them and housed them so that they could do this life-saving work.

And to the leaders at my hospital who devised our immunization plan, and the ethicists who figured out who should go first (thanks Nancy), and the workers who made the glass vials to hold the vaccine, the plastic syringes to deliver it precisely, and surgically sharp needles so that there would be no pain whatsoever when those beautiful little mRNA filled lipid particles got injected into my left deltoid muscle by a highly skilled and compassionate nurse.

From there, the miracle of nature takes hold causing my cells to transcribe that RNA into spike proteins which will trigger my magical B-cells and T-cells to recognize that nasty spike protein as foreign in case it ever shows its ugly head to my respiratory mucosa, where these cells and the antibodies and chemicals they produce would stomp that wretched virus down without me ever knowing it or missing a beat, and keep me safe not only to live and thrive another day but also hopefully prevent me from spreading the virus to those I love and others I don’t even know but pass within just feet of.

For these miracles of nature and the chain of human toil and genius involving innumerable individuals over many years, many whom will never be thanked or recognized, I am truly and forever grateful.

Dr. Aaronson is a hospitalist and chief medical informatics officer at Virginia Mason Medical Center in Seattle.

This moment, for which I am so grateful and fortunate, represents a link in a remarkable chain of events that spans decades and represents the acme of human achievement.

Courtesy Barry Aaronson, MD

My gratitude starts with scientists who years before this pandemic, perfected the ability to extract DNA from viruses, sequence it, and transcribe it to RNA. From there my gratitude goes to scientists who years ago developed an ingenious animal model for mRNA vaccines. The next link of gratitude is for scientists who at the start of this year quickly identified a deadly novel coronavirus and to scientists who rapidly sequenced its villainous DNA.

Next, I give thanks to scientists who promptly identified the segment of that DNA that codes for the spike proteins that the virus uses to invade our cells. And then I am grateful to the scientists who made the mRNA that corresponds to that specific DNA sequence, and to the scientists who figured out how create a lipid womb to protect that precious mRNA payload during its perilous journey from factory floor to the depths of our deltoid musculature.

I am no less grateful to the brave people who volunteered for the Pfizer trial, taking the risk of being the first humans ever to participate in an mRNA trial with stakes so high, and to the investigators who ran that trial and the scientists at Pfizer, the Food and Drug Administration, and the Western Coalition who reviewed the data and approved the vaccine without bowing to political pressure.

My gratitude extends to the factory workers who manufactured the vaccine in mass quantities, and the workers who manufactured the equipment that those factories rely on, and the pilots of planes and drivers of trucks who transported the vaccine to my hospital in Seattle, and to the workers who made those planes and trucks that carried that precious cargo. And the workers who devised super-cold storage systems and the workers who built those systems, and the people who fed them and clothed them and housed them so that they could do this life-saving work.

And to the leaders at my hospital who devised our immunization plan, and the ethicists who figured out who should go first (thanks Nancy), and the workers who made the glass vials to hold the vaccine, the plastic syringes to deliver it precisely, and surgically sharp needles so that there would be no pain whatsoever when those beautiful little mRNA filled lipid particles got injected into my left deltoid muscle by a highly skilled and compassionate nurse.

From there, the miracle of nature takes hold causing my cells to transcribe that RNA into spike proteins which will trigger my magical B-cells and T-cells to recognize that nasty spike protein as foreign in case it ever shows its ugly head to my respiratory mucosa, where these cells and the antibodies and chemicals they produce would stomp that wretched virus down without me ever knowing it or missing a beat, and keep me safe not only to live and thrive another day but also hopefully prevent me from spreading the virus to those I love and others I don’t even know but pass within just feet of.

For these miracles of nature and the chain of human toil and genius involving innumerable individuals over many years, many whom will never be thanked or recognized, I am truly and forever grateful.

Dr. Aaronson is a hospitalist and chief medical informatics officer at Virginia Mason Medical Center in Seattle.

This moment, for which I am so grateful and fortunate, represents a link in a remarkable chain of events that spans decades and represents the acme of human achievement.

Courtesy Barry Aaronson, MD

My gratitude starts with scientists who years before this pandemic, perfected the ability to extract DNA from viruses, sequence it, and transcribe it to RNA. From there my gratitude goes to scientists who years ago developed an ingenious animal model for mRNA vaccines. The next link of gratitude is for scientists who at the start of this year quickly identified a deadly novel coronavirus and to scientists who rapidly sequenced its villainous DNA.

Next, I give thanks to scientists who promptly identified the segment of that DNA that codes for the spike proteins that the virus uses to invade our cells. And then I am grateful to the scientists who made the mRNA that corresponds to that specific DNA sequence, and to the scientists who figured out how create a lipid womb to protect that precious mRNA payload during its perilous journey from factory floor to the depths of our deltoid musculature.

I am no less grateful to the brave people who volunteered for the Pfizer trial, taking the risk of being the first humans ever to participate in an mRNA trial with stakes so high, and to the investigators who ran that trial and the scientists at Pfizer, the Food and Drug Administration, and the Western Coalition who reviewed the data and approved the vaccine without bowing to political pressure.

My gratitude extends to the factory workers who manufactured the vaccine in mass quantities, and the workers who manufactured the equipment that those factories rely on, and the pilots of planes and drivers of trucks who transported the vaccine to my hospital in Seattle, and to the workers who made those planes and trucks that carried that precious cargo. And the workers who devised super-cold storage systems and the workers who built those systems, and the people who fed them and clothed them and housed them so that they could do this life-saving work.

And to the leaders at my hospital who devised our immunization plan, and the ethicists who figured out who should go first (thanks Nancy), and the workers who made the glass vials to hold the vaccine, the plastic syringes to deliver it precisely, and surgically sharp needles so that there would be no pain whatsoever when those beautiful little mRNA filled lipid particles got injected into my left deltoid muscle by a highly skilled and compassionate nurse.

From there, the miracle of nature takes hold causing my cells to transcribe that RNA into spike proteins which will trigger my magical B-cells and T-cells to recognize that nasty spike protein as foreign in case it ever shows its ugly head to my respiratory mucosa, where these cells and the antibodies and chemicals they produce would stomp that wretched virus down without me ever knowing it or missing a beat, and keep me safe not only to live and thrive another day but also hopefully prevent me from spreading the virus to those I love and others I don’t even know but pass within just feet of.

For these miracles of nature and the chain of human toil and genius involving innumerable individuals over many years, many whom will never be thanked or recognized, I am truly and forever grateful.

Dr. Aaronson is a hospitalist and chief medical informatics officer at Virginia Mason Medical Center in Seattle.

ILLUSTRATIVE CASE

A 57-year-old man who was given a diagnosis of T2D a year ago presents for an office visit. His hemoglobin A1C level at diagnosis was 8.3%. He is otherwise healthy and has been adhering well to a plan of metformin 1000 mg twice daily, regular exercise, and a low-­carbohydrate diet you recommended. His most recent hemoglobin A1C is 7.3%. He is pleased with his progress, so he is discouraged when you tell him that he is not yet at goal. He asks if there are other things that he can do to further lower his hemoglobin A1C. What can you recommend for him?

According to the National Diabetes Statistics Report, 2020 from the Centers for Disease Control and Prevention, approximately 34.1 million US adults ≥ 18 years of age (13% of the adult population) have diabetes, 50% of whom have a hemoglobin A1C > 7%. The report also states that approximately 88 million US adults—more than one-third of the population—have prediabetes.²

The American Diabetes Association (ADA) estimated that diabetes-related health care costs in the United States for 2017 totaled $237 billion, an increase of 26% from 2012. More than $30 billion of this expense comes directly from diabetes medications; the remainder of these costs are related to lost wages, clinic visits, hospitalizations, and treatment for diabetic complications and comorbidities. After controlling for age and gender, medical expenditures for people with diabetes are 2.3 times higher than for those without diabetes.³

The 2019 ADA Nutrition Therapy for Adults With Diabetes or Prediabetes: A Consensus Report makes general recommendations concerning fiber intake for patients with diabetes or prediabetes, stating that these patients should consume approximately 14 g of fiber for every 1000 kcal consumed, giving preference to whole-food sources rather than supplements.⁴ The report indicates that some studies have shown hemoglobin A1C reductions of 0.2% to 0.3% with daily fiber intake exceeding 50 g. However, this level of intake can cause unpleasant gastrointestinal adverse effects, including bloating, diarrhea, and flatulence.^4,5

STUDY SUMMARY

Effect on A1C exceeded the FDA threshold for new drugs

This systematic review and meta-analysis searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials to identify randomized controlled trials that studied the effects of viscous fiber supplementation on glycemic control in patients with T2D. Eligible studies included those that: (1) had a duration ≥ 3 weeks; (2) allowed isolation of the viscous fiber effects; and (3) reported at least 1 of the following glycemic measures: hemoglobin A1C (n = 1148 patients), fasting glucose (n = 1394), fasting insulin (n = 228), homeostatic model assessment of insulin resistance (HOMA-IR; n = 652), and fructosamine (n = 23).

As an adjunct to standard of care, viscous fiber supplements significantly improved hemoglobin A1C and other glycemic markers in patients with T2D.

Data were pooled using the generic inverse variance method and expressed as mean difference (MD) with 95% confidence intervals (CIs). Heterogeneity was assessed and quantified (Cochran Q and I² statistics, respectively). I² ≥ 50% indicates substantial heterogeneity. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the overall strength of evidence.

Twenty-eight eligible studies were compared. The median age of included patients was 60 years. The median dose of viscous fiber was 13.1 g/d (range, 2.55-21). Viscous fiber type varied between the studies and included psyllium, guar gum, β-glucan, and konjac, and was consumed in powder, tablet, capsule, and limited food-based forms (in 1 of the included studies). The median trial duration was 8 weeks, with 11 trials lasting ≥ 12 weeks.

Continue to: The study found...

The study found moderate-grade evidence that, when added to standard of care, viscous fiber supplementation reduced hemoglobin A1C (MD = –0.58%; 95% CI, –0.88 to –0.28; P = .0002; I² = 91%), fasting glucose (MD = –14.8 mg/dL; 95% CI, –23.8 to –5.58; P = .001; I² = 92%), and HOMA-IR (MD = –1.89; 95% CI, –3.45 to –0.33; P = .02; I² = 94%) compared with control. The effect on hemoglobin A1C exceeds the ≥ 0.3% threshold established by the US Food and Drug Administration for new antihyperglycemic drug development. There was no significant effect on fasting insulin or fructosamine, although the sample size for fructosamine was small. No significant evidence of a dose-dependent response effect was found. The studies had substantial heterogeneity. No evaluation of potential or real harm was noted in the analysis.

WHAT’S NEW

Potential glycemic benefit without large dietary increase

The glucose-lowering effects of increased fiber intake have often been hypothesized, but this meta-analysis is the first to focus specifically on the effect of viscous fiber supplements in patients with T2D. Prior meta-analyses, including those cited in the 2019 ADA recommendations mentioned above, included primarily whole-food dietary sources of fiber in the treatment arms and generally had more modest effects on outcomes.^4,6,7

By focusing on viscous fiber supplements, this study isolated the effect of these supplements vs fiber-rich dietary changes. It illustrates a greater potential benefit with supplements than whole-food dietary ­sources of fiber, and at a lower dose of fiber than was seen in prior studies without requiring substantial increases in caloric intake. Viscous fiber supplementation is a potential adjunct to the usual evidence-based standards of care for glycemic control in patients with T2D.

CAVEATS

Limited study durations may raise uncertainty about long-term benefits

This meta-analysis does have its limitations. The heterogeneity among the studies analyzed makes it difficult to establish a single recommendation regarding dose, type, and brand of fiber to be used. Only 11 of the 28 studies lasted longer than 12 weeks, with a median duration of 8 weeks, making any long-term effects on hemoglobin A1C unknown. No adverse effects or reactions were described to evaluate safety and tolerability of the viscous fiber supplementation. No patient-oriented outcomes were reported.

CHALLENGES TO IMPLEMENTATION

Patients may not be eager to supplement with viscous fiber

The biggest challenge to implementation is patient compliance. Some forms of supplemental fiber are less palatable than others and may cause unpleasant gastrointestinal adverse effects, which may be an impediment for some patients. Cost may also be an issue for some patients. Diabetes medications can be expensive; however, they are often covered, at least partially, by medical insurance. Over-the-counter supplements are unlikely to be covered for most patients.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 57-year-old man who was given a diagnosis of T2D a year ago presents for an office visit. His hemoglobin A1C level at diagnosis was 8.3%. He is otherwise healthy and has been adhering well to a plan of metformin 1000 mg twice daily, regular exercise, and a low-­carbohydrate diet you recommended. His most recent hemoglobin A1C is 7.3%. He is pleased with his progress, so he is discouraged when you tell him that he is not yet at goal. He asks if there are other things that he can do to further lower his hemoglobin A1C. What can you recommend for him?

According to the National Diabetes Statistics Report, 2020 from the Centers for Disease Control and Prevention, approximately 34.1 million US adults ≥ 18 years of age (13% of the adult population) have diabetes, 50% of whom have a hemoglobin A1C > 7%. The report also states that approximately 88 million US adults—more than one-third of the population—have prediabetes.²

The American Diabetes Association (ADA) estimated that diabetes-related health care costs in the United States for 2017 totaled $237 billion, an increase of 26% from 2012. More than $30 billion of this expense comes directly from diabetes medications; the remainder of these costs are related to lost wages, clinic visits, hospitalizations, and treatment for diabetic complications and comorbidities. After controlling for age and gender, medical expenditures for people with diabetes are 2.3 times higher than for those without diabetes.³

The 2019 ADA Nutrition Therapy for Adults With Diabetes or Prediabetes: A Consensus Report makes general recommendations concerning fiber intake for patients with diabetes or prediabetes, stating that these patients should consume approximately 14 g of fiber for every 1000 kcal consumed, giving preference to whole-food sources rather than supplements.⁴ The report indicates that some studies have shown hemoglobin A1C reductions of 0.2% to 0.3% with daily fiber intake exceeding 50 g. However, this level of intake can cause unpleasant gastrointestinal adverse effects, including bloating, diarrhea, and flatulence.^4,5

STUDY SUMMARY

Effect on A1C exceeded the FDA threshold for new drugs

This systematic review and meta-analysis searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials to identify randomized controlled trials that studied the effects of viscous fiber supplementation on glycemic control in patients with T2D. Eligible studies included those that: (1) had a duration ≥ 3 weeks; (2) allowed isolation of the viscous fiber effects; and (3) reported at least 1 of the following glycemic measures: hemoglobin A1C (n = 1148 patients), fasting glucose (n = 1394), fasting insulin (n = 228), homeostatic model assessment of insulin resistance (HOMA-IR; n = 652), and fructosamine (n = 23).

As an adjunct to standard of care, viscous fiber supplements significantly improved hemoglobin A1C and other glycemic markers in patients with T2D.

Data were pooled using the generic inverse variance method and expressed as mean difference (MD) with 95% confidence intervals (CIs). Heterogeneity was assessed and quantified (Cochran Q and I² statistics, respectively). I² ≥ 50% indicates substantial heterogeneity. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the overall strength of evidence.

Twenty-eight eligible studies were compared. The median age of included patients was 60 years. The median dose of viscous fiber was 13.1 g/d (range, 2.55-21). Viscous fiber type varied between the studies and included psyllium, guar gum, β-glucan, and konjac, and was consumed in powder, tablet, capsule, and limited food-based forms (in 1 of the included studies). The median trial duration was 8 weeks, with 11 trials lasting ≥ 12 weeks.

Continue to: The study found...

The study found moderate-grade evidence that, when added to standard of care, viscous fiber supplementation reduced hemoglobin A1C (MD = –0.58%; 95% CI, –0.88 to –0.28; P = .0002; I² = 91%), fasting glucose (MD = –14.8 mg/dL; 95% CI, –23.8 to –5.58; P = .001; I² = 92%), and HOMA-IR (MD = –1.89; 95% CI, –3.45 to –0.33; P = .02; I² = 94%) compared with control. The effect on hemoglobin A1C exceeds the ≥ 0.3% threshold established by the US Food and Drug Administration for new antihyperglycemic drug development. There was no significant effect on fasting insulin or fructosamine, although the sample size for fructosamine was small. No significant evidence of a dose-dependent response effect was found. The studies had substantial heterogeneity. No evaluation of potential or real harm was noted in the analysis.

WHAT’S NEW

Potential glycemic benefit without large dietary increase

The glucose-lowering effects of increased fiber intake have often been hypothesized, but this meta-analysis is the first to focus specifically on the effect of viscous fiber supplements in patients with T2D. Prior meta-analyses, including those cited in the 2019 ADA recommendations mentioned above, included primarily whole-food dietary sources of fiber in the treatment arms and generally had more modest effects on outcomes.^4,6,7

By focusing on viscous fiber supplements, this study isolated the effect of these supplements vs fiber-rich dietary changes. It illustrates a greater potential benefit with supplements than whole-food dietary ­sources of fiber, and at a lower dose of fiber than was seen in prior studies without requiring substantial increases in caloric intake. Viscous fiber supplementation is a potential adjunct to the usual evidence-based standards of care for glycemic control in patients with T2D.

CAVEATS

Limited study durations may raise uncertainty about long-term benefits

This meta-analysis does have its limitations. The heterogeneity among the studies analyzed makes it difficult to establish a single recommendation regarding dose, type, and brand of fiber to be used. Only 11 of the 28 studies lasted longer than 12 weeks, with a median duration of 8 weeks, making any long-term effects on hemoglobin A1C unknown. No adverse effects or reactions were described to evaluate safety and tolerability of the viscous fiber supplementation. No patient-oriented outcomes were reported.

CHALLENGES TO IMPLEMENTATION

Patients may not be eager to supplement with viscous fiber

The biggest challenge to implementation is patient compliance. Some forms of supplemental fiber are less palatable than others and may cause unpleasant gastrointestinal adverse effects, which may be an impediment for some patients. Cost may also be an issue for some patients. Diabetes medications can be expensive; however, they are often covered, at least partially, by medical insurance. Over-the-counter supplements are unlikely to be covered for most patients.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 57-year-old man who was given a diagnosis of T2D a year ago presents for an office visit. His hemoglobin A1C level at diagnosis was 8.3%. He is otherwise healthy and has been adhering well to a plan of metformin 1000 mg twice daily, regular exercise, and a low-­carbohydrate diet you recommended. His most recent hemoglobin A1C is 7.3%. He is pleased with his progress, so he is discouraged when you tell him that he is not yet at goal. He asks if there are other things that he can do to further lower his hemoglobin A1C. What can you recommend for him?

According to the National Diabetes Statistics Report, 2020 from the Centers for Disease Control and Prevention, approximately 34.1 million US adults ≥ 18 years of age (13% of the adult population) have diabetes, 50% of whom have a hemoglobin A1C > 7%. The report also states that approximately 88 million US adults—more than one-third of the population—have prediabetes.²

The American Diabetes Association (ADA) estimated that diabetes-related health care costs in the United States for 2017 totaled $237 billion, an increase of 26% from 2012. More than $30 billion of this expense comes directly from diabetes medications; the remainder of these costs are related to lost wages, clinic visits, hospitalizations, and treatment for diabetic complications and comorbidities. After controlling for age and gender, medical expenditures for people with diabetes are 2.3 times higher than for those without diabetes.³

The 2019 ADA Nutrition Therapy for Adults With Diabetes or Prediabetes: A Consensus Report makes general recommendations concerning fiber intake for patients with diabetes or prediabetes, stating that these patients should consume approximately 14 g of fiber for every 1000 kcal consumed, giving preference to whole-food sources rather than supplements.⁴ The report indicates that some studies have shown hemoglobin A1C reductions of 0.2% to 0.3% with daily fiber intake exceeding 50 g. However, this level of intake can cause unpleasant gastrointestinal adverse effects, including bloating, diarrhea, and flatulence.^4,5

STUDY SUMMARY

Effect on A1C exceeded the FDA threshold for new drugs

This systematic review and meta-analysis searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials to identify randomized controlled trials that studied the effects of viscous fiber supplementation on glycemic control in patients with T2D. Eligible studies included those that: (1) had a duration ≥ 3 weeks; (2) allowed isolation of the viscous fiber effects; and (3) reported at least 1 of the following glycemic measures: hemoglobin A1C (n = 1148 patients), fasting glucose (n = 1394), fasting insulin (n = 228), homeostatic model assessment of insulin resistance (HOMA-IR; n = 652), and fructosamine (n = 23).

As an adjunct to standard of care, viscous fiber supplements significantly improved hemoglobin A1C and other glycemic markers in patients with T2D.

Data were pooled using the generic inverse variance method and expressed as mean difference (MD) with 95% confidence intervals (CIs). Heterogeneity was assessed and quantified (Cochran Q and I² statistics, respectively). I² ≥ 50% indicates substantial heterogeneity. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the overall strength of evidence.

Twenty-eight eligible studies were compared. The median age of included patients was 60 years. The median dose of viscous fiber was 13.1 g/d (range, 2.55-21). Viscous fiber type varied between the studies and included psyllium, guar gum, β-glucan, and konjac, and was consumed in powder, tablet, capsule, and limited food-based forms (in 1 of the included studies). The median trial duration was 8 weeks, with 11 trials lasting ≥ 12 weeks.

Continue to: The study found...

The study found moderate-grade evidence that, when added to standard of care, viscous fiber supplementation reduced hemoglobin A1C (MD = –0.58%; 95% CI, –0.88 to –0.28; P = .0002; I² = 91%), fasting glucose (MD = –14.8 mg/dL; 95% CI, –23.8 to –5.58; P = .001; I² = 92%), and HOMA-IR (MD = –1.89; 95% CI, –3.45 to –0.33; P = .02; I² = 94%) compared with control. The effect on hemoglobin A1C exceeds the ≥ 0.3% threshold established by the US Food and Drug Administration for new antihyperglycemic drug development. There was no significant effect on fasting insulin or fructosamine, although the sample size for fructosamine was small. No significant evidence of a dose-dependent response effect was found. The studies had substantial heterogeneity. No evaluation of potential or real harm was noted in the analysis.

WHAT’S NEW

Potential glycemic benefit without large dietary increase

The glucose-lowering effects of increased fiber intake have often been hypothesized, but this meta-analysis is the first to focus specifically on the effect of viscous fiber supplements in patients with T2D. Prior meta-analyses, including those cited in the 2019 ADA recommendations mentioned above, included primarily whole-food dietary sources of fiber in the treatment arms and generally had more modest effects on outcomes.^4,6,7

By focusing on viscous fiber supplements, this study isolated the effect of these supplements vs fiber-rich dietary changes. It illustrates a greater potential benefit with supplements than whole-food dietary ­sources of fiber, and at a lower dose of fiber than was seen in prior studies without requiring substantial increases in caloric intake. Viscous fiber supplementation is a potential adjunct to the usual evidence-based standards of care for glycemic control in patients with T2D.

CAVEATS

Limited study durations may raise uncertainty about long-term benefits

This meta-analysis does have its limitations. The heterogeneity among the studies analyzed makes it difficult to establish a single recommendation regarding dose, type, and brand of fiber to be used. Only 11 of the 28 studies lasted longer than 12 weeks, with a median duration of 8 weeks, making any long-term effects on hemoglobin A1C unknown. No adverse effects or reactions were described to evaluate safety and tolerability of the viscous fiber supplementation. No patient-oriented outcomes were reported.

CHALLENGES TO IMPLEMENTATION

Patients may not be eager to supplement with viscous fiber

The biggest challenge to implementation is patient compliance. Some forms of supplemental fiber are less palatable than others and may cause unpleasant gastrointestinal adverse effects, which may be an impediment for some patients. Cost may also be an issue for some patients. Diabetes medications can be expensive; however, they are often covered, at least partially, by medical insurance. Over-the-counter supplements are unlikely to be covered for most patients.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

THE CASE

Emily T.* is a 15-year-old, cisgender, homeless runaway. While on the streets, she was lured to a hotel where a “pimp” informed her she was going to work for him. She repeatedly tried to leave, but he would strike her, so she eventually succumbed. She was forced to have sex with several men and rarely allowed to use condoms.

On 1 occasion, when she went to a hospital with her pimp to visit a patient, her aunt (a nurse on duty at that facility) saw Ms. T and called the police. The pimp was arrested. Ms. T was interviewed by the police and gave a statement but refused a forensic exam.

Because of her involvement with the pimp, she was incarcerated. In prison, she was seen by a physician. On evaluation, she reported difficulty sleeping, flashbacks, and feelings of shame and guilt.¹

● How would you proceed with this patient?

* The patient’s name has been changed to protect her identity.

Child and adolescent sex trafficking is defined as the sexual exploitation of minors through force, fraud, or coercion. Specifically, it includes the recruitment, harboring, transportation, or advertising of a minor, and includes the exchange of anything of value in return for sexual activity. Commercial sexual exploitation and sex trafficking against minors include crimes such as prostitution; survival sex (exchanging sex/sexual acts for money or something of value, such as shelter, food, or drugs); pornography; sex tourism, mail-order-bride trade, and early marriage; or sexual performances (peep shows or strip clubs).²

Providing optimal care for children and adolescents exploited by sex trafficking depends on knowing risk factors, having an awareness of recommended screening and assessment tools, and employing a trauma-­informed approach to interviews, examination, and support.²

Continue to: Recognize clues to trafficking

The Centers for Disease Control and Prevention (CDC) offers a framework for trafficking prevention. Health care providers are encouraged to use the CDC Social-Ecological Model which describes targeted prevention strategies at the individual, relationship, community, and societal levels.³

Risk factors for entering trafficking. Younger age increases a child’s vulnerability to exploitation, due to a lack of maturity, limited cognitive development, and ease of deception. The mean age of trafficking survivors is 15 years.⁴ History of child abuse and other traumatic experiences can lead children to run away from home. It is estimated that, once on the streets, most teens will be recruited by a trafficker within 48 hours.⁵ Poor self-esteem, depression, substance abuse, history of truancy, and early sexual maturation also increase the risk of becoming involved in trafficking (TABLE 1).^2,6-8

Clinical findings suggestive of trafficking. Many physicians grasp the critical role they play in confronting trafficking, but they lack specific training, experience, and assessment tools.³ Notably, in 1 retrospective study, 46% of victims had been seen by a provider within the previous 2 months.⁶ One of the major challenges to identifying survivors of trafficking is to recognize critical signs, of which there are many (TABLE 1^2,6-8). Often these include a history of sexual assault, multiple pregnancies, requests for contraception at an early age, or evidence of physical injury.

Screen to identify trafficking

Universal, validated screening tools to accurately identify trafficked youth is an area of growing research. Some tools have been validated, but only for specific populations such as homeless or incarcerated youth or in emergency department (ED) patients. Tools for sex trafficking identification that may be useful in primary care include the Child Sex Trafficking (CST) screen validated in ED settings (TABLE 2),⁹ the Commercial Sexual Exploitation-Identification Tool (CSE-IT) in multiple settings (TABLE 3),^10,11 and the Quick Youth Indicators for Trafficking (QYIT) in homeless youth (TABLE 4).¹¹ The QYIT is the first validated labor and sex trafficking screening tool in homeless young adults. Children who screen positive for sex trafficking should be further assessed using a comprehensive tool.

Barriers to effective recognition of trafficked individuals. Financial factors limit access to health care. Also, survivors have cited multiple barriers for health professionals that prevent identification of survivors’ trafficked status.^12,13 Once in the medical setting, disclosure is impacted by time constraints, fear of judgment by clinicians, and the risk of re-traumatization. Survivors have also cited lack of privacy, control strategies by their traffickers, lack of provider empathy, and fear of police as barriers to disclosure.¹⁴

Continue to: The medical impact of trafficking

The medical impact of trafficking

Sexual exploitation is a traumatic experience that is known to cause harm across multiple domains including serious physical injuries related to violence, as well as reproductive and mental health consequences.^15,16

Acute and chronic illnesses. In an initial evaluation, assess the survivor’s acute medical conditions (TABLE 5).^15,16 Common acute issues include physical injuries due to assault, infections, and reproductive complications.¹⁷ Health concerns can also result from stressors such as deprivation of food and sleep, hazardous living conditions, and limited access to care.¹⁷

Suspect possible sex trafficking when a patient has a history of sexual assault and multiple pregnancies, requests contraception at an early age, and/or has evidence of physical injury.

As part of caring for sex-trafficking survivors, assess for, and treat, chronic health issues such as pain, gastrointestinal complaints, poor dental care, malnutrition, and fatigue.^16,18 Substance use, as well as chronic mental health concerns (eg, anxiety, depression, posttraumatic stress disorder [PTSD]) may also influence the clinical presentation.

Physical injuries. A cross-sectional study of female survivors of sex trafficking in the United States found that 89% sustained physical injury resulting from violence, including fractures, open wounds, head injury, dental problems, burns, and anogenital trauma.^16,17 In many cases, acute injury may not be present in the clinical setting since care is often delayed, but a full examination can reveal signs of prior trauma.¹⁶

Reproductive health concerns. Significant, long-term impact on reproductive health can result due to forced penetration by multiple perpetrators, sodomy, and sex without protection or lubricants. Survivors are therefore at high risk for unplanned and unwanted pregnancies, sexually transmitted infections (STIs), pelvic pain, and infertility.¹⁶

Continue to: Psychological effects and trauma exposure

Psychological effects and trauma exposure. Survivors often have experienced abuse and neglect prior to commercial exploitation, and they may exhibit long-term sequelae. Survivors may present with major depression, anxiety, panic attacks, suicidality, addiction, PTSD, or aggression.¹⁶ Long-term sequelae for patients can include dysfunctional relationships due to an inability to trust, self-destructive behaviors, and significant shame.^2,18

Care and treatment of trafficked youth

Initial presentation may occur in a variety of health care settings. Use a trauma-informed approach emphasizing physical and emotional safety and positive relationships, to reduce risk to the survivor, staff, and providers.¹⁹ Establishing trust and rapport may provide better short-term safety, as well as help build stronger long-term relationships that can lead to better health outcomes.

Clinical examination. Provide traumatized patients with a sense of safety, control, and autonomy in the health care setting. During the physical exam, be aware of the impact of re-traumatization as patients are asked to undress, endure sensitive examinations, and undergo invasive procedures. Explain the examination, ask for permission at each step, and use slow movements. Allow the patient to guide certain sensitive exams.¹⁵ Adopt an approach that recognizes the impact of trauma, avoids revictimization, and acknowledges the resilience of survivors.²⁰

Treatment plan. After the initial exam, treat acute physical injuries and determine if any further testing is needed. Offer emergency contraception, STI prophylaxis, pre-exposure prophylaxis, and vaccines.¹⁵ After assessing patient readiness, offer local resources, identify safe methods for communication, identify individuals who could intervene in a crisis, and consider a safety plan (TABLE 6).

Coordination of care. Consider referrals to behavioral health services, substance recovery centers, food programs, housing resources, and a primary care clinic.¹⁵ ED clinicians may be asked to complete a sexual or physical assault forensic examination. After obtaining informed consent, one needs to¹⁹

• document skin signs such as scars, bites, strangulation marks, and tattoos. Note the size, shape, color, location, and other characteristics of each lesion.
• perform an oral, genital, and rectal examination and use a sexual assault evidence kit as indicated.
• use body diagrams and take photographs of all injuries/physical findings.
• order diagnostic testing as appropriate (eg, imaging to assess fractures).

Continue to: THE CASE

THE CASE

During Ms. T’s incarceration, she was tested for STIs and treated for gonorrhea, trichomonas, and bacterial vaginosis. She was educated about sexual health, was counseled on contraception, and accepted condoms. She was referred to a therapist and given information on additional community resources she could contact upon her release.

During a physical examination, explain the process, ask for permission at each step, use slow movements, and allow the patient to guide certain sensitive exams.

A year after her release, she was incarcerated again. She also had an unplanned pregnancy. With the support she received from community programs, social workers, and her primary care provider, she moved in with her family, where she is currently living. She denies any ongoing trafficking activity.

CORRESPONDENCE
Piali Basu, DO, MPH, UCSF Primary Care, 185 Berry Street, Lobby 1, Suite 1000, San Francisco, CA 94107; [email protected]

THE CASE

Emily T.* is a 15-year-old, cisgender, homeless runaway. While on the streets, she was lured to a hotel where a “pimp” informed her she was going to work for him. She repeatedly tried to leave, but he would strike her, so she eventually succumbed. She was forced to have sex with several men and rarely allowed to use condoms.

On 1 occasion, when she went to a hospital with her pimp to visit a patient, her aunt (a nurse on duty at that facility) saw Ms. T and called the police. The pimp was arrested. Ms. T was interviewed by the police and gave a statement but refused a forensic exam.

Because of her involvement with the pimp, she was incarcerated. In prison, she was seen by a physician. On evaluation, she reported difficulty sleeping, flashbacks, and feelings of shame and guilt.¹

● How would you proceed with this patient?

* The patient’s name has been changed to protect her identity.

Child and adolescent sex trafficking is defined as the sexual exploitation of minors through force, fraud, or coercion. Specifically, it includes the recruitment, harboring, transportation, or advertising of a minor, and includes the exchange of anything of value in return for sexual activity. Commercial sexual exploitation and sex trafficking against minors include crimes such as prostitution; survival sex (exchanging sex/sexual acts for money or something of value, such as shelter, food, or drugs); pornography; sex tourism, mail-order-bride trade, and early marriage; or sexual performances (peep shows or strip clubs).²

Providing optimal care for children and adolescents exploited by sex trafficking depends on knowing risk factors, having an awareness of recommended screening and assessment tools, and employing a trauma-­informed approach to interviews, examination, and support.²

Continue to: Recognize clues to trafficking

The Centers for Disease Control and Prevention (CDC) offers a framework for trafficking prevention. Health care providers are encouraged to use the CDC Social-Ecological Model which describes targeted prevention strategies at the individual, relationship, community, and societal levels.³

Risk factors for entering trafficking. Younger age increases a child’s vulnerability to exploitation, due to a lack of maturity, limited cognitive development, and ease of deception. The mean age of trafficking survivors is 15 years.⁴ History of child abuse and other traumatic experiences can lead children to run away from home. It is estimated that, once on the streets, most teens will be recruited by a trafficker within 48 hours.⁵ Poor self-esteem, depression, substance abuse, history of truancy, and early sexual maturation also increase the risk of becoming involved in trafficking (TABLE 1).^2,6-8

Clinical findings suggestive of trafficking. Many physicians grasp the critical role they play in confronting trafficking, but they lack specific training, experience, and assessment tools.³ Notably, in 1 retrospective study, 46% of victims had been seen by a provider within the previous 2 months.⁶ One of the major challenges to identifying survivors of trafficking is to recognize critical signs, of which there are many (TABLE 1^2,6-8). Often these include a history of sexual assault, multiple pregnancies, requests for contraception at an early age, or evidence of physical injury.

Screen to identify trafficking

Universal, validated screening tools to accurately identify trafficked youth is an area of growing research. Some tools have been validated, but only for specific populations such as homeless or incarcerated youth or in emergency department (ED) patients. Tools for sex trafficking identification that may be useful in primary care include the Child Sex Trafficking (CST) screen validated in ED settings (TABLE 2),⁹ the Commercial Sexual Exploitation-Identification Tool (CSE-IT) in multiple settings (TABLE 3),^10,11 and the Quick Youth Indicators for Trafficking (QYIT) in homeless youth (TABLE 4).¹¹ The QYIT is the first validated labor and sex trafficking screening tool in homeless young adults. Children who screen positive for sex trafficking should be further assessed using a comprehensive tool.

Barriers to effective recognition of trafficked individuals. Financial factors limit access to health care. Also, survivors have cited multiple barriers for health professionals that prevent identification of survivors’ trafficked status.^12,13 Once in the medical setting, disclosure is impacted by time constraints, fear of judgment by clinicians, and the risk of re-traumatization. Survivors have also cited lack of privacy, control strategies by their traffickers, lack of provider empathy, and fear of police as barriers to disclosure.¹⁴

Continue to: The medical impact of trafficking

The medical impact of trafficking

Sexual exploitation is a traumatic experience that is known to cause harm across multiple domains including serious physical injuries related to violence, as well as reproductive and mental health consequences.^15,16

Acute and chronic illnesses. In an initial evaluation, assess the survivor’s acute medical conditions (TABLE 5).^15,16 Common acute issues include physical injuries due to assault, infections, and reproductive complications.¹⁷ Health concerns can also result from stressors such as deprivation of food and sleep, hazardous living conditions, and limited access to care.¹⁷

Suspect possible sex trafficking when a patient has a history of sexual assault and multiple pregnancies, requests contraception at an early age, and/or has evidence of physical injury.

As part of caring for sex-trafficking survivors, assess for, and treat, chronic health issues such as pain, gastrointestinal complaints, poor dental care, malnutrition, and fatigue.^16,18 Substance use, as well as chronic mental health concerns (eg, anxiety, depression, posttraumatic stress disorder [PTSD]) may also influence the clinical presentation.

Physical injuries. A cross-sectional study of female survivors of sex trafficking in the United States found that 89% sustained physical injury resulting from violence, including fractures, open wounds, head injury, dental problems, burns, and anogenital trauma.^16,17 In many cases, acute injury may not be present in the clinical setting since care is often delayed, but a full examination can reveal signs of prior trauma.¹⁶

Reproductive health concerns. Significant, long-term impact on reproductive health can result due to forced penetration by multiple perpetrators, sodomy, and sex without protection or lubricants. Survivors are therefore at high risk for unplanned and unwanted pregnancies, sexually transmitted infections (STIs), pelvic pain, and infertility.¹⁶

Continue to: Psychological effects and trauma exposure

Psychological effects and trauma exposure. Survivors often have experienced abuse and neglect prior to commercial exploitation, and they may exhibit long-term sequelae. Survivors may present with major depression, anxiety, panic attacks, suicidality, addiction, PTSD, or aggression.¹⁶ Long-term sequelae for patients can include dysfunctional relationships due to an inability to trust, self-destructive behaviors, and significant shame.^2,18

Care and treatment of trafficked youth

Initial presentation may occur in a variety of health care settings. Use a trauma-informed approach emphasizing physical and emotional safety and positive relationships, to reduce risk to the survivor, staff, and providers.¹⁹ Establishing trust and rapport may provide better short-term safety, as well as help build stronger long-term relationships that can lead to better health outcomes.

Clinical examination. Provide traumatized patients with a sense of safety, control, and autonomy in the health care setting. During the physical exam, be aware of the impact of re-traumatization as patients are asked to undress, endure sensitive examinations, and undergo invasive procedures. Explain the examination, ask for permission at each step, and use slow movements. Allow the patient to guide certain sensitive exams.¹⁵ Adopt an approach that recognizes the impact of trauma, avoids revictimization, and acknowledges the resilience of survivors.²⁰

Treatment plan. After the initial exam, treat acute physical injuries and determine if any further testing is needed. Offer emergency contraception, STI prophylaxis, pre-exposure prophylaxis, and vaccines.¹⁵ After assessing patient readiness, offer local resources, identify safe methods for communication, identify individuals who could intervene in a crisis, and consider a safety plan (TABLE 6).

Coordination of care. Consider referrals to behavioral health services, substance recovery centers, food programs, housing resources, and a primary care clinic.¹⁵ ED clinicians may be asked to complete a sexual or physical assault forensic examination. After obtaining informed consent, one needs to¹⁹

• document skin signs such as scars, bites, strangulation marks, and tattoos. Note the size, shape, color, location, and other characteristics of each lesion.
• perform an oral, genital, and rectal examination and use a sexual assault evidence kit as indicated.
• use body diagrams and take photographs of all injuries/physical findings.
• order diagnostic testing as appropriate (eg, imaging to assess fractures).

Continue to: THE CASE

THE CASE

During Ms. T’s incarceration, she was tested for STIs and treated for gonorrhea, trichomonas, and bacterial vaginosis. She was educated about sexual health, was counseled on contraception, and accepted condoms. She was referred to a therapist and given information on additional community resources she could contact upon her release.

During a physical examination, explain the process, ask for permission at each step, use slow movements, and allow the patient to guide certain sensitive exams.

A year after her release, she was incarcerated again. She also had an unplanned pregnancy. With the support she received from community programs, social workers, and her primary care provider, she moved in with her family, where she is currently living. She denies any ongoing trafficking activity.

CORRESPONDENCE
Piali Basu, DO, MPH, UCSF Primary Care, 185 Berry Street, Lobby 1, Suite 1000, San Francisco, CA 94107; [email protected]

THE CASE

Emily T.* is a 15-year-old, cisgender, homeless runaway. While on the streets, she was lured to a hotel where a “pimp” informed her she was going to work for him. She repeatedly tried to leave, but he would strike her, so she eventually succumbed. She was forced to have sex with several men and rarely allowed to use condoms.

On 1 occasion, when she went to a hospital with her pimp to visit a patient, her aunt (a nurse on duty at that facility) saw Ms. T and called the police. The pimp was arrested. Ms. T was interviewed by the police and gave a statement but refused a forensic exam.

Because of her involvement with the pimp, she was incarcerated. In prison, she was seen by a physician. On evaluation, she reported difficulty sleeping, flashbacks, and feelings of shame and guilt.¹

● How would you proceed with this patient?

* The patient’s name has been changed to protect her identity.

Child and adolescent sex trafficking is defined as the sexual exploitation of minors through force, fraud, or coercion. Specifically, it includes the recruitment, harboring, transportation, or advertising of a minor, and includes the exchange of anything of value in return for sexual activity. Commercial sexual exploitation and sex trafficking against minors include crimes such as prostitution; survival sex (exchanging sex/sexual acts for money or something of value, such as shelter, food, or drugs); pornography; sex tourism, mail-order-bride trade, and early marriage; or sexual performances (peep shows or strip clubs).²

Providing optimal care for children and adolescents exploited by sex trafficking depends on knowing risk factors, having an awareness of recommended screening and assessment tools, and employing a trauma-­informed approach to interviews, examination, and support.²

Continue to: Recognize clues to trafficking

The Centers for Disease Control and Prevention (CDC) offers a framework for trafficking prevention. Health care providers are encouraged to use the CDC Social-Ecological Model which describes targeted prevention strategies at the individual, relationship, community, and societal levels.³

Risk factors for entering trafficking. Younger age increases a child’s vulnerability to exploitation, due to a lack of maturity, limited cognitive development, and ease of deception. The mean age of trafficking survivors is 15 years.⁴ History of child abuse and other traumatic experiences can lead children to run away from home. It is estimated that, once on the streets, most teens will be recruited by a trafficker within 48 hours.⁵ Poor self-esteem, depression, substance abuse, history of truancy, and early sexual maturation also increase the risk of becoming involved in trafficking (TABLE 1).^2,6-8

Clinical findings suggestive of trafficking. Many physicians grasp the critical role they play in confronting trafficking, but they lack specific training, experience, and assessment tools.³ Notably, in 1 retrospective study, 46% of victims had been seen by a provider within the previous 2 months.⁶ One of the major challenges to identifying survivors of trafficking is to recognize critical signs, of which there are many (TABLE 1^2,6-8). Often these include a history of sexual assault, multiple pregnancies, requests for contraception at an early age, or evidence of physical injury.

Screen to identify trafficking

Universal, validated screening tools to accurately identify trafficked youth is an area of growing research. Some tools have been validated, but only for specific populations such as homeless or incarcerated youth or in emergency department (ED) patients. Tools for sex trafficking identification that may be useful in primary care include the Child Sex Trafficking (CST) screen validated in ED settings (TABLE 2),⁹ the Commercial Sexual Exploitation-Identification Tool (CSE-IT) in multiple settings (TABLE 3),^10,11 and the Quick Youth Indicators for Trafficking (QYIT) in homeless youth (TABLE 4).¹¹ The QYIT is the first validated labor and sex trafficking screening tool in homeless young adults. Children who screen positive for sex trafficking should be further assessed using a comprehensive tool.

Barriers to effective recognition of trafficked individuals. Financial factors limit access to health care. Also, survivors have cited multiple barriers for health professionals that prevent identification of survivors’ trafficked status.^12,13 Once in the medical setting, disclosure is impacted by time constraints, fear of judgment by clinicians, and the risk of re-traumatization. Survivors have also cited lack of privacy, control strategies by their traffickers, lack of provider empathy, and fear of police as barriers to disclosure.¹⁴

Continue to: The medical impact of trafficking

The medical impact of trafficking

Sexual exploitation is a traumatic experience that is known to cause harm across multiple domains including serious physical injuries related to violence, as well as reproductive and mental health consequences.^15,16

Acute and chronic illnesses. In an initial evaluation, assess the survivor’s acute medical conditions (TABLE 5).^15,16 Common acute issues include physical injuries due to assault, infections, and reproductive complications.¹⁷ Health concerns can also result from stressors such as deprivation of food and sleep, hazardous living conditions, and limited access to care.¹⁷

Suspect possible sex trafficking when a patient has a history of sexual assault and multiple pregnancies, requests contraception at an early age, and/or has evidence of physical injury.

As part of caring for sex-trafficking survivors, assess for, and treat, chronic health issues such as pain, gastrointestinal complaints, poor dental care, malnutrition, and fatigue.^16,18 Substance use, as well as chronic mental health concerns (eg, anxiety, depression, posttraumatic stress disorder [PTSD]) may also influence the clinical presentation.

Physical injuries. A cross-sectional study of female survivors of sex trafficking in the United States found that 89% sustained physical injury resulting from violence, including fractures, open wounds, head injury, dental problems, burns, and anogenital trauma.^16,17 In many cases, acute injury may not be present in the clinical setting since care is often delayed, but a full examination can reveal signs of prior trauma.¹⁶

Reproductive health concerns. Significant, long-term impact on reproductive health can result due to forced penetration by multiple perpetrators, sodomy, and sex without protection or lubricants. Survivors are therefore at high risk for unplanned and unwanted pregnancies, sexually transmitted infections (STIs), pelvic pain, and infertility.¹⁶

Continue to: Psychological effects and trauma exposure

Psychological effects and trauma exposure. Survivors often have experienced abuse and neglect prior to commercial exploitation, and they may exhibit long-term sequelae. Survivors may present with major depression, anxiety, panic attacks, suicidality, addiction, PTSD, or aggression.¹⁶ Long-term sequelae for patients can include dysfunctional relationships due to an inability to trust, self-destructive behaviors, and significant shame.^2,18

Care and treatment of trafficked youth

Initial presentation may occur in a variety of health care settings. Use a trauma-informed approach emphasizing physical and emotional safety and positive relationships, to reduce risk to the survivor, staff, and providers.¹⁹ Establishing trust and rapport may provide better short-term safety, as well as help build stronger long-term relationships that can lead to better health outcomes.

Clinical examination. Provide traumatized patients with a sense of safety, control, and autonomy in the health care setting. During the physical exam, be aware of the impact of re-traumatization as patients are asked to undress, endure sensitive examinations, and undergo invasive procedures. Explain the examination, ask for permission at each step, and use slow movements. Allow the patient to guide certain sensitive exams.¹⁵ Adopt an approach that recognizes the impact of trauma, avoids revictimization, and acknowledges the resilience of survivors.²⁰

Treatment plan. After the initial exam, treat acute physical injuries and determine if any further testing is needed. Offer emergency contraception, STI prophylaxis, pre-exposure prophylaxis, and vaccines.¹⁵ After assessing patient readiness, offer local resources, identify safe methods for communication, identify individuals who could intervene in a crisis, and consider a safety plan (TABLE 6).

Coordination of care. Consider referrals to behavioral health services, substance recovery centers, food programs, housing resources, and a primary care clinic.¹⁵ ED clinicians may be asked to complete a sexual or physical assault forensic examination. After obtaining informed consent, one needs to¹⁹

• document skin signs such as scars, bites, strangulation marks, and tattoos. Note the size, shape, color, location, and other characteristics of each lesion.
• perform an oral, genital, and rectal examination and use a sexual assault evidence kit as indicated.
• use body diagrams and take photographs of all injuries/physical findings.
• order diagnostic testing as appropriate (eg, imaging to assess fractures).

Continue to: THE CASE

THE CASE

During Ms. T’s incarceration, she was tested for STIs and treated for gonorrhea, trichomonas, and bacterial vaginosis. She was educated about sexual health, was counseled on contraception, and accepted condoms. She was referred to a therapist and given information on additional community resources she could contact upon her release.

During a physical examination, explain the process, ask for permission at each step, use slow movements, and allow the patient to guide certain sensitive exams.

A year after her release, she was incarcerated again. She also had an unplanned pregnancy. With the support she received from community programs, social workers, and her primary care provider, she moved in with her family, where she is currently living. She denies any ongoing trafficking activity.

CORRESPONDENCE
Piali Basu, DO, MPH, UCSF Primary Care, 185 Berry Street, Lobby 1, Suite 1000, San Francisco, CA 94107; [email protected]

Atopic dermatitis (AD), also known as eczema, is a chronic inflammatory skin condition that is well known for its relapsing, pruritic rash in children and adults. Less recognized are its associated conditions—allergic rhinitis, asthma, food allergies, attention-deficit/hyperactivity disorder (ADHD), depression, and anxiety—and its burden on patients and their families. In fact, families that have children with AD report lower overall quality of life than those with otherwise healthy children.¹ Given AD’s prevalence across age groups and its effect on the family, family physicians are uniquely positioned to diagnose, care for, and counsel patients with AD and its associated maladies.

The prevalence and pathogenesis of AD

AD affects up to 20% of children and 5% of adults in the United States.² AD typically manifests before a child reaches age 5 (often in the first 6 months of life), and it is slightly more common in females (1.3:1). A family history of atopy (eczema, asthma, allergic rhinitis) is common. In fact, children with one atopic parent have a 2- to 3-fold increased risk of atopic dermatitis; those with 2 atopic parents have a 3- to 5-fold increased risk.³

The pathophysiology of AD is complex, culminating in impaired barrier function of the skin and transepidermal water loss resulting in dry and inflamed skin. Additionally, alterations in a cell-mediated immune response leading to an immunoglobulin (Ig) E-mediated hypersensitivity is also theorized to play a role in the development of AD.

Signs and symptoms

Signs at birth. Physical signs of atopic dermatitis typically appear between birth and 6 months. In infancy, lesions generally occur on the scalp, face (FIGURES 1A and 1B), neck, and extensor surfaces of the extremities. Lesions are typically papules and vesicles, sometimes accompanied by serous exudate and crusting. Eczematous lesions typically spare the groin and diaper area, and their presence in this area should raise suspicion for an alternative diagnosis.

Beginning at age 2 years, eczematous lesions are more commonly limited to the folds of the flexor surfaces. Instead of the weeping and crusting lesions seen in infancy, eczema in older children manifests as dry, lichenified papules and plaques in areas that are typically affected in adults: the wrist, hands, ankles, and popliteal and antecubital fossa.²

Although lesions in adults are similar to those of childhood, they may manifest in a more localized area (hand or eyelid, for example). As is the case in childhood, the lesions are dry, sometimes lichenified, and found on the flexural surfaces (FIGURES 2A and 2B).²

Symptom triggers are unproven

While anecdotal reports cite various triggers for AD flares, a systematic review found little scientific evidence to substantiate identifiable triggers.⁴ Triggers often cited and studied are foods, dust mite exposure, airborne allergens, detergents, sunlight, fabrics, bacterial infections, and stress. While as many as one-third of people with AD who also have confirmed dust mite allergy report worsening of symptoms when exposed to dust, a Cochrane review of 7 randomized controlled trials totaling 324 adults and children with eczema found that efforts at dust mite mitigation (laundering of bed covers, increased vacuuming, spraying for mites) were not effective in reducing symptoms.⁵

Continue to: How quality of life diminishes with AD

How quality of life diminishes with AD

AD substantially lessens quality of life. For children, the most distressing physical symptoms include itching that inhibits sleep and provokes scratching, pain, and bleeding. Emotional distress can cause irritability, crying, and uncooperativeness with treatments. Parents also report that they frequently restrict their children from activities, such as playing in the heat or swimming, that may lead to worsening of their eczema.⁶

The loss of sleep associated with AD is not completely understood but is likely multifactorial. Pruritus and scratching leading to sleeplessness is the most obvious culprit, but an altered circadian rhythm, immune system response, and changes in skin physiology are also likely factors.⁷ Whatever the cause, sleep disturbance is reported in as many as 60% of patients with AD, and the degree of sleep disturbance is proportional to increases in disease severity and worsening of quality-of-life scores.⁸ Lost sleep is not limited to patients; parents of children with AD also report significant loss of sleep and subsequent decreased work productivity and quality of life.⁹

Children with AD are often the target of bullying.¹⁰ A 2015 survey by the National Eczema Association indicates that 1 in 5 children reported being bullied due to their AD.¹¹

Associated conditions and comorbidities

AD increases patients’ risks for other illnesses, due either to their underlying atopy or to the effects of AD symptoms (TABLE^12-17).

Atopic march

Atopic march—the clinical succession of AD, allergic rhinitis, and asthma—is a well-­established clinical progression. The presence of all 3 conditions appears to be more common in children diagnosed with AD before 2 years of age.¹² Typically, allergic rhinitis manifests at around age 4, and asthma develops between ages 6 and 8. The severity of AD predicts progression. Compared with an 8% chance of asthma developing among the general population, children with mild AD have a 20% to 30% chance of developing asthma, and those with severe AD have about a 70% chance.¹²

Continue to: Food allergies

Patients with AD are at higher risk for food-induced anaphylaxis, with up to one-third of AD patients having an IgE-mediated food allergy.¹³ While it is theorized that the impaired skin barrier of an atopic child may allow for early sensitization and allergy development, a landmark 2015 study demonstrated that early allergen introduction (specifically, peanuts) may serve as a preventive strategy in those at high risk of food allergies.¹⁴ Current guidelines recommend that physicians be aware of the increased possibility of food allergies in those with AD, and consider evaluating a child for milk, egg, peanut, wheat, and soy allergy if the child is younger than 5 years and has eczema that does not resolve with treatment, or has eczema and a history of an allergic reaction to a specific food.¹⁵

Interestingly, despite the strong association between AD and food allergies, it is not clear that food allergies trigger atopic flares; as such, elimination diets are not universally recommended in those without a proven food allergy.

Psychiatric diagnoses

Children with AD have an increased prevalence of several psychiatric conditions, including ADHD, depression, anxiety, conduct disorder, and autism when compared with peers who do not have AD, and the probability correlates with the severity of AD.¹⁶ While there is a clear link—secondary to nocturnal pruritis—between AD and sleep deprivation, it is not clear whether the sleep deprivation leads to an increase in these psychiatric conditions or if AD is an independent risk factor.

Consider recommending bleach baths in cases of moderate-to-severe atopic dermatitis with frequent bacterial infections.

What we do know is that one of the strongest associations between AD and a psychiatric condition is with ADHD, with a recent pooled meta-analysis showing a 46% increase in risk.¹⁷ The incidence of depression among children with AD appears to correlate with the severity of AD symptoms: estimated at 5% with mild AD, 7% with moderate disease, and 14% with severe disease (compared with 3% without AD). Similar incremental increases are seen when correlating AD and anxiety.¹⁶

Nonpharmacologic care

Bathing

Bathing habits are critical to controlling AD. While bathing serves to both hydrate the skin and remove allergens, the water’s evaporation off the skin surface can lead to increased transepidermal water loss. Combining bathing and immediate application of a moisturizer improves skin hydration in patients with AD vs bathing alone.¹⁸ Thus, consensus guidelines recommend once-daily bathing (bath or shower) to remove scale and crust, followed by immediate application of a moisturizing emollient.¹⁹

Continue to: Emollients

Application of moisturizing emollients is the mainstay of nonpharmacologic care of AD, and there is strong evidence that their regimented use reduces disease burden and the need for prescription treatment.¹⁹ Emollient creams and ointments help retain moisture and improve the skin’s barrier. While ointments may provide a better barrier, patients tend to prefer creams as they are less greasy than ointments.

Emollient therapy may also help prevent development of AD, especially in those infants thought to be at high risk with a family history of atopy. In a multinational randomized controlled trial, infants who received daily full-body application of emollient beginning at 3 weeks of life were significantly less likely than controls to develop AD by 6 months.²⁰ While the mechanism of action is not clearly understood, it is believed that early emollient use prevents skin dehydration and maintains the skin’s barrier integrity, thus decreasing allergen epidermal penetration and subsequent inflammation.

Bleach bath

A bleach bath, prepared by adding 1/2 cup of unconcentrated bleach (5.25% sodium hypochlorite) to a standard 40-gallon bathtub, produces a chlorine mixture equivalent to an average swimming pool. Soaking in a bleach bath for 10 minutes once or twice weekly is thought to reduce inflammation and bacteria on the skin, but studies of its efficacy in improving atopic symptoms are mixed.

In a pooled analysis of 5 studies evaluating bleach baths vs standard baths, there was no significant difference in disease severity at 4 weeks.²¹ Thus, while bleach baths were effective in decreasing disease severity, they appeared to be no more effective than a standard water bath.²¹ Bleach baths may be helpful, however, in cases of moderate-to-severe disease with frequent bacterial infections.¹⁹

Pharmacologic therapy

Steroids

For symptoms refractory to nonpharmacologic skin care, topical steroids are the initial pharmacologic treatment for AD.19 Choose steroid potency based on symptom severity and disease location. Low- to medium-potency is appropriate for mild disease, and medium- to high-potency is useful for ­moderate-to-severe symptoms. High-­potency steroids are generally avoided on the face and skin folds; however, they can be used for short periods in these areas to induce remission. They must then be quickly tapered and discontinued.

Continue to: Frequency

Frequency. Topical corticosteroids are typically applied twice daily, although recent studies indicate that once-daily application is just as efficacious.²² In addition to treatment of an acute flare, topical steroids are useful as maintenance therapy for patients with recurrent outbreaks in the same anatomical site. Guidelines suggest once- or twice-weekly application of a medium-potency steroid to prolong time between flares.¹⁹

For children, a practical guide is for caregivers to apply the amount of steroid covering 1 adult fingertip to an area of the child’s skin equal to that of 2 adult palms.²³ Topical steroids are generally well tolerated and have a good safety profile. Adverse effects are proportional to the amount and duration of use and include purpura, telangiectasias, striae, and skin atrophy. The risk of skin atrophy increases with higher potency steroids, occlusion (covering affected area after steroid application), use on thin-skinned areas, and older patient age.²⁴

A Cochrane review found that efforts at dust mite mitigation (laundering of bed covers, increased vacuuming, spraying for mites) were not effective in reducing symptoms of atopic dermatitis.

Reassure patients/parents about the safety of topical steroids, as fears regarding the potential adverse effects can limit compliance. In one study of 200 patients with AD, 72.5% of respondents expressed fear of using steroids on their own skin or that of their child, and 24% admitted being noncompliant with therapy based on these concerns.²⁵

Treating flares. Oral steroids are sometimes needed to abort or control an AD flare in older children and adults. A tapering course of prednisone over 5 to 7 days, transitioning to medium- to high-dose topical steroids, may be needed to achieve symptom control.

Topical calcineurin inhibitors

Topical calcineurin inhibitors, including tacrolimus and pimecrolimus, are generally second-line therapy to topical corticosteroids. However, as nonsteroidal agents, topical calcineurin inhibitors do not cause skin atrophy and can be a first-line option in areas where atrophy is more common (face, eyelids, neck, and skin folds).²⁶

Continue to: A Cochrane review found...

Interestingly, despite the strong association between atopic dermatitis and food allergies, it is not clear that food allergies trigger atopic flares.

A Cochrane review found tacrolimus 0.1% to be better than low‐potency topical corticosteroids on the face and neck areas, while results were equivocal when compared with moderate‐potency topical corticosteroids on the trunk and extremities (no difference based on physician assessment, but marginal benefit favoring tacrolimus based on participant scoring).²⁷ When compared head-to-head, tacrolimus was more effective than pimecrolimus, although tacrolimus has a higher rate of local irritation. The most common adverse effects are stinging and burning at the application site, although these adverse effects generally improve with repeated application.

There have been long-term safety concerns with topical calcineurin inhibitors—chiefly a 2006 Food and Drug Administration (FDA) black box warning regarding a possible link between topical calcineurin inhibitors and cancer. However, while there may be a slight increased risk of lymphoma in AD patients, a recent meta-analysis did not find an association between topical calcineurin inhibitors use and lymphoma.²⁸ Given the initial concern—and pending additional data—the FDA currently recommends reserving topical calcineurin inhibitors for second-line therapy and only for the minimum amount of time to induce improvement. It also recommends avoiding their use in patients younger than 2 years and in those with compromised immune systems.

Cisaborole

Cisaborole, a topical phosphodiesterase 4 (PDE4) inhibitor, received FDA approval in 2016 for mild-to-moderate AD. By inhibiting PDE4, the drug limits inflammation. In a multicenter randomized trial, patients applying cisaborole 2% twice a day noted reductions in pruritus, inflammation, excoriation, and lichenification.²⁹ Adverse effects are minimal and limited to application site irritation.

Systemic treatments

While beyond the care of a family physician, symptoms refractory to conservative, nonpharmacologic measures and combinations of topical pharmaceuticals can be treated with systemic immunomodulators such as cyclosporine, azathioprine, and methotrexate. Phototherapy is also effective in patients with more widespread skin involvement. Dupilumab, an injectable monoclonal antibody that binds to interleukin-4 receptor and inhibits inflammation, is approved to treat moderate-to-severe AD in adults.³⁰

Ineffective therapies: Oral montelukast and probiotics

While oral antihistamines are frequently prescribed and used, there are no studies evaluating the use of antihistamines (H1) as monotherapy for AD.³¹ Nonetheless, while not altering the disease process, the sedative effect of antihistamines may palliate the nocturnal pruritus frequently associated with AD. Although nonsedating antihistamines may still have a role for atopic patients with concurrent seasonal and environmental allergies, there is no evidence to support their use in the treatment of AD.

Continue to: Data are limited...

Data are limited on the effectiveness of leukotriene receptor antagonists for AD, and all studies meeting inclusion for a Cochrane review assessed oral montelukast. The review found no benefit with the use of montelukast 10 mg in terms of severity of disease, pruritus, or need for topical steroids.³²

A practical guide is for caregivers to apply the amount of steroid covering 1 adult fingertip to an area of the child’s skin equal to that of 2 adult palms.

A systematic review investigating the benefit of probiotics for the treatment of AD found no improvement in patient-rated eczema scores for quality of life.³³ Additionally, a review of 11 randomized controlled trials including 596 participants found no evidence to suggest efficacy of fish oil, zinc, selenium, vitamin D, vitamin E, pyridoxine, sea buckthorn oil, hempseed oil, or sunflower oil in the treatment of AD.³⁴

Education can reduce AD severity

Family physicians can be a source of education and support for patients and families of patients with AD. Support programs for adults with AD—including education, relaxation techniques, and cognitive behavioral therapy—have been shown to decrease disease severity.³⁵ Comparable improvement in disease severity has been demonstrated in children with AD when similar education is provided to them and their families.

CORRESPONDENCE
Franklin Berkey, DO, Penn State Health, 1850 East Park Avenue, Suite 207, State College, PA 16803; fberkey@ pennstatehealth.psu.edu.

Atopic dermatitis (AD), also known as eczema, is a chronic inflammatory skin condition that is well known for its relapsing, pruritic rash in children and adults. Less recognized are its associated conditions—allergic rhinitis, asthma, food allergies, attention-deficit/hyperactivity disorder (ADHD), depression, and anxiety—and its burden on patients and their families. In fact, families that have children with AD report lower overall quality of life than those with otherwise healthy children.¹ Given AD’s prevalence across age groups and its effect on the family, family physicians are uniquely positioned to diagnose, care for, and counsel patients with AD and its associated maladies.

The prevalence and pathogenesis of AD

AD affects up to 20% of children and 5% of adults in the United States.² AD typically manifests before a child reaches age 5 (often in the first 6 months of life), and it is slightly more common in females (1.3:1). A family history of atopy (eczema, asthma, allergic rhinitis) is common. In fact, children with one atopic parent have a 2- to 3-fold increased risk of atopic dermatitis; those with 2 atopic parents have a 3- to 5-fold increased risk.³

The pathophysiology of AD is complex, culminating in impaired barrier function of the skin and transepidermal water loss resulting in dry and inflamed skin. Additionally, alterations in a cell-mediated immune response leading to an immunoglobulin (Ig) E-mediated hypersensitivity is also theorized to play a role in the development of AD.

Signs and symptoms

Signs at birth. Physical signs of atopic dermatitis typically appear between birth and 6 months. In infancy, lesions generally occur on the scalp, face (FIGURES 1A and 1B), neck, and extensor surfaces of the extremities. Lesions are typically papules and vesicles, sometimes accompanied by serous exudate and crusting. Eczematous lesions typically spare the groin and diaper area, and their presence in this area should raise suspicion for an alternative diagnosis.

Beginning at age 2 years, eczematous lesions are more commonly limited to the folds of the flexor surfaces. Instead of the weeping and crusting lesions seen in infancy, eczema in older children manifests as dry, lichenified papules and plaques in areas that are typically affected in adults: the wrist, hands, ankles, and popliteal and antecubital fossa.²

Although lesions in adults are similar to those of childhood, they may manifest in a more localized area (hand or eyelid, for example). As is the case in childhood, the lesions are dry, sometimes lichenified, and found on the flexural surfaces (FIGURES 2A and 2B).²

Symptom triggers are unproven

While anecdotal reports cite various triggers for AD flares, a systematic review found little scientific evidence to substantiate identifiable triggers.⁴ Triggers often cited and studied are foods, dust mite exposure, airborne allergens, detergents, sunlight, fabrics, bacterial infections, and stress. While as many as one-third of people with AD who also have confirmed dust mite allergy report worsening of symptoms when exposed to dust, a Cochrane review of 7 randomized controlled trials totaling 324 adults and children with eczema found that efforts at dust mite mitigation (laundering of bed covers, increased vacuuming, spraying for mites) were not effective in reducing symptoms.⁵

Continue to: How quality of life diminishes with AD

How quality of life diminishes with AD

AD substantially lessens quality of life. For children, the most distressing physical symptoms include itching that inhibits sleep and provokes scratching, pain, and bleeding. Emotional distress can cause irritability, crying, and uncooperativeness with treatments. Parents also report that they frequently restrict their children from activities, such as playing in the heat or swimming, that may lead to worsening of their eczema.⁶

The loss of sleep associated with AD is not completely understood but is likely multifactorial. Pruritus and scratching leading to sleeplessness is the most obvious culprit, but an altered circadian rhythm, immune system response, and changes in skin physiology are also likely factors.⁷ Whatever the cause, sleep disturbance is reported in as many as 60% of patients with AD, and the degree of sleep disturbance is proportional to increases in disease severity and worsening of quality-of-life scores.⁸ Lost sleep is not limited to patients; parents of children with AD also report significant loss of sleep and subsequent decreased work productivity and quality of life.⁹

Children with AD are often the target of bullying.¹⁰ A 2015 survey by the National Eczema Association indicates that 1 in 5 children reported being bullied due to their AD.¹¹

Associated conditions and comorbidities

AD increases patients’ risks for other illnesses, due either to their underlying atopy or to the effects of AD symptoms (TABLE^12-17).

Atopic march

Atopic march—the clinical succession of AD, allergic rhinitis, and asthma—is a well-­established clinical progression. The presence of all 3 conditions appears to be more common in children diagnosed with AD before 2 years of age.¹² Typically, allergic rhinitis manifests at around age 4, and asthma develops between ages 6 and 8. The severity of AD predicts progression. Compared with an 8% chance of asthma developing among the general population, children with mild AD have a 20% to 30% chance of developing asthma, and those with severe AD have about a 70% chance.¹²

Continue to: Food allergies

Patients with AD are at higher risk for food-induced anaphylaxis, with up to one-third of AD patients having an IgE-mediated food allergy.¹³ While it is theorized that the impaired skin barrier of an atopic child may allow for early sensitization and allergy development, a landmark 2015 study demonstrated that early allergen introduction (specifically, peanuts) may serve as a preventive strategy in those at high risk of food allergies.¹⁴ Current guidelines recommend that physicians be aware of the increased possibility of food allergies in those with AD, and consider evaluating a child for milk, egg, peanut, wheat, and soy allergy if the child is younger than 5 years and has eczema that does not resolve with treatment, or has eczema and a history of an allergic reaction to a specific food.¹⁵

Interestingly, despite the strong association between AD and food allergies, it is not clear that food allergies trigger atopic flares; as such, elimination diets are not universally recommended in those without a proven food allergy.

Psychiatric diagnoses

Children with AD have an increased prevalence of several psychiatric conditions, including ADHD, depression, anxiety, conduct disorder, and autism when compared with peers who do not have AD, and the probability correlates with the severity of AD.¹⁶ While there is a clear link—secondary to nocturnal pruritis—between AD and sleep deprivation, it is not clear whether the sleep deprivation leads to an increase in these psychiatric conditions or if AD is an independent risk factor.

Consider recommending bleach baths in cases of moderate-to-severe atopic dermatitis with frequent bacterial infections.

What we do know is that one of the strongest associations between AD and a psychiatric condition is with ADHD, with a recent pooled meta-analysis showing a 46% increase in risk.¹⁷ The incidence of depression among children with AD appears to correlate with the severity of AD symptoms: estimated at 5% with mild AD, 7% with moderate disease, and 14% with severe disease (compared with 3% without AD). Similar incremental increases are seen when correlating AD and anxiety.¹⁶

Nonpharmacologic care

Bathing

Bathing habits are critical to controlling AD. While bathing serves to both hydrate the skin and remove allergens, the water’s evaporation off the skin surface can lead to increased transepidermal water loss. Combining bathing and immediate application of a moisturizer improves skin hydration in patients with AD vs bathing alone.¹⁸ Thus, consensus guidelines recommend once-daily bathing (bath or shower) to remove scale and crust, followed by immediate application of a moisturizing emollient.¹⁹

Continue to: Emollients

Application of moisturizing emollients is the mainstay of nonpharmacologic care of AD, and there is strong evidence that their regimented use reduces disease burden and the need for prescription treatment.¹⁹ Emollient creams and ointments help retain moisture and improve the skin’s barrier. While ointments may provide a better barrier, patients tend to prefer creams as they are less greasy than ointments.

Emollient therapy may also help prevent development of AD, especially in those infants thought to be at high risk with a family history of atopy. In a multinational randomized controlled trial, infants who received daily full-body application of emollient beginning at 3 weeks of life were significantly less likely than controls to develop AD by 6 months.²⁰ While the mechanism of action is not clearly understood, it is believed that early emollient use prevents skin dehydration and maintains the skin’s barrier integrity, thus decreasing allergen epidermal penetration and subsequent inflammation.

Bleach bath

A bleach bath, prepared by adding 1/2 cup of unconcentrated bleach (5.25% sodium hypochlorite) to a standard 40-gallon bathtub, produces a chlorine mixture equivalent to an average swimming pool. Soaking in a bleach bath for 10 minutes once or twice weekly is thought to reduce inflammation and bacteria on the skin, but studies of its efficacy in improving atopic symptoms are mixed.

In a pooled analysis of 5 studies evaluating bleach baths vs standard baths, there was no significant difference in disease severity at 4 weeks.²¹ Thus, while bleach baths were effective in decreasing disease severity, they appeared to be no more effective than a standard water bath.²¹ Bleach baths may be helpful, however, in cases of moderate-to-severe disease with frequent bacterial infections.¹⁹

Pharmacologic therapy

Steroids

For symptoms refractory to nonpharmacologic skin care, topical steroids are the initial pharmacologic treatment for AD.19 Choose steroid potency based on symptom severity and disease location. Low- to medium-potency is appropriate for mild disease, and medium- to high-potency is useful for ­moderate-to-severe symptoms. High-­potency steroids are generally avoided on the face and skin folds; however, they can be used for short periods in these areas to induce remission. They must then be quickly tapered and discontinued.

Continue to: Frequency

Frequency. Topical corticosteroids are typically applied twice daily, although recent studies indicate that once-daily application is just as efficacious.²² In addition to treatment of an acute flare, topical steroids are useful as maintenance therapy for patients with recurrent outbreaks in the same anatomical site. Guidelines suggest once- or twice-weekly application of a medium-potency steroid to prolong time between flares.¹⁹

For children, a practical guide is for caregivers to apply the amount of steroid covering 1 adult fingertip to an area of the child’s skin equal to that of 2 adult palms.²³ Topical steroids are generally well tolerated and have a good safety profile. Adverse effects are proportional to the amount and duration of use and include purpura, telangiectasias, striae, and skin atrophy. The risk of skin atrophy increases with higher potency steroids, occlusion (covering affected area after steroid application), use on thin-skinned areas, and older patient age.²⁴

A Cochrane review found that efforts at dust mite mitigation (laundering of bed covers, increased vacuuming, spraying for mites) were not effective in reducing symptoms of atopic dermatitis.

Reassure patients/parents about the safety of topical steroids, as fears regarding the potential adverse effects can limit compliance. In one study of 200 patients with AD, 72.5% of respondents expressed fear of using steroids on their own skin or that of their child, and 24% admitted being noncompliant with therapy based on these concerns.²⁵

Treating flares. Oral steroids are sometimes needed to abort or control an AD flare in older children and adults. A tapering course of prednisone over 5 to 7 days, transitioning to medium- to high-dose topical steroids, may be needed to achieve symptom control.

Topical calcineurin inhibitors

Topical calcineurin inhibitors, including tacrolimus and pimecrolimus, are generally second-line therapy to topical corticosteroids. However, as nonsteroidal agents, topical calcineurin inhibitors do not cause skin atrophy and can be a first-line option in areas where atrophy is more common (face, eyelids, neck, and skin folds).²⁶

Continue to: A Cochrane review found...

Interestingly, despite the strong association between atopic dermatitis and food allergies, it is not clear that food allergies trigger atopic flares.

A Cochrane review found tacrolimus 0.1% to be better than low‐potency topical corticosteroids on the face and neck areas, while results were equivocal when compared with moderate‐potency topical corticosteroids on the trunk and extremities (no difference based on physician assessment, but marginal benefit favoring tacrolimus based on participant scoring).²⁷ When compared head-to-head, tacrolimus was more effective than pimecrolimus, although tacrolimus has a higher rate of local irritation. The most common adverse effects are stinging and burning at the application site, although these adverse effects generally improve with repeated application.

There have been long-term safety concerns with topical calcineurin inhibitors—chiefly a 2006 Food and Drug Administration (FDA) black box warning regarding a possible link between topical calcineurin inhibitors and cancer. However, while there may be a slight increased risk of lymphoma in AD patients, a recent meta-analysis did not find an association between topical calcineurin inhibitors use and lymphoma.²⁸ Given the initial concern—and pending additional data—the FDA currently recommends reserving topical calcineurin inhibitors for second-line therapy and only for the minimum amount of time to induce improvement. It also recommends avoiding their use in patients younger than 2 years and in those with compromised immune systems.

Cisaborole

Cisaborole, a topical phosphodiesterase 4 (PDE4) inhibitor, received FDA approval in 2016 for mild-to-moderate AD. By inhibiting PDE4, the drug limits inflammation. In a multicenter randomized trial, patients applying cisaborole 2% twice a day noted reductions in pruritus, inflammation, excoriation, and lichenification.²⁹ Adverse effects are minimal and limited to application site irritation.

Systemic treatments

While beyond the care of a family physician, symptoms refractory to conservative, nonpharmacologic measures and combinations of topical pharmaceuticals can be treated with systemic immunomodulators such as cyclosporine, azathioprine, and methotrexate. Phototherapy is also effective in patients with more widespread skin involvement. Dupilumab, an injectable monoclonal antibody that binds to interleukin-4 receptor and inhibits inflammation, is approved to treat moderate-to-severe AD in adults.³⁰

Ineffective therapies: Oral montelukast and probiotics

While oral antihistamines are frequently prescribed and used, there are no studies evaluating the use of antihistamines (H1) as monotherapy for AD.³¹ Nonetheless, while not altering the disease process, the sedative effect of antihistamines may palliate the nocturnal pruritus frequently associated with AD. Although nonsedating antihistamines may still have a role for atopic patients with concurrent seasonal and environmental allergies, there is no evidence to support their use in the treatment of AD.

Continue to: Data are limited...

Data are limited on the effectiveness of leukotriene receptor antagonists for AD, and all studies meeting inclusion for a Cochrane review assessed oral montelukast. The review found no benefit with the use of montelukast 10 mg in terms of severity of disease, pruritus, or need for topical steroids.³²

A practical guide is for caregivers to apply the amount of steroid covering 1 adult fingertip to an area of the child’s skin equal to that of 2 adult palms.

A systematic review investigating the benefit of probiotics for the treatment of AD found no improvement in patient-rated eczema scores for quality of life.³³ Additionally, a review of 11 randomized controlled trials including 596 participants found no evidence to suggest efficacy of fish oil, zinc, selenium, vitamin D, vitamin E, pyridoxine, sea buckthorn oil, hempseed oil, or sunflower oil in the treatment of AD.³⁴

Education can reduce AD severity

Family physicians can be a source of education and support for patients and families of patients with AD. Support programs for adults with AD—including education, relaxation techniques, and cognitive behavioral therapy—have been shown to decrease disease severity.³⁵ Comparable improvement in disease severity has been demonstrated in children with AD when similar education is provided to them and their families.

CORRESPONDENCE
Franklin Berkey, DO, Penn State Health, 1850 East Park Avenue, Suite 207, State College, PA 16803; fberkey@ pennstatehealth.psu.edu.

Atopic dermatitis (AD), also known as eczema, is a chronic inflammatory skin condition that is well known for its relapsing, pruritic rash in children and adults. Less recognized are its associated conditions—allergic rhinitis, asthma, food allergies, attention-deficit/hyperactivity disorder (ADHD), depression, and anxiety—and its burden on patients and their families. In fact, families that have children with AD report lower overall quality of life than those with otherwise healthy children.¹ Given AD’s prevalence across age groups and its effect on the family, family physicians are uniquely positioned to diagnose, care for, and counsel patients with AD and its associated maladies.

The prevalence and pathogenesis of AD

AD affects up to 20% of children and 5% of adults in the United States.² AD typically manifests before a child reaches age 5 (often in the first 6 months of life), and it is slightly more common in females (1.3:1). A family history of atopy (eczema, asthma, allergic rhinitis) is common. In fact, children with one atopic parent have a 2- to 3-fold increased risk of atopic dermatitis; those with 2 atopic parents have a 3- to 5-fold increased risk.³

The pathophysiology of AD is complex, culminating in impaired barrier function of the skin and transepidermal water loss resulting in dry and inflamed skin. Additionally, alterations in a cell-mediated immune response leading to an immunoglobulin (Ig) E-mediated hypersensitivity is also theorized to play a role in the development of AD.

Signs and symptoms

Signs at birth. Physical signs of atopic dermatitis typically appear between birth and 6 months. In infancy, lesions generally occur on the scalp, face (FIGURES 1A and 1B), neck, and extensor surfaces of the extremities. Lesions are typically papules and vesicles, sometimes accompanied by serous exudate and crusting. Eczematous lesions typically spare the groin and diaper area, and their presence in this area should raise suspicion for an alternative diagnosis.

Beginning at age 2 years, eczematous lesions are more commonly limited to the folds of the flexor surfaces. Instead of the weeping and crusting lesions seen in infancy, eczema in older children manifests as dry, lichenified papules and plaques in areas that are typically affected in adults: the wrist, hands, ankles, and popliteal and antecubital fossa.²

Although lesions in adults are similar to those of childhood, they may manifest in a more localized area (hand or eyelid, for example). As is the case in childhood, the lesions are dry, sometimes lichenified, and found on the flexural surfaces (FIGURES 2A and 2B).²

Symptom triggers are unproven

While anecdotal reports cite various triggers for AD flares, a systematic review found little scientific evidence to substantiate identifiable triggers.⁴ Triggers often cited and studied are foods, dust mite exposure, airborne allergens, detergents, sunlight, fabrics, bacterial infections, and stress. While as many as one-third of people with AD who also have confirmed dust mite allergy report worsening of symptoms when exposed to dust, a Cochrane review of 7 randomized controlled trials totaling 324 adults and children with eczema found that efforts at dust mite mitigation (laundering of bed covers, increased vacuuming, spraying for mites) were not effective in reducing symptoms.⁵

Continue to: How quality of life diminishes with AD

How quality of life diminishes with AD

AD substantially lessens quality of life. For children, the most distressing physical symptoms include itching that inhibits sleep and provokes scratching, pain, and bleeding. Emotional distress can cause irritability, crying, and uncooperativeness with treatments. Parents also report that they frequently restrict their children from activities, such as playing in the heat or swimming, that may lead to worsening of their eczema.⁶

The loss of sleep associated with AD is not completely understood but is likely multifactorial. Pruritus and scratching leading to sleeplessness is the most obvious culprit, but an altered circadian rhythm, immune system response, and changes in skin physiology are also likely factors.⁷ Whatever the cause, sleep disturbance is reported in as many as 60% of patients with AD, and the degree of sleep disturbance is proportional to increases in disease severity and worsening of quality-of-life scores.⁸ Lost sleep is not limited to patients; parents of children with AD also report significant loss of sleep and subsequent decreased work productivity and quality of life.⁹

Children with AD are often the target of bullying.¹⁰ A 2015 survey by the National Eczema Association indicates that 1 in 5 children reported being bullied due to their AD.¹¹

Associated conditions and comorbidities

AD increases patients’ risks for other illnesses, due either to their underlying atopy or to the effects of AD symptoms (TABLE^12-17).

Atopic march

Atopic march—the clinical succession of AD, allergic rhinitis, and asthma—is a well-­established clinical progression. The presence of all 3 conditions appears to be more common in children diagnosed with AD before 2 years of age.¹² Typically, allergic rhinitis manifests at around age 4, and asthma develops between ages 6 and 8. The severity of AD predicts progression. Compared with an 8% chance of asthma developing among the general population, children with mild AD have a 20% to 30% chance of developing asthma, and those with severe AD have about a 70% chance.¹²

Continue to: Food allergies

Patients with AD are at higher risk for food-induced anaphylaxis, with up to one-third of AD patients having an IgE-mediated food allergy.¹³ While it is theorized that the impaired skin barrier of an atopic child may allow for early sensitization and allergy development, a landmark 2015 study demonstrated that early allergen introduction (specifically, peanuts) may serve as a preventive strategy in those at high risk of food allergies.¹⁴ Current guidelines recommend that physicians be aware of the increased possibility of food allergies in those with AD, and consider evaluating a child for milk, egg, peanut, wheat, and soy allergy if the child is younger than 5 years and has eczema that does not resolve with treatment, or has eczema and a history of an allergic reaction to a specific food.¹⁵

Interestingly, despite the strong association between AD and food allergies, it is not clear that food allergies trigger atopic flares; as such, elimination diets are not universally recommended in those without a proven food allergy.

Psychiatric diagnoses

Children with AD have an increased prevalence of several psychiatric conditions, including ADHD, depression, anxiety, conduct disorder, and autism when compared with peers who do not have AD, and the probability correlates with the severity of AD.¹⁶ While there is a clear link—secondary to nocturnal pruritis—between AD and sleep deprivation, it is not clear whether the sleep deprivation leads to an increase in these psychiatric conditions or if AD is an independent risk factor.

Consider recommending bleach baths in cases of moderate-to-severe atopic dermatitis with frequent bacterial infections.

What we do know is that one of the strongest associations between AD and a psychiatric condition is with ADHD, with a recent pooled meta-analysis showing a 46% increase in risk.¹⁷ The incidence of depression among children with AD appears to correlate with the severity of AD symptoms: estimated at 5% with mild AD, 7% with moderate disease, and 14% with severe disease (compared with 3% without AD). Similar incremental increases are seen when correlating AD and anxiety.¹⁶

Nonpharmacologic care

Bathing

Bathing habits are critical to controlling AD. While bathing serves to both hydrate the skin and remove allergens, the water’s evaporation off the skin surface can lead to increased transepidermal water loss. Combining bathing and immediate application of a moisturizer improves skin hydration in patients with AD vs bathing alone.¹⁸ Thus, consensus guidelines recommend once-daily bathing (bath or shower) to remove scale and crust, followed by immediate application of a moisturizing emollient.¹⁹

Continue to: Emollients

Application of moisturizing emollients is the mainstay of nonpharmacologic care of AD, and there is strong evidence that their regimented use reduces disease burden and the need for prescription treatment.¹⁹ Emollient creams and ointments help retain moisture and improve the skin’s barrier. While ointments may provide a better barrier, patients tend to prefer creams as they are less greasy than ointments.

Emollient therapy may also help prevent development of AD, especially in those infants thought to be at high risk with a family history of atopy. In a multinational randomized controlled trial, infants who received daily full-body application of emollient beginning at 3 weeks of life were significantly less likely than controls to develop AD by 6 months.²⁰ While the mechanism of action is not clearly understood, it is believed that early emollient use prevents skin dehydration and maintains the skin’s barrier integrity, thus decreasing allergen epidermal penetration and subsequent inflammation.

Bleach bath

A bleach bath, prepared by adding 1/2 cup of unconcentrated bleach (5.25% sodium hypochlorite) to a standard 40-gallon bathtub, produces a chlorine mixture equivalent to an average swimming pool. Soaking in a bleach bath for 10 minutes once or twice weekly is thought to reduce inflammation and bacteria on the skin, but studies of its efficacy in improving atopic symptoms are mixed.

In a pooled analysis of 5 studies evaluating bleach baths vs standard baths, there was no significant difference in disease severity at 4 weeks.²¹ Thus, while bleach baths were effective in decreasing disease severity, they appeared to be no more effective than a standard water bath.²¹ Bleach baths may be helpful, however, in cases of moderate-to-severe disease with frequent bacterial infections.¹⁹

Pharmacologic therapy

Steroids

For symptoms refractory to nonpharmacologic skin care, topical steroids are the initial pharmacologic treatment for AD.19 Choose steroid potency based on symptom severity and disease location. Low- to medium-potency is appropriate for mild disease, and medium- to high-potency is useful for ­moderate-to-severe symptoms. High-­potency steroids are generally avoided on the face and skin folds; however, they can be used for short periods in these areas to induce remission. They must then be quickly tapered and discontinued.

Continue to: Frequency

Frequency. Topical corticosteroids are typically applied twice daily, although recent studies indicate that once-daily application is just as efficacious.²² In addition to treatment of an acute flare, topical steroids are useful as maintenance therapy for patients with recurrent outbreaks in the same anatomical site. Guidelines suggest once- or twice-weekly application of a medium-potency steroid to prolong time between flares.¹⁹

For children, a practical guide is for caregivers to apply the amount of steroid covering 1 adult fingertip to an area of the child’s skin equal to that of 2 adult palms.²³ Topical steroids are generally well tolerated and have a good safety profile. Adverse effects are proportional to the amount and duration of use and include purpura, telangiectasias, striae, and skin atrophy. The risk of skin atrophy increases with higher potency steroids, occlusion (covering affected area after steroid application), use on thin-skinned areas, and older patient age.²⁴

A Cochrane review found that efforts at dust mite mitigation (laundering of bed covers, increased vacuuming, spraying for mites) were not effective in reducing symptoms of atopic dermatitis.

Reassure patients/parents about the safety of topical steroids, as fears regarding the potential adverse effects can limit compliance. In one study of 200 patients with AD, 72.5% of respondents expressed fear of using steroids on their own skin or that of their child, and 24% admitted being noncompliant with therapy based on these concerns.²⁵

Treating flares. Oral steroids are sometimes needed to abort or control an AD flare in older children and adults. A tapering course of prednisone over 5 to 7 days, transitioning to medium- to high-dose topical steroids, may be needed to achieve symptom control.

Topical calcineurin inhibitors

Topical calcineurin inhibitors, including tacrolimus and pimecrolimus, are generally second-line therapy to topical corticosteroids. However, as nonsteroidal agents, topical calcineurin inhibitors do not cause skin atrophy and can be a first-line option in areas where atrophy is more common (face, eyelids, neck, and skin folds).²⁶

Continue to: A Cochrane review found...

Interestingly, despite the strong association between atopic dermatitis and food allergies, it is not clear that food allergies trigger atopic flares.

A Cochrane review found tacrolimus 0.1% to be better than low‐potency topical corticosteroids on the face and neck areas, while results were equivocal when compared with moderate‐potency topical corticosteroids on the trunk and extremities (no difference based on physician assessment, but marginal benefit favoring tacrolimus based on participant scoring).²⁷ When compared head-to-head, tacrolimus was more effective than pimecrolimus, although tacrolimus has a higher rate of local irritation. The most common adverse effects are stinging and burning at the application site, although these adverse effects generally improve with repeated application.

There have been long-term safety concerns with topical calcineurin inhibitors—chiefly a 2006 Food and Drug Administration (FDA) black box warning regarding a possible link between topical calcineurin inhibitors and cancer. However, while there may be a slight increased risk of lymphoma in AD patients, a recent meta-analysis did not find an association between topical calcineurin inhibitors use and lymphoma.²⁸ Given the initial concern—and pending additional data—the FDA currently recommends reserving topical calcineurin inhibitors for second-line therapy and only for the minimum amount of time to induce improvement. It also recommends avoiding their use in patients younger than 2 years and in those with compromised immune systems.

Cisaborole

Cisaborole, a topical phosphodiesterase 4 (PDE4) inhibitor, received FDA approval in 2016 for mild-to-moderate AD. By inhibiting PDE4, the drug limits inflammation. In a multicenter randomized trial, patients applying cisaborole 2% twice a day noted reductions in pruritus, inflammation, excoriation, and lichenification.²⁹ Adverse effects are minimal and limited to application site irritation.

Systemic treatments

While beyond the care of a family physician, symptoms refractory to conservative, nonpharmacologic measures and combinations of topical pharmaceuticals can be treated with systemic immunomodulators such as cyclosporine, azathioprine, and methotrexate. Phototherapy is also effective in patients with more widespread skin involvement. Dupilumab, an injectable monoclonal antibody that binds to interleukin-4 receptor and inhibits inflammation, is approved to treat moderate-to-severe AD in adults.³⁰

Ineffective therapies: Oral montelukast and probiotics

While oral antihistamines are frequently prescribed and used, there are no studies evaluating the use of antihistamines (H1) as monotherapy for AD.³¹ Nonetheless, while not altering the disease process, the sedative effect of antihistamines may palliate the nocturnal pruritus frequently associated with AD. Although nonsedating antihistamines may still have a role for atopic patients with concurrent seasonal and environmental allergies, there is no evidence to support their use in the treatment of AD.

Continue to: Data are limited...

Data are limited on the effectiveness of leukotriene receptor antagonists for AD, and all studies meeting inclusion for a Cochrane review assessed oral montelukast. The review found no benefit with the use of montelukast 10 mg in terms of severity of disease, pruritus, or need for topical steroids.³²

A practical guide is for caregivers to apply the amount of steroid covering 1 adult fingertip to an area of the child’s skin equal to that of 2 adult palms.

A systematic review investigating the benefit of probiotics for the treatment of AD found no improvement in patient-rated eczema scores for quality of life.³³ Additionally, a review of 11 randomized controlled trials including 596 participants found no evidence to suggest efficacy of fish oil, zinc, selenium, vitamin D, vitamin E, pyridoxine, sea buckthorn oil, hempseed oil, or sunflower oil in the treatment of AD.³⁴

Education can reduce AD severity

Family physicians can be a source of education and support for patients and families of patients with AD. Support programs for adults with AD—including education, relaxation techniques, and cognitive behavioral therapy—have been shown to decrease disease severity.³⁵ Comparable improvement in disease severity has been demonstrated in children with AD when similar education is provided to them and their families.

CORRESPONDENCE
Franklin Berkey, DO, Penn State Health, 1850 East Park Avenue, Suite 207, State College, PA 16803; fberkey@ pennstatehealth.psu.edu.

Repeated intravenous infusions of ketamine provide rapid relief for patients with posttraumatic stress disorder, new research suggests.

In what investigators are calling the first randomized controlled trial of repeated ketamine administration for chronic PTSD, 30 patients received six infusions of ketamine or midazolam (used as a psychoactive placebo) over 2 consecutive weeks. 

Between baseline and week 2, those receiving ketamine showed significantly greater improvement than those receiving midazolam. Total scores on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) for the first group were almost 12 points lower than the latter group at week 2, meeting the study’s primary outcome measure.

In addition, 67% vs. 20% of the patients, respectively, were considered to be treatment responders; time to loss of response for those in the ketamine group was 28 days.

Although the overall findings were as expected, “what was surprising was how robust the results were,” lead author Adriana Feder, MD, associate professor of psychiatry, Icahn School of Medicine, Mount Sinai, New York, told this news organization.

It was also a bit surprising that, in a study of just 30 participants, “we were able to show such a clear difference” between the two treatment groups, said Dr. Feder, who is also a coinventor on issued patents for the use of ketamine as therapy for PTSD, and codirector of the Ehrenkranz Lab for the Study of Human Resilience at Mount Sinai.

The findings were published online Jan. 5 in the American Journal of Psychiatry.
 

Unmet need

Ketamine is a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist that was first approved by the U.S. Food and Drug Administration for anesthetic use in 1970. It has also been shown to be effective for treatment-resistant depression.

PTSD has a lifetime prevalence of about 6% in the United States. “While trauma-focused psychotherapies have the most empirical support, they are limited by significant rates of nonresponse, partial response, and treatment dropout,” the investigators write. Also, there are “few available pharmacotherapies for PTSD, and their efficacy is insufficient,” they add.  

“There’s a real need for new treatment interventions that are effective for PTSD and also work rapidly, because it can take weeks to months for currently available treatments to work for PTSD,” Dr. Feder said.

The researchers previously conducted a “proof-of-concept” randomized controlled trial of single infusions of ketamine for chronic PTSD. Results published in 2014 in JAMA Psychiatry showed significant reduction in PTSD symptoms 24 hours after infusion.

For the current study, the investigative team wanted to assess whether ketamine was viable as a longer-term treatment.

“We were encouraged by our initial promising findings” of the earlier trial, Dr. Feder said. “We wanted to do the second study to see if ketamine really works for PTSD, to see if we could replicate the rapid improvement and also examine whether a course of six infusions over 2 weeks could maintain the improvement.”

Thirty patients (aged 18-70; mean age, 39 years) with chronic PTSD from civilian or military trauma were enrolled (mean PTSD duration, 15 years).

The most cited primary trauma was sexual assault or molestation (n = 13), followed by physical assault or abuse (n = 8), witnessing a violent assault or death (n = 4), witnessing the 9/11 attacks (n = 3), and combat exposure (n = 2).

During the 2-week treatment phase, half of the patients were randomly assigned to receive six infusions of ketamine hydrochloride at a dose of 0.5 mg/kg (86.7% women; mean CAPS-5 score, 42), while the other half received six infusions of midazolam at a dose of 0.045 mg/kg (66.7% women; mean CAPS-5 score, 40).

In addition to the primary outcome measure of 2-week changes on the CAPS-5, secondary outcomes included score changes on the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Impact of Event Scale-Revised (IES-R).

Treatment response was defined as a 30% or more improvement in symptoms on the CAPS-5. A number of measures were also used to assess potential treatment-related adverse events (AEs).
 

Safe, effective

Results showed significantly lower total CAPS-5 scores for the ketamine group vs. the midazolam group at week 1 (score difference, 8.8 points; P = .03) and at week 2 (score difference, 11.88 points; P = .004).

Those receiving ketamine also showed improvements in three of the four PTSD symptom clusters on the CAPS-5: avoidance (P < .0001), negative mood and cognitions (P = .02), and intrusions (P = .03). The fourth symptom cluster – arousal and reactivity – did not show a significant improvement.

In addition, the ketamine group showed significantly greater improvement scores on the MADRS at both week 1 and week 2.

Treatment response at 2 weeks was achieved by 10 members of the ketamine group and by three members of the midazolam group (P = .03).

Secondary analyses showed rapid improvement in the treatment responders within the ketamine group, with a mean change of 26 points on the total IES-R score between baseline and 24 hours after their first infusion, and a mean change of 13.4 points on the MADRS total past-24-hour score, a 53% improvement on average.

“A response at 2 weeks is very rapid but they got better sometimes within the first day,” Dr. Feder noted.

There were no serious AEs reported. Although some dissociative symptoms occurred during ketamine infusions, with the highest levels reported at the end of the infusion, these symptoms had resolved by the next assessment, conducted 2 hours after infusion.

The most frequently reported AE in the ketamine group, compared with midazolam, after the start of infusions was blurred vision (53% vs. 0%), followed by dizziness (33% vs. 13%), fatigue (33% vs. 87%), headache (27% vs. 13%), and nausea or vomiting (20% vs. 7%).
 

‘Large-magnitude improvement’

The overall findings show that, in this patient population, “repeated intravenous ketamine infusions administered over 2 weeks were associated with a large-magnitude, clinically significant improvement in PTSD symptoms,” the investigators write.

The results “were very satisfying,” added Dr. Feder. “It was heartening also to hear what some of the participants would say. Some told us about how their symptoms and feelings had changed during the course of treatment with ketamine, where they felt stronger and better able to cope with their trauma and memories.”

She noted, however, that this was not a study designed to specifically assess ketamine in treatment-resistant PTSD. “Some patients had had multiple treatments before that hadn’t worked, while others had not received treatment before. Efficacy for treatment-resistant PTSD is an important question for future research,” Dr. Feder said.

Other areas worth future exploration include treatment efficacy in patients with different types of trauma and whether outcomes can last longer in patients receiving ketamine plus psychotherapy treatment, she noted.

“I don’t want to ignore the fact that currently available treatments work for a number of people with chronic PTSD. But because there are many more for whom [the treatments] don’t work, or they’re insufficiently helped by those treatments, this is certainly one potentially very promising approach that can be added” to a clinician’s toolbox, Dr. Feder said.
 

Speaks to clinical utility

Commenting for this news organization, Gerard Sanacora, MD, PhD, professor of psychiatry at Yale University, New Haven, Connecticut, called this a “very solid and well-designed” study.

“It definitely builds on what’s been found in the past, but it’s a critical piece of information speaking to the clinical utility of this treatment for PTSD,” said Dr. Sanacora, who is also director of the Yale Depression Research Program and was not involved with the current research.

He agreed with the investigators that PTSD has long been a condition that is difficult to treat.

“It’s an area that has a great unmet need for treatment options. Beyond that, as ketamine is becoming more widely used, there’s increasing demand for off-label uses. This [study] actually provides some evidence that there may be efficacy there,” Dr. Sanacora said.

Although he cautioned that this was a small study, and thus further research with a larger patient population will be needed, it provides a compelling foundation to build upon.

“This study provides clear evidence to support a larger study to really give a definitive statement on the efficacy and safety of its use for PTSD. I don’t think this is the study that provides that definitive evidence, but it is a very strong indication, and it very strongly supports the initiation of a large study to address that,” said Dr. Sanacora.

He noted that, although he’s used the term “cautious optimism” for studies in the past, he has “real optimism” that ketamine will be effective for PTSD based on the results of this current study.

“We still need some more data to really convince us of that before we can say with any clear statement that it is effective and safe, but I’m very optimistic,” Dr. Sanacora concluded. “I think the data are very strong.”

The study was funded by the Brain and Behavior Research Foundation, Mount Sinai Innovation Partners and the Mount Sinai i3 Accelerator, Gerald and Glenda Greenwald, and the Ehrenkranz Laboratory for Human Resilience. Dr. Feder is a coinventor on issued patents for the use of ketamine as therapy for PTSD. A list of all disclosures for the other study authors are listed in the original article.

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

Repeated intravenous infusions of ketamine provide rapid relief for patients with posttraumatic stress disorder, new research suggests.

In what investigators are calling the first randomized controlled trial of repeated ketamine administration for chronic PTSD, 30 patients received six infusions of ketamine or midazolam (used as a psychoactive placebo) over 2 consecutive weeks. 

Between baseline and week 2, those receiving ketamine showed significantly greater improvement than those receiving midazolam. Total scores on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) for the first group were almost 12 points lower than the latter group at week 2, meeting the study’s primary outcome measure.

In addition, 67% vs. 20% of the patients, respectively, were considered to be treatment responders; time to loss of response for those in the ketamine group was 28 days.

Although the overall findings were as expected, “what was surprising was how robust the results were,” lead author Adriana Feder, MD, associate professor of psychiatry, Icahn School of Medicine, Mount Sinai, New York, told this news organization.

It was also a bit surprising that, in a study of just 30 participants, “we were able to show such a clear difference” between the two treatment groups, said Dr. Feder, who is also a coinventor on issued patents for the use of ketamine as therapy for PTSD, and codirector of the Ehrenkranz Lab for the Study of Human Resilience at Mount Sinai.

The findings were published online Jan. 5 in the American Journal of Psychiatry.
 

Unmet need

Ketamine is a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist that was first approved by the U.S. Food and Drug Administration for anesthetic use in 1970. It has also been shown to be effective for treatment-resistant depression.

PTSD has a lifetime prevalence of about 6% in the United States. “While trauma-focused psychotherapies have the most empirical support, they are limited by significant rates of nonresponse, partial response, and treatment dropout,” the investigators write. Also, there are “few available pharmacotherapies for PTSD, and their efficacy is insufficient,” they add.  

“There’s a real need for new treatment interventions that are effective for PTSD and also work rapidly, because it can take weeks to months for currently available treatments to work for PTSD,” Dr. Feder said.

The researchers previously conducted a “proof-of-concept” randomized controlled trial of single infusions of ketamine for chronic PTSD. Results published in 2014 in JAMA Psychiatry showed significant reduction in PTSD symptoms 24 hours after infusion.

For the current study, the investigative team wanted to assess whether ketamine was viable as a longer-term treatment.

“We were encouraged by our initial promising findings” of the earlier trial, Dr. Feder said. “We wanted to do the second study to see if ketamine really works for PTSD, to see if we could replicate the rapid improvement and also examine whether a course of six infusions over 2 weeks could maintain the improvement.”

Thirty patients (aged 18-70; mean age, 39 years) with chronic PTSD from civilian or military trauma were enrolled (mean PTSD duration, 15 years).

The most cited primary trauma was sexual assault or molestation (n = 13), followed by physical assault or abuse (n = 8), witnessing a violent assault or death (n = 4), witnessing the 9/11 attacks (n = 3), and combat exposure (n = 2).

During the 2-week treatment phase, half of the patients were randomly assigned to receive six infusions of ketamine hydrochloride at a dose of 0.5 mg/kg (86.7% women; mean CAPS-5 score, 42), while the other half received six infusions of midazolam at a dose of 0.045 mg/kg (66.7% women; mean CAPS-5 score, 40).

In addition to the primary outcome measure of 2-week changes on the CAPS-5, secondary outcomes included score changes on the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Impact of Event Scale-Revised (IES-R).

Treatment response was defined as a 30% or more improvement in symptoms on the CAPS-5. A number of measures were also used to assess potential treatment-related adverse events (AEs).
 

Safe, effective

Results showed significantly lower total CAPS-5 scores for the ketamine group vs. the midazolam group at week 1 (score difference, 8.8 points; P = .03) and at week 2 (score difference, 11.88 points; P = .004).

Those receiving ketamine also showed improvements in three of the four PTSD symptom clusters on the CAPS-5: avoidance (P < .0001), negative mood and cognitions (P = .02), and intrusions (P = .03). The fourth symptom cluster – arousal and reactivity – did not show a significant improvement.

In addition, the ketamine group showed significantly greater improvement scores on the MADRS at both week 1 and week 2.

Treatment response at 2 weeks was achieved by 10 members of the ketamine group and by three members of the midazolam group (P = .03).

Secondary analyses showed rapid improvement in the treatment responders within the ketamine group, with a mean change of 26 points on the total IES-R score between baseline and 24 hours after their first infusion, and a mean change of 13.4 points on the MADRS total past-24-hour score, a 53% improvement on average.

“A response at 2 weeks is very rapid but they got better sometimes within the first day,” Dr. Feder noted.

There were no serious AEs reported. Although some dissociative symptoms occurred during ketamine infusions, with the highest levels reported at the end of the infusion, these symptoms had resolved by the next assessment, conducted 2 hours after infusion.

The most frequently reported AE in the ketamine group, compared with midazolam, after the start of infusions was blurred vision (53% vs. 0%), followed by dizziness (33% vs. 13%), fatigue (33% vs. 87%), headache (27% vs. 13%), and nausea or vomiting (20% vs. 7%).
 

‘Large-magnitude improvement’

The overall findings show that, in this patient population, “repeated intravenous ketamine infusions administered over 2 weeks were associated with a large-magnitude, clinically significant improvement in PTSD symptoms,” the investigators write.

The results “were very satisfying,” added Dr. Feder. “It was heartening also to hear what some of the participants would say. Some told us about how their symptoms and feelings had changed during the course of treatment with ketamine, where they felt stronger and better able to cope with their trauma and memories.”

She noted, however, that this was not a study designed to specifically assess ketamine in treatment-resistant PTSD. “Some patients had had multiple treatments before that hadn’t worked, while others had not received treatment before. Efficacy for treatment-resistant PTSD is an important question for future research,” Dr. Feder said.

Other areas worth future exploration include treatment efficacy in patients with different types of trauma and whether outcomes can last longer in patients receiving ketamine plus psychotherapy treatment, she noted.

“I don’t want to ignore the fact that currently available treatments work for a number of people with chronic PTSD. But because there are many more for whom [the treatments] don’t work, or they’re insufficiently helped by those treatments, this is certainly one potentially very promising approach that can be added” to a clinician’s toolbox, Dr. Feder said.
 

Speaks to clinical utility

Commenting for this news organization, Gerard Sanacora, MD, PhD, professor of psychiatry at Yale University, New Haven, Connecticut, called this a “very solid and well-designed” study.

“It definitely builds on what’s been found in the past, but it’s a critical piece of information speaking to the clinical utility of this treatment for PTSD,” said Dr. Sanacora, who is also director of the Yale Depression Research Program and was not involved with the current research.

He agreed with the investigators that PTSD has long been a condition that is difficult to treat.

“It’s an area that has a great unmet need for treatment options. Beyond that, as ketamine is becoming more widely used, there’s increasing demand for off-label uses. This [study] actually provides some evidence that there may be efficacy there,” Dr. Sanacora said.

Although he cautioned that this was a small study, and thus further research with a larger patient population will be needed, it provides a compelling foundation to build upon.

“This study provides clear evidence to support a larger study to really give a definitive statement on the efficacy and safety of its use for PTSD. I don’t think this is the study that provides that definitive evidence, but it is a very strong indication, and it very strongly supports the initiation of a large study to address that,” said Dr. Sanacora.

He noted that, although he’s used the term “cautious optimism” for studies in the past, he has “real optimism” that ketamine will be effective for PTSD based on the results of this current study.

“We still need some more data to really convince us of that before we can say with any clear statement that it is effective and safe, but I’m very optimistic,” Dr. Sanacora concluded. “I think the data are very strong.”

The study was funded by the Brain and Behavior Research Foundation, Mount Sinai Innovation Partners and the Mount Sinai i3 Accelerator, Gerald and Glenda Greenwald, and the Ehrenkranz Laboratory for Human Resilience. Dr. Feder is a coinventor on issued patents for the use of ketamine as therapy for PTSD. A list of all disclosures for the other study authors are listed in the original article.

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

Repeated intravenous infusions of ketamine provide rapid relief for patients with posttraumatic stress disorder, new research suggests.

In what investigators are calling the first randomized controlled trial of repeated ketamine administration for chronic PTSD, 30 patients received six infusions of ketamine or midazolam (used as a psychoactive placebo) over 2 consecutive weeks. 

Between baseline and week 2, those receiving ketamine showed significantly greater improvement than those receiving midazolam. Total scores on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) for the first group were almost 12 points lower than the latter group at week 2, meeting the study’s primary outcome measure.

In addition, 67% vs. 20% of the patients, respectively, were considered to be treatment responders; time to loss of response for those in the ketamine group was 28 days.

Although the overall findings were as expected, “what was surprising was how robust the results were,” lead author Adriana Feder, MD, associate professor of psychiatry, Icahn School of Medicine, Mount Sinai, New York, told this news organization.

It was also a bit surprising that, in a study of just 30 participants, “we were able to show such a clear difference” between the two treatment groups, said Dr. Feder, who is also a coinventor on issued patents for the use of ketamine as therapy for PTSD, and codirector of the Ehrenkranz Lab for the Study of Human Resilience at Mount Sinai.

The findings were published online Jan. 5 in the American Journal of Psychiatry.
 

Unmet need

Ketamine is a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist that was first approved by the U.S. Food and Drug Administration for anesthetic use in 1970. It has also been shown to be effective for treatment-resistant depression.

PTSD has a lifetime prevalence of about 6% in the United States. “While trauma-focused psychotherapies have the most empirical support, they are limited by significant rates of nonresponse, partial response, and treatment dropout,” the investigators write. Also, there are “few available pharmacotherapies for PTSD, and their efficacy is insufficient,” they add.  

“There’s a real need for new treatment interventions that are effective for PTSD and also work rapidly, because it can take weeks to months for currently available treatments to work for PTSD,” Dr. Feder said.

The researchers previously conducted a “proof-of-concept” randomized controlled trial of single infusions of ketamine for chronic PTSD. Results published in 2014 in JAMA Psychiatry showed significant reduction in PTSD symptoms 24 hours after infusion.

For the current study, the investigative team wanted to assess whether ketamine was viable as a longer-term treatment.

“We were encouraged by our initial promising findings” of the earlier trial, Dr. Feder said. “We wanted to do the second study to see if ketamine really works for PTSD, to see if we could replicate the rapid improvement and also examine whether a course of six infusions over 2 weeks could maintain the improvement.”

Thirty patients (aged 18-70; mean age, 39 years) with chronic PTSD from civilian or military trauma were enrolled (mean PTSD duration, 15 years).

The most cited primary trauma was sexual assault or molestation (n = 13), followed by physical assault or abuse (n = 8), witnessing a violent assault or death (n = 4), witnessing the 9/11 attacks (n = 3), and combat exposure (n = 2).

During the 2-week treatment phase, half of the patients were randomly assigned to receive six infusions of ketamine hydrochloride at a dose of 0.5 mg/kg (86.7% women; mean CAPS-5 score, 42), while the other half received six infusions of midazolam at a dose of 0.045 mg/kg (66.7% women; mean CAPS-5 score, 40).

In addition to the primary outcome measure of 2-week changes on the CAPS-5, secondary outcomes included score changes on the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Impact of Event Scale-Revised (IES-R).

Treatment response was defined as a 30% or more improvement in symptoms on the CAPS-5. A number of measures were also used to assess potential treatment-related adverse events (AEs).
 

Safe, effective

Results showed significantly lower total CAPS-5 scores for the ketamine group vs. the midazolam group at week 1 (score difference, 8.8 points; P = .03) and at week 2 (score difference, 11.88 points; P = .004).

Those receiving ketamine also showed improvements in three of the four PTSD symptom clusters on the CAPS-5: avoidance (P < .0001), negative mood and cognitions (P = .02), and intrusions (P = .03). The fourth symptom cluster – arousal and reactivity – did not show a significant improvement.

In addition, the ketamine group showed significantly greater improvement scores on the MADRS at both week 1 and week 2.

Treatment response at 2 weeks was achieved by 10 members of the ketamine group and by three members of the midazolam group (P = .03).

Secondary analyses showed rapid improvement in the treatment responders within the ketamine group, with a mean change of 26 points on the total IES-R score between baseline and 24 hours after their first infusion, and a mean change of 13.4 points on the MADRS total past-24-hour score, a 53% improvement on average.

“A response at 2 weeks is very rapid but they got better sometimes within the first day,” Dr. Feder noted.

There were no serious AEs reported. Although some dissociative symptoms occurred during ketamine infusions, with the highest levels reported at the end of the infusion, these symptoms had resolved by the next assessment, conducted 2 hours after infusion.

The most frequently reported AE in the ketamine group, compared with midazolam, after the start of infusions was blurred vision (53% vs. 0%), followed by dizziness (33% vs. 13%), fatigue (33% vs. 87%), headache (27% vs. 13%), and nausea or vomiting (20% vs. 7%).
 

‘Large-magnitude improvement’

The overall findings show that, in this patient population, “repeated intravenous ketamine infusions administered over 2 weeks were associated with a large-magnitude, clinically significant improvement in PTSD symptoms,” the investigators write.

The results “were very satisfying,” added Dr. Feder. “It was heartening also to hear what some of the participants would say. Some told us about how their symptoms and feelings had changed during the course of treatment with ketamine, where they felt stronger and better able to cope with their trauma and memories.”

She noted, however, that this was not a study designed to specifically assess ketamine in treatment-resistant PTSD. “Some patients had had multiple treatments before that hadn’t worked, while others had not received treatment before. Efficacy for treatment-resistant PTSD is an important question for future research,” Dr. Feder said.

Other areas worth future exploration include treatment efficacy in patients with different types of trauma and whether outcomes can last longer in patients receiving ketamine plus psychotherapy treatment, she noted.

“I don’t want to ignore the fact that currently available treatments work for a number of people with chronic PTSD. But because there are many more for whom [the treatments] don’t work, or they’re insufficiently helped by those treatments, this is certainly one potentially very promising approach that can be added” to a clinician’s toolbox, Dr. Feder said.
 

Speaks to clinical utility

Commenting for this news organization, Gerard Sanacora, MD, PhD, professor of psychiatry at Yale University, New Haven, Connecticut, called this a “very solid and well-designed” study.

“It definitely builds on what’s been found in the past, but it’s a critical piece of information speaking to the clinical utility of this treatment for PTSD,” said Dr. Sanacora, who is also director of the Yale Depression Research Program and was not involved with the current research.

He agreed with the investigators that PTSD has long been a condition that is difficult to treat.

“It’s an area that has a great unmet need for treatment options. Beyond that, as ketamine is becoming more widely used, there’s increasing demand for off-label uses. This [study] actually provides some evidence that there may be efficacy there,” Dr. Sanacora said.

Although he cautioned that this was a small study, and thus further research with a larger patient population will be needed, it provides a compelling foundation to build upon.

“This study provides clear evidence to support a larger study to really give a definitive statement on the efficacy and safety of its use for PTSD. I don’t think this is the study that provides that definitive evidence, but it is a very strong indication, and it very strongly supports the initiation of a large study to address that,” said Dr. Sanacora.

He noted that, although he’s used the term “cautious optimism” for studies in the past, he has “real optimism” that ketamine will be effective for PTSD based on the results of this current study.

“We still need some more data to really convince us of that before we can say with any clear statement that it is effective and safe, but I’m very optimistic,” Dr. Sanacora concluded. “I think the data are very strong.”

The study was funded by the Brain and Behavior Research Foundation, Mount Sinai Innovation Partners and the Mount Sinai i3 Accelerator, Gerald and Glenda Greenwald, and the Ehrenkranz Laboratory for Human Resilience. Dr. Feder is a coinventor on issued patents for the use of ketamine as therapy for PTSD. A list of all disclosures for the other study authors are listed in the original article.

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

Chronic kidney disease (CKD) is a significant comorbidity of diabetes mellitus. The Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney Foundation defines CKD as the presence of kidney damage or decreased kidney function for ≥ 3 months. CKD caused by diabetes is called diabetic kidney disease (DKD), which is 1 of 3 principal microvascular complications of diabetes. DKD can progress to end-stage renal disease (ESRD), requiring kidney replacement therapy, and is the leading cause of CKD and ESRD in the United States.^1-3 Studies have also shown that, particularly in patients with diabetes, CKD considerably increases the risk of cardiovascular events, which often occur prior to ESRD.^1,4

This article provides the latest recommendations for evaluating and managing DKD to help you prevent or slow its progression.

Defining and categorizing diabetic kidney disease

CKD is defined as persistently elevated excretion of urinary albumin (albuminuria) and decreased estimated glomerular filtration rate (eGFR), or as the presence of signs of progressive kidney damage.^5,6 DKD, also known as diabetic nephropathy, is CKD attributed to long-term diabetes. A patient’s eGFR is the established basis for assignment to a stage (1, 2, 3a, 3b, 4, or 5) of CKD (TABLE 1⁷) and, along with the category of albuminuria (A1, A2, or A3), can indicate prognosis.

Taking its toll in diabetes

As many as 40% of patients with diabetes develop DKD.^8-10 Most studies of DKD have been conducted in patients with type 1 diabetes (T1D), because the time of clinical onset is typically known.

Type 1 diabetes. DKD usually occurs 10 to 15 years, or later, after the onset of diabetes.⁶ As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.^5,11 After approximately 22.5 years without albuminuria, patients with T1D have approximately a 1% annual risk of DKD.¹²

Type 2 diabetes (T2D). DKD is often present at diagnosis, likely due to a delay in diagnosis and briefer clinical exposure, compared to T1D. Albuminuria has been reported in as many as 40% of patients with T2D approximately 10 years after onset of diabetes.^12,13

Multiple risk factors with no standout “predictor”

Genetic susceptibility, ethnicity, glycemic control, smoking, blood pressure (BP), and the eGFR have been identified as risk factors for renal involvement in diabetes; obesity, oral contraceptives, and age can also contribute. Although each risk factor increases the risk of DKD, no single factor is adequately predictive. Moderately increased albuminuria, the earliest sign of DKD, is associated with progressive nephropathy.¹²

Continue to: How great is the risk?

How great is the risk? From disease onset to proteinuria and from proteinuria to ESRD, the risk of DKD in T1D and T2D is similar. With appropriate treatment, albuminuria can regress, and the risk of ESRD can be < 20% at 10 years in T1D.¹² As in T1D, good glycemic control might result in regression of albuminuria in T2D.¹⁴

As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.

For unknown reasons, the degree of albuminuria can exist independent of the progression of DKD. Factors responsible for a progressive decline in eGFR in DKD without albuminuria are unknown.^12,15

Patient evaluation with an eye toward comorbidities

A comprehensive initial medical evaluation for DKD includes a review of microvascular complications; visits to specialists; lifestyle and behavior patterns (eg, diet, sleep, substance use, and social support); and medication adherence, adverse drug effects, and alternative medicines. Although DKD is often a clinical diagnosis, it can be ruled in by persistent albuminuria or decreased eGFR, or both, in established diabetes or diabetic retinopathy when other causes are unlikely (see “Recommended DKD screening protocol,” below).

Screening for mental health conditions and barriers to self-management is also key.⁶

Comorbidities, of course, can complicate disease management in patients with diabetes.^16-20 Providers and patients therefore need to be aware of potential diabetic comorbidities. For example, DKD and even moderately increased albuminuria significantly increase the risk of cardiovascular disease (CVD).¹² Other possible comorbidities include (but are not limited to) nonalcoholic steatohepatitis, fracture, hearing impairment, cancer (eg, liver, pancreas, endometrium, colon, rectum, breast, and bladder), pancreatitis, hypogonadism, obstructive sleep apnea, periodontal disease, anxiety, depression, and eating disorders.⁶

Continue to: Recommended DKD screening protocol

In all cases of T2D, in cases of T1D of ≥ 5 years’ duration, and in patients with diabetes and comorbid hypertension, perform annual screening for albuminuria, an elevated creatinine level, and a decline in eGFR.

Screen for potential comorbidities of DKD: For example, the risk of cardiovascular disease is significantly elevated in even moderately increased albuminuria.

To confirm the diagnosis of DKD, at least 2 of 3 urine specimens must demonstrate an elevated urinary albumin:creatinine ratio (UACR) over a 3- to 6-month period.²¹ Apart from renal damage, exercise within 24 hours before specimen collection, infection, fever, congestive heart failure, hyperglycemia, menstruation, and hypertension can elevate the UACR.⁶

Levels of the UACR are established as follows²²:

• Normal UACR is defined as < 30 milligrams of albumin per gram of creatinine (expressed as “mg/g”).
• Increased urinary albumin excretion is defined as ≥ 30 mg/g.
• Moderately increased albuminuria, a predictor of potential nephropathy, is the excretion of 30 to 300 mg/g.
• Severely increased albuminuria is excretion > 300 mg/g; it is often followed by a gradual decline in eGFR that, without treatment, eventually leads to ESRD.

The rate of decline in eGFR once albuminuria is severely increased is equivalent in T1D and T2D.¹² Without intervention, the time from severely increased albuminuria to ESRD in T1D and T2D averages approximately 6 or 7 years.

Clinical features

DKD is typically a clinical diagnosis seen in patients with longstanding diabetes, albuminuria, retinopathy, or a reduced eGFR in the absence of another primary cause of kidney damage. In patients with T1D and DKD, signs of retinopathy and neuropathy are almost always present at diagnosis, unless a diagnosis is made early in the course of diabetes.¹² Therefore, the presence of retinopathy suggests that diabetes is the likely cause of CKD.

Continue to: The presence of microvascular disease...

The presence of microvascular disease in patients with T2D and DKD is less predictable.¹² In T2D patients who do not have retinopathy, consider causes of CKD other than DKD. Features suggesting that the cause of CKD is an underlying condition other than diabetes are rapidly increasing albuminuria or decreasing eGFR; urinary sediment comprising red blood cells or white blood cells; and nephrotic syndrome.⁶

As the prevalence of diabetes increases, it has become more common to diagnose DKD by eGFR without albuminuria—underscoring the importance of routine monitoring of eGFR in patients with diabetes.⁶

Sources of expert guidance. The Chronic Kidney Disease Epidemiology Collaboration equation²³ is preferred for calculating eGFR from serum creatinine: An eGFR < 60 mL/min/1.73 m² is considered abnormal.^3,12 At these rates, the prevalence of complications related to CKD rises and screening for complications becomes necessary.

A more comprehensive classification of the stages of CKD, incorporating albuminuria and progression of CKD, has been recommended by Kidney Disease: Improving Global Outcomes (KDIGO).⁷ Because eGFR and excretion of albumin vary, abnormal test results need to be verified over time to stage the degree of CKD.^3,12 Kidney damage often manifests as albuminuria, but also as hematuria, other types of abnormal urinary sediment, radiographic abnormalities, and other abnormal presentations.

Management

Nutritional factors

Excessive protein intake has been shown to increase albuminuria, worsen renal function, and increase CVD mortality in DKD.^24-26 Therefore, daily dietary protein intake of 0.8 g/kg body weight is recommended for patients who are not on dialysis.³ Patients on dialysis might require higher protein intake to preserve muscle mass caused by protein-energy wasting, which is common in dialysis patients.⁶

Continue to: Low sodium intake

Low sodium intake in CKD patients has been shown to decrease BP and thus slow the progression of renal disease and lower the risk of CVD. The recommended dietary sodium intake in CKD patients is 1500-3000 mg/d.³

Low potassium intake. Hyperkalemia is a serious complication of CKD. A low-potassium diet is recommended in ESRD patients who have a potassium level > 5.5 mEq/L.⁶

Blood pressure

Preventing and treating hypertension is critical to slowing the progression of CKD and reducing cardiovascular risk. BP should be measured at every clinic visit. Aside from lifestyle changes, medication might be needed to reach target BP.

The American Diabetes Association recommends a BP goal of ≤ 140/90 mm Hg for hypertensive patients with diabetes, although they do state that a lower BP target (≤ 130/80 mm Hg) might be more appropriate for patients with DKD.²⁷

The American College of Cardiology recommends that hypertensive patients with CKD have a BP target of ≤ 130/80 mm Hg.²⁸

Continue to: ACE inhibitors and ARBs

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have renoprotective benefits. These agents are recommended as first-line medications for patients with diabetes, hypertension, and an eGFR < 60 mL/min/1.73 m² and a UACR > 300 mg/g.^29-31 Evidence also supports their use when the UACR is 30 to 299 mg/g.

Studies have shown that, in patients with DKD, ACE inhibitors and ARBs can slow the progression of renal disease.^29,30,32 There is no difference between ACE inhibitors and ARBs in their effectiveness for preventing progression of DKD.⁶ There is no added benefit in combining an ACE inhibitor and an ARB³³; notably, combination ACE inhibitor and ARB therapy can increase the risk of adverse events, such as hyperkalemia and acute kidney injury, especially in patients with DKD.³³

There is no evidence for starting an ACE inhibitor or ARB to prevent CKD in patients with diabetes who are not hypertensive.⁵

ACE inhibitors and ARBs should be used with caution in women of childbearing age, who should use a reliable form of contraception if taking one of these drugs.

Diuretics. Thiazide-type and loop diuretics might potentiate the positive effects of ACE inhibitors and ARBs. KDOQI guidelines recommend that, in patients who require a second agent to control BP, a diuretic should be considered in combination with an ACE inhibitor or an ARB.²⁰ A loop diuretic is preferred if the eGFR is < 30 mL/min/1.73 m².

Continue to: Nondihydropyridine calcium-channel blockers

Nondihydropyridine calcium-channel blockers (CCBs), such as diltiazem and verapamil, have been shown to be more effective then dihydrophyridine CCBs, such as amlodipine and nifedipine, in slowing the progression of renal disease because of their antiproteinuric effects. However, the antiproteinuric effects of nondihydropyridine CCBs are not as strong as those of ACE inhibitors or ARBs, and these drugs do not appear to potentiate the effects of an ACE inhibitor or ARB when used in combination.²⁰

Confirmation of suspected DKD requires an elevated albumin:creatinine ratio in at least 2 of 3 urine specimens over a 3- to 6-month period.

Nondihydropyridine CCBs might be a reasonable alternative in patients who cannot tolerate an ACE inhibitor or an ARB.

Mineralocorticoid receptor antagonists in combination with an ACE inhibitor or ARB have been demonstrated to reduce albuminuria in short-term studies.^34,35

Glycemic levels

Studies conducted in patients with T1D, and others in patients with T2D, have shown that tight glycemic control can delay the onset and slow the progression of albuminuria and a decline in the eGFR.^10,36-39 The target glycated hemoglobin (A1C) should be < 7% to prevent or slow progression of DKD.⁴⁰ However, patients with DKD have an increased risk of hypoglycemic events and increased mortality with more intensive glycemic control.^40,41 Given those findings, some patients with DKD and significant comorbidities, ESRD, or limited life expectancy might need to have an A1C target set at 8%.^6,42

Adjustments to antidiabetes medications in DKD

In patients with stages 3 to 5 DKD, several common antidiabetic medications might need to be adjusted or discontinued because they decrease creatinine clearance.

Continue to: First-generation sulfonylureas

First-generation sulfonylureas should be avoided in DKD. Glipizide and gliclazide are preferred among second-generation sulfonylureas because they do not increase the risk of hypoglycemia in DKD patients, although patients taking these medications still require close monitoring of their blood glucose level.²⁰

Metformin. In 2016, recommendations changed for the use of metformin in patients with DKD: The eGFR, not the serum creatinine level, should guide treatment.⁴³ Metformin can be used safely in patients with (1) an eGFR of < 60 mL/min/1.73 m² and (2) an eGFR of 30 mL/min/1.73 m² with close monitoring. Metformin should not be initiated if the eGFR is < 45 mL/min/1.73 m².⁴³ 

Antidiabetes medications with direct effect on the kidney

Several antidiabetes medications have a direct effect on the kidney apart from their effect on the blood glucose level.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce albuminuria and slow the decrease of eGFR independent of glycemic control. In addition, SGLT2 inhibitors have also been shown to have cardiovascular benefits in patients with DKD.^44,45 

Glucagon-like peptide 1 (GLP-1) receptor agonists have been shown to delay and decrease the progression of DKD.^46-48 Also, similar to what is seen with SGLT2 inhibitors, GLP-1 agonists have demonstrable cardiovascular benefit in patients with DKD.^46,48

Continue to: Dyslipidemia and DKD

Because the risk of CVD is increased in patients with DKD, addressing other modifiable risk factors, including dyslipidemia, is recommended in these patients. Patients with diabetes and stages 1 to 4 DKD should be treated with a high-intensity statin or a combination of a statin and ezetimibe.^49,50

Tight glycemic control in T1D and T2D can delay the onset, and slow the progression, of albuminuria and a decline in the eGFR.

If a patient is taking a statin and starting dialysis, it’s important to discuss with him or her whether to continue the statin, based on perceived benefits and risks. It is not recommended that statins be initiated in patients on dialysis unless there is a specific cardiovascular indication for doing so. Risk reduction with a statin has been shown to be significantly less in dialysis patients than in patients who are not being treated with dialysis.⁴⁹

Complications of CKD

Anemia is a common complication of CKD. KDIGO recommends measuring the ­hemoglobin concentration annually in DKD stage 3 patients without anemia; at least every 6 months in stage 4 patients; and at least every 3 months in stage 5. DKD patients with anemia should have additional laboratory testing: the absolute reticulocyte count, serum ferritin, serum transferrin saturation, vitamin B12, and folate.⁵¹

Mineral and bone disorder should be screened for in patients with DKD. TABLE 2⁵² outlines when clinical laboratory tests should be ordered to assess for mineral bone disease.

When to refer to a nephrologist

Refer patients with stage 4 or 5 CKD (eGFR, ≤ 30 mL/min/1.73 m²) to a nephrologist for discussion of kidney replacement therapy.⁶ Patients with stage 3a CKD and severely increased albuminuria or with stage 3b CKD and moderately or severely increased albuminuria should also be referred to a nephrologist for intervention to delay disease progression.

Continue to: Identifying the need for early referral...

Nutritional control is important in DKD: A lowsodium diet can slow progression of DKD, and a low-potassium diet can prevent hyperkalemia in end-stage renal disease.

Identifying the need for early referral to a nephrologist has been shown to reduce the cost, and improve the quality, of care.⁵³ Other indications for earlier referral include uncertainty about the etiology of renal disease, persistent or severe albuminuria, persistent hematuria, a rapid decline in eGFR, and acute kidney injury. Additionally, referral at an earlier stage of DKD might be needed to assist with complications associated with DKD, such as anemia, secondary hyperparathyroidism, mineral and bone disorder, resistant hypertension, fluid overload, and electrolyte disturbances.⁶

ACKNOWLEDGEMENT
The authors thank Colleen Colbert, PhD, and Iqbal Ahmad, PhD, for their review and critique of the manuscript of this article. They also thank Christopher Babiuch, MD, for his guidance in the preparation of the manuscript.

CORRESPONDENCE
Faraz Ahmad, MD, MPH, Care Point East Family Medicine, 543 Taylor Avenue, 2nd floor, Columbus, OH 43203; faraz. [email protected].

Chronic kidney disease (CKD) is a significant comorbidity of diabetes mellitus. The Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney Foundation defines CKD as the presence of kidney damage or decreased kidney function for ≥ 3 months. CKD caused by diabetes is called diabetic kidney disease (DKD), which is 1 of 3 principal microvascular complications of diabetes. DKD can progress to end-stage renal disease (ESRD), requiring kidney replacement therapy, and is the leading cause of CKD and ESRD in the United States.^1-3 Studies have also shown that, particularly in patients with diabetes, CKD considerably increases the risk of cardiovascular events, which often occur prior to ESRD.^1,4

This article provides the latest recommendations for evaluating and managing DKD to help you prevent or slow its progression.

Defining and categorizing diabetic kidney disease

CKD is defined as persistently elevated excretion of urinary albumin (albuminuria) and decreased estimated glomerular filtration rate (eGFR), or as the presence of signs of progressive kidney damage.^5,6 DKD, also known as diabetic nephropathy, is CKD attributed to long-term diabetes. A patient’s eGFR is the established basis for assignment to a stage (1, 2, 3a, 3b, 4, or 5) of CKD (TABLE 1⁷) and, along with the category of albuminuria (A1, A2, or A3), can indicate prognosis.

Taking its toll in diabetes

As many as 40% of patients with diabetes develop DKD.^8-10 Most studies of DKD have been conducted in patients with type 1 diabetes (T1D), because the time of clinical onset is typically known.

Type 1 diabetes. DKD usually occurs 10 to 15 years, or later, after the onset of diabetes.⁶ As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.^5,11 After approximately 22.5 years without albuminuria, patients with T1D have approximately a 1% annual risk of DKD.¹²

Type 2 diabetes (T2D). DKD is often present at diagnosis, likely due to a delay in diagnosis and briefer clinical exposure, compared to T1D. Albuminuria has been reported in as many as 40% of patients with T2D approximately 10 years after onset of diabetes.^12,13

Multiple risk factors with no standout “predictor”

Genetic susceptibility, ethnicity, glycemic control, smoking, blood pressure (BP), and the eGFR have been identified as risk factors for renal involvement in diabetes; obesity, oral contraceptives, and age can also contribute. Although each risk factor increases the risk of DKD, no single factor is adequately predictive. Moderately increased albuminuria, the earliest sign of DKD, is associated with progressive nephropathy.¹²

Continue to: How great is the risk?

How great is the risk? From disease onset to proteinuria and from proteinuria to ESRD, the risk of DKD in T1D and T2D is similar. With appropriate treatment, albuminuria can regress, and the risk of ESRD can be < 20% at 10 years in T1D.¹² As in T1D, good glycemic control might result in regression of albuminuria in T2D.¹⁴

As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.

For unknown reasons, the degree of albuminuria can exist independent of the progression of DKD. Factors responsible for a progressive decline in eGFR in DKD without albuminuria are unknown.^12,15

Patient evaluation with an eye toward comorbidities

A comprehensive initial medical evaluation for DKD includes a review of microvascular complications; visits to specialists; lifestyle and behavior patterns (eg, diet, sleep, substance use, and social support); and medication adherence, adverse drug effects, and alternative medicines. Although DKD is often a clinical diagnosis, it can be ruled in by persistent albuminuria or decreased eGFR, or both, in established diabetes or diabetic retinopathy when other causes are unlikely (see “Recommended DKD screening protocol,” below).

Screening for mental health conditions and barriers to self-management is also key.⁶

Comorbidities, of course, can complicate disease management in patients with diabetes.^16-20 Providers and patients therefore need to be aware of potential diabetic comorbidities. For example, DKD and even moderately increased albuminuria significantly increase the risk of cardiovascular disease (CVD).¹² Other possible comorbidities include (but are not limited to) nonalcoholic steatohepatitis, fracture, hearing impairment, cancer (eg, liver, pancreas, endometrium, colon, rectum, breast, and bladder), pancreatitis, hypogonadism, obstructive sleep apnea, periodontal disease, anxiety, depression, and eating disorders.⁶

Continue to: Recommended DKD screening protocol

In all cases of T2D, in cases of T1D of ≥ 5 years’ duration, and in patients with diabetes and comorbid hypertension, perform annual screening for albuminuria, an elevated creatinine level, and a decline in eGFR.

Screen for potential comorbidities of DKD: For example, the risk of cardiovascular disease is significantly elevated in even moderately increased albuminuria.

To confirm the diagnosis of DKD, at least 2 of 3 urine specimens must demonstrate an elevated urinary albumin:creatinine ratio (UACR) over a 3- to 6-month period.²¹ Apart from renal damage, exercise within 24 hours before specimen collection, infection, fever, congestive heart failure, hyperglycemia, menstruation, and hypertension can elevate the UACR.⁶

Levels of the UACR are established as follows²²:

• Normal UACR is defined as < 30 milligrams of albumin per gram of creatinine (expressed as “mg/g”).
• Increased urinary albumin excretion is defined as ≥ 30 mg/g.
• Moderately increased albuminuria, a predictor of potential nephropathy, is the excretion of 30 to 300 mg/g.
• Severely increased albuminuria is excretion > 300 mg/g; it is often followed by a gradual decline in eGFR that, without treatment, eventually leads to ESRD.

The rate of decline in eGFR once albuminuria is severely increased is equivalent in T1D and T2D.¹² Without intervention, the time from severely increased albuminuria to ESRD in T1D and T2D averages approximately 6 or 7 years.

Clinical features

DKD is typically a clinical diagnosis seen in patients with longstanding diabetes, albuminuria, retinopathy, or a reduced eGFR in the absence of another primary cause of kidney damage. In patients with T1D and DKD, signs of retinopathy and neuropathy are almost always present at diagnosis, unless a diagnosis is made early in the course of diabetes.¹² Therefore, the presence of retinopathy suggests that diabetes is the likely cause of CKD.

Continue to: The presence of microvascular disease...

The presence of microvascular disease in patients with T2D and DKD is less predictable.¹² In T2D patients who do not have retinopathy, consider causes of CKD other than DKD. Features suggesting that the cause of CKD is an underlying condition other than diabetes are rapidly increasing albuminuria or decreasing eGFR; urinary sediment comprising red blood cells or white blood cells; and nephrotic syndrome.⁶

As the prevalence of diabetes increases, it has become more common to diagnose DKD by eGFR without albuminuria—underscoring the importance of routine monitoring of eGFR in patients with diabetes.⁶

Sources of expert guidance. The Chronic Kidney Disease Epidemiology Collaboration equation²³ is preferred for calculating eGFR from serum creatinine: An eGFR < 60 mL/min/1.73 m² is considered abnormal.^3,12 At these rates, the prevalence of complications related to CKD rises and screening for complications becomes necessary.

A more comprehensive classification of the stages of CKD, incorporating albuminuria and progression of CKD, has been recommended by Kidney Disease: Improving Global Outcomes (KDIGO).⁷ Because eGFR and excretion of albumin vary, abnormal test results need to be verified over time to stage the degree of CKD.^3,12 Kidney damage often manifests as albuminuria, but also as hematuria, other types of abnormal urinary sediment, radiographic abnormalities, and other abnormal presentations.

Management

Nutritional factors

Excessive protein intake has been shown to increase albuminuria, worsen renal function, and increase CVD mortality in DKD.^24-26 Therefore, daily dietary protein intake of 0.8 g/kg body weight is recommended for patients who are not on dialysis.³ Patients on dialysis might require higher protein intake to preserve muscle mass caused by protein-energy wasting, which is common in dialysis patients.⁶

Continue to: Low sodium intake

Low sodium intake in CKD patients has been shown to decrease BP and thus slow the progression of renal disease and lower the risk of CVD. The recommended dietary sodium intake in CKD patients is 1500-3000 mg/d.³

Low potassium intake. Hyperkalemia is a serious complication of CKD. A low-potassium diet is recommended in ESRD patients who have a potassium level > 5.5 mEq/L.⁶

Blood pressure

Preventing and treating hypertension is critical to slowing the progression of CKD and reducing cardiovascular risk. BP should be measured at every clinic visit. Aside from lifestyle changes, medication might be needed to reach target BP.

The American Diabetes Association recommends a BP goal of ≤ 140/90 mm Hg for hypertensive patients with diabetes, although they do state that a lower BP target (≤ 130/80 mm Hg) might be more appropriate for patients with DKD.²⁷

The American College of Cardiology recommends that hypertensive patients with CKD have a BP target of ≤ 130/80 mm Hg.²⁸

Continue to: ACE inhibitors and ARBs

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have renoprotective benefits. These agents are recommended as first-line medications for patients with diabetes, hypertension, and an eGFR < 60 mL/min/1.73 m² and a UACR > 300 mg/g.^29-31 Evidence also supports their use when the UACR is 30 to 299 mg/g.

Studies have shown that, in patients with DKD, ACE inhibitors and ARBs can slow the progression of renal disease.^29,30,32 There is no difference between ACE inhibitors and ARBs in their effectiveness for preventing progression of DKD.⁶ There is no added benefit in combining an ACE inhibitor and an ARB³³; notably, combination ACE inhibitor and ARB therapy can increase the risk of adverse events, such as hyperkalemia and acute kidney injury, especially in patients with DKD.³³

There is no evidence for starting an ACE inhibitor or ARB to prevent CKD in patients with diabetes who are not hypertensive.⁵

ACE inhibitors and ARBs should be used with caution in women of childbearing age, who should use a reliable form of contraception if taking one of these drugs.

Diuretics. Thiazide-type and loop diuretics might potentiate the positive effects of ACE inhibitors and ARBs. KDOQI guidelines recommend that, in patients who require a second agent to control BP, a diuretic should be considered in combination with an ACE inhibitor or an ARB.²⁰ A loop diuretic is preferred if the eGFR is < 30 mL/min/1.73 m².

Continue to: Nondihydropyridine calcium-channel blockers

Nondihydropyridine calcium-channel blockers (CCBs), such as diltiazem and verapamil, have been shown to be more effective then dihydrophyridine CCBs, such as amlodipine and nifedipine, in slowing the progression of renal disease because of their antiproteinuric effects. However, the antiproteinuric effects of nondihydropyridine CCBs are not as strong as those of ACE inhibitors or ARBs, and these drugs do not appear to potentiate the effects of an ACE inhibitor or ARB when used in combination.²⁰

Confirmation of suspected DKD requires an elevated albumin:creatinine ratio in at least 2 of 3 urine specimens over a 3- to 6-month period.

Nondihydropyridine CCBs might be a reasonable alternative in patients who cannot tolerate an ACE inhibitor or an ARB.

Mineralocorticoid receptor antagonists in combination with an ACE inhibitor or ARB have been demonstrated to reduce albuminuria in short-term studies.^34,35

Glycemic levels

Studies conducted in patients with T1D, and others in patients with T2D, have shown that tight glycemic control can delay the onset and slow the progression of albuminuria and a decline in the eGFR.^10,36-39 The target glycated hemoglobin (A1C) should be < 7% to prevent or slow progression of DKD.⁴⁰ However, patients with DKD have an increased risk of hypoglycemic events and increased mortality with more intensive glycemic control.^40,41 Given those findings, some patients with DKD and significant comorbidities, ESRD, or limited life expectancy might need to have an A1C target set at 8%.^6,42

Adjustments to antidiabetes medications in DKD

In patients with stages 3 to 5 DKD, several common antidiabetic medications might need to be adjusted or discontinued because they decrease creatinine clearance.

Continue to: First-generation sulfonylureas

First-generation sulfonylureas should be avoided in DKD. Glipizide and gliclazide are preferred among second-generation sulfonylureas because they do not increase the risk of hypoglycemia in DKD patients, although patients taking these medications still require close monitoring of their blood glucose level.²⁰

Metformin. In 2016, recommendations changed for the use of metformin in patients with DKD: The eGFR, not the serum creatinine level, should guide treatment.⁴³ Metformin can be used safely in patients with (1) an eGFR of < 60 mL/min/1.73 m² and (2) an eGFR of 30 mL/min/1.73 m² with close monitoring. Metformin should not be initiated if the eGFR is < 45 mL/min/1.73 m².⁴³ 

Antidiabetes medications with direct effect on the kidney

Several antidiabetes medications have a direct effect on the kidney apart from their effect on the blood glucose level.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce albuminuria and slow the decrease of eGFR independent of glycemic control. In addition, SGLT2 inhibitors have also been shown to have cardiovascular benefits in patients with DKD.^44,45 

Glucagon-like peptide 1 (GLP-1) receptor agonists have been shown to delay and decrease the progression of DKD.^46-48 Also, similar to what is seen with SGLT2 inhibitors, GLP-1 agonists have demonstrable cardiovascular benefit in patients with DKD.^46,48

Continue to: Dyslipidemia and DKD

Because the risk of CVD is increased in patients with DKD, addressing other modifiable risk factors, including dyslipidemia, is recommended in these patients. Patients with diabetes and stages 1 to 4 DKD should be treated with a high-intensity statin or a combination of a statin and ezetimibe.^49,50

Tight glycemic control in T1D and T2D can delay the onset, and slow the progression, of albuminuria and a decline in the eGFR.

If a patient is taking a statin and starting dialysis, it’s important to discuss with him or her whether to continue the statin, based on perceived benefits and risks. It is not recommended that statins be initiated in patients on dialysis unless there is a specific cardiovascular indication for doing so. Risk reduction with a statin has been shown to be significantly less in dialysis patients than in patients who are not being treated with dialysis.⁴⁹

Complications of CKD

Anemia is a common complication of CKD. KDIGO recommends measuring the ­hemoglobin concentration annually in DKD stage 3 patients without anemia; at least every 6 months in stage 4 patients; and at least every 3 months in stage 5. DKD patients with anemia should have additional laboratory testing: the absolute reticulocyte count, serum ferritin, serum transferrin saturation, vitamin B12, and folate.⁵¹

Mineral and bone disorder should be screened for in patients with DKD. TABLE 2⁵² outlines when clinical laboratory tests should be ordered to assess for mineral bone disease.

When to refer to a nephrologist

Refer patients with stage 4 or 5 CKD (eGFR, ≤ 30 mL/min/1.73 m²) to a nephrologist for discussion of kidney replacement therapy.⁶ Patients with stage 3a CKD and severely increased albuminuria or with stage 3b CKD and moderately or severely increased albuminuria should also be referred to a nephrologist for intervention to delay disease progression.

Continue to: Identifying the need for early referral...

Nutritional control is important in DKD: A lowsodium diet can slow progression of DKD, and a low-potassium diet can prevent hyperkalemia in end-stage renal disease.

Identifying the need for early referral to a nephrologist has been shown to reduce the cost, and improve the quality, of care.⁵³ Other indications for earlier referral include uncertainty about the etiology of renal disease, persistent or severe albuminuria, persistent hematuria, a rapid decline in eGFR, and acute kidney injury. Additionally, referral at an earlier stage of DKD might be needed to assist with complications associated with DKD, such as anemia, secondary hyperparathyroidism, mineral and bone disorder, resistant hypertension, fluid overload, and electrolyte disturbances.⁶

ACKNOWLEDGEMENT
The authors thank Colleen Colbert, PhD, and Iqbal Ahmad, PhD, for their review and critique of the manuscript of this article. They also thank Christopher Babiuch, MD, for his guidance in the preparation of the manuscript.

CORRESPONDENCE
Faraz Ahmad, MD, MPH, Care Point East Family Medicine, 543 Taylor Avenue, 2nd floor, Columbus, OH 43203; faraz. [email protected].

Chronic kidney disease (CKD) is a significant comorbidity of diabetes mellitus. The Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney Foundation defines CKD as the presence of kidney damage or decreased kidney function for ≥ 3 months. CKD caused by diabetes is called diabetic kidney disease (DKD), which is 1 of 3 principal microvascular complications of diabetes. DKD can progress to end-stage renal disease (ESRD), requiring kidney replacement therapy, and is the leading cause of CKD and ESRD in the United States.^1-3 Studies have also shown that, particularly in patients with diabetes, CKD considerably increases the risk of cardiovascular events, which often occur prior to ESRD.^1,4

This article provides the latest recommendations for evaluating and managing DKD to help you prevent or slow its progression.

Defining and categorizing diabetic kidney disease

CKD is defined as persistently elevated excretion of urinary albumin (albuminuria) and decreased estimated glomerular filtration rate (eGFR), or as the presence of signs of progressive kidney damage.^5,6 DKD, also known as diabetic nephropathy, is CKD attributed to long-term diabetes. A patient’s eGFR is the established basis for assignment to a stage (1, 2, 3a, 3b, 4, or 5) of CKD (TABLE 1⁷) and, along with the category of albuminuria (A1, A2, or A3), can indicate prognosis.

Taking its toll in diabetes

As many as 40% of patients with diabetes develop DKD.^8-10 Most studies of DKD have been conducted in patients with type 1 diabetes (T1D), because the time of clinical onset is typically known.

Type 1 diabetes. DKD usually occurs 10 to 15 years, or later, after the onset of diabetes.⁶ As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.^5,11 After approximately 22.5 years without albuminuria, patients with T1D have approximately a 1% annual risk of DKD.¹²

Type 2 diabetes (T2D). DKD is often present at diagnosis, likely due to a delay in diagnosis and briefer clinical exposure, compared to T1D. Albuminuria has been reported in as many as 40% of patients with T2D approximately 10 years after onset of diabetes.^12,13

Multiple risk factors with no standout “predictor”

Genetic susceptibility, ethnicity, glycemic control, smoking, blood pressure (BP), and the eGFR have been identified as risk factors for renal involvement in diabetes; obesity, oral contraceptives, and age can also contribute. Although each risk factor increases the risk of DKD, no single factor is adequately predictive. Moderately increased albuminuria, the earliest sign of DKD, is associated with progressive nephropathy.¹²

Continue to: How great is the risk?

How great is the risk? From disease onset to proteinuria and from proteinuria to ESRD, the risk of DKD in T1D and T2D is similar. With appropriate treatment, albuminuria can regress, and the risk of ESRD can be < 20% at 10 years in T1D.¹² As in T1D, good glycemic control might result in regression of albuminuria in T2D.¹⁴

As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.

For unknown reasons, the degree of albuminuria can exist independent of the progression of DKD. Factors responsible for a progressive decline in eGFR in DKD without albuminuria are unknown.^12,15

Patient evaluation with an eye toward comorbidities

A comprehensive initial medical evaluation for DKD includes a review of microvascular complications; visits to specialists; lifestyle and behavior patterns (eg, diet, sleep, substance use, and social support); and medication adherence, adverse drug effects, and alternative medicines. Although DKD is often a clinical diagnosis, it can be ruled in by persistent albuminuria or decreased eGFR, or both, in established diabetes or diabetic retinopathy when other causes are unlikely (see “Recommended DKD screening protocol,” below).

Screening for mental health conditions and barriers to self-management is also key.⁶

Comorbidities, of course, can complicate disease management in patients with diabetes.^16-20 Providers and patients therefore need to be aware of potential diabetic comorbidities. For example, DKD and even moderately increased albuminuria significantly increase the risk of cardiovascular disease (CVD).¹² Other possible comorbidities include (but are not limited to) nonalcoholic steatohepatitis, fracture, hearing impairment, cancer (eg, liver, pancreas, endometrium, colon, rectum, breast, and bladder), pancreatitis, hypogonadism, obstructive sleep apnea, periodontal disease, anxiety, depression, and eating disorders.⁶

Continue to: Recommended DKD screening protocol

In all cases of T2D, in cases of T1D of ≥ 5 years’ duration, and in patients with diabetes and comorbid hypertension, perform annual screening for albuminuria, an elevated creatinine level, and a decline in eGFR.

Screen for potential comorbidities of DKD: For example, the risk of cardiovascular disease is significantly elevated in even moderately increased albuminuria.

To confirm the diagnosis of DKD, at least 2 of 3 urine specimens must demonstrate an elevated urinary albumin:creatinine ratio (UACR) over a 3- to 6-month period.²¹ Apart from renal damage, exercise within 24 hours before specimen collection, infection, fever, congestive heart failure, hyperglycemia, menstruation, and hypertension can elevate the UACR.⁶

Levels of the UACR are established as follows²²:

• Normal UACR is defined as < 30 milligrams of albumin per gram of creatinine (expressed as “mg/g”).
• Increased urinary albumin excretion is defined as ≥ 30 mg/g.
• Moderately increased albuminuria, a predictor of potential nephropathy, is the excretion of 30 to 300 mg/g.
• Severely increased albuminuria is excretion > 300 mg/g; it is often followed by a gradual decline in eGFR that, without treatment, eventually leads to ESRD.

The rate of decline in eGFR once albuminuria is severely increased is equivalent in T1D and T2D.¹² Without intervention, the time from severely increased albuminuria to ESRD in T1D and T2D averages approximately 6 or 7 years.

Clinical features

DKD is typically a clinical diagnosis seen in patients with longstanding diabetes, albuminuria, retinopathy, or a reduced eGFR in the absence of another primary cause of kidney damage. In patients with T1D and DKD, signs of retinopathy and neuropathy are almost always present at diagnosis, unless a diagnosis is made early in the course of diabetes.¹² Therefore, the presence of retinopathy suggests that diabetes is the likely cause of CKD.

Continue to: The presence of microvascular disease...

The presence of microvascular disease in patients with T2D and DKD is less predictable.¹² In T2D patients who do not have retinopathy, consider causes of CKD other than DKD. Features suggesting that the cause of CKD is an underlying condition other than diabetes are rapidly increasing albuminuria or decreasing eGFR; urinary sediment comprising red blood cells or white blood cells; and nephrotic syndrome.⁶

As the prevalence of diabetes increases, it has become more common to diagnose DKD by eGFR without albuminuria—underscoring the importance of routine monitoring of eGFR in patients with diabetes.⁶

Sources of expert guidance. The Chronic Kidney Disease Epidemiology Collaboration equation²³ is preferred for calculating eGFR from serum creatinine: An eGFR < 60 mL/min/1.73 m² is considered abnormal.^3,12 At these rates, the prevalence of complications related to CKD rises and screening for complications becomes necessary.

A more comprehensive classification of the stages of CKD, incorporating albuminuria and progression of CKD, has been recommended by Kidney Disease: Improving Global Outcomes (KDIGO).⁷ Because eGFR and excretion of albumin vary, abnormal test results need to be verified over time to stage the degree of CKD.^3,12 Kidney damage often manifests as albuminuria, but also as hematuria, other types of abnormal urinary sediment, radiographic abnormalities, and other abnormal presentations.

Management

Nutritional factors

Excessive protein intake has been shown to increase albuminuria, worsen renal function, and increase CVD mortality in DKD.^24-26 Therefore, daily dietary protein intake of 0.8 g/kg body weight is recommended for patients who are not on dialysis.³ Patients on dialysis might require higher protein intake to preserve muscle mass caused by protein-energy wasting, which is common in dialysis patients.⁶

Continue to: Low sodium intake

Low sodium intake in CKD patients has been shown to decrease BP and thus slow the progression of renal disease and lower the risk of CVD. The recommended dietary sodium intake in CKD patients is 1500-3000 mg/d.³

Low potassium intake. Hyperkalemia is a serious complication of CKD. A low-potassium diet is recommended in ESRD patients who have a potassium level > 5.5 mEq/L.⁶

Blood pressure

Preventing and treating hypertension is critical to slowing the progression of CKD and reducing cardiovascular risk. BP should be measured at every clinic visit. Aside from lifestyle changes, medication might be needed to reach target BP.

The American Diabetes Association recommends a BP goal of ≤ 140/90 mm Hg for hypertensive patients with diabetes, although they do state that a lower BP target (≤ 130/80 mm Hg) might be more appropriate for patients with DKD.²⁷

The American College of Cardiology recommends that hypertensive patients with CKD have a BP target of ≤ 130/80 mm Hg.²⁸

Continue to: ACE inhibitors and ARBs

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have renoprotective benefits. These agents are recommended as first-line medications for patients with diabetes, hypertension, and an eGFR < 60 mL/min/1.73 m² and a UACR > 300 mg/g.^29-31 Evidence also supports their use when the UACR is 30 to 299 mg/g.

Studies have shown that, in patients with DKD, ACE inhibitors and ARBs can slow the progression of renal disease.^29,30,32 There is no difference between ACE inhibitors and ARBs in their effectiveness for preventing progression of DKD.⁶ There is no added benefit in combining an ACE inhibitor and an ARB³³; notably, combination ACE inhibitor and ARB therapy can increase the risk of adverse events, such as hyperkalemia and acute kidney injury, especially in patients with DKD.³³

There is no evidence for starting an ACE inhibitor or ARB to prevent CKD in patients with diabetes who are not hypertensive.⁵

ACE inhibitors and ARBs should be used with caution in women of childbearing age, who should use a reliable form of contraception if taking one of these drugs.

Diuretics. Thiazide-type and loop diuretics might potentiate the positive effects of ACE inhibitors and ARBs. KDOQI guidelines recommend that, in patients who require a second agent to control BP, a diuretic should be considered in combination with an ACE inhibitor or an ARB.²⁰ A loop diuretic is preferred if the eGFR is < 30 mL/min/1.73 m².

Continue to: Nondihydropyridine calcium-channel blockers

Nondihydropyridine calcium-channel blockers (CCBs), such as diltiazem and verapamil, have been shown to be more effective then dihydrophyridine CCBs, such as amlodipine and nifedipine, in slowing the progression of renal disease because of their antiproteinuric effects. However, the antiproteinuric effects of nondihydropyridine CCBs are not as strong as those of ACE inhibitors or ARBs, and these drugs do not appear to potentiate the effects of an ACE inhibitor or ARB when used in combination.²⁰

Confirmation of suspected DKD requires an elevated albumin:creatinine ratio in at least 2 of 3 urine specimens over a 3- to 6-month period.

Nondihydropyridine CCBs might be a reasonable alternative in patients who cannot tolerate an ACE inhibitor or an ARB.

Mineralocorticoid receptor antagonists in combination with an ACE inhibitor or ARB have been demonstrated to reduce albuminuria in short-term studies.^34,35

Glycemic levels

Studies conducted in patients with T1D, and others in patients with T2D, have shown that tight glycemic control can delay the onset and slow the progression of albuminuria and a decline in the eGFR.^10,36-39 The target glycated hemoglobin (A1C) should be < 7% to prevent or slow progression of DKD.⁴⁰ However, patients with DKD have an increased risk of hypoglycemic events and increased mortality with more intensive glycemic control.^40,41 Given those findings, some patients with DKD and significant comorbidities, ESRD, or limited life expectancy might need to have an A1C target set at 8%.^6,42

Adjustments to antidiabetes medications in DKD

In patients with stages 3 to 5 DKD, several common antidiabetic medications might need to be adjusted or discontinued because they decrease creatinine clearance.

Continue to: First-generation sulfonylureas

First-generation sulfonylureas should be avoided in DKD. Glipizide and gliclazide are preferred among second-generation sulfonylureas because they do not increase the risk of hypoglycemia in DKD patients, although patients taking these medications still require close monitoring of their blood glucose level.²⁰

Metformin. In 2016, recommendations changed for the use of metformin in patients with DKD: The eGFR, not the serum creatinine level, should guide treatment.⁴³ Metformin can be used safely in patients with (1) an eGFR of < 60 mL/min/1.73 m² and (2) an eGFR of 30 mL/min/1.73 m² with close monitoring. Metformin should not be initiated if the eGFR is < 45 mL/min/1.73 m².⁴³ 

Antidiabetes medications with direct effect on the kidney

Several antidiabetes medications have a direct effect on the kidney apart from their effect on the blood glucose level.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce albuminuria and slow the decrease of eGFR independent of glycemic control. In addition, SGLT2 inhibitors have also been shown to have cardiovascular benefits in patients with DKD.^44,45 

Glucagon-like peptide 1 (GLP-1) receptor agonists have been shown to delay and decrease the progression of DKD.^46-48 Also, similar to what is seen with SGLT2 inhibitors, GLP-1 agonists have demonstrable cardiovascular benefit in patients with DKD.^46,48

Continue to: Dyslipidemia and DKD

Because the risk of CVD is increased in patients with DKD, addressing other modifiable risk factors, including dyslipidemia, is recommended in these patients. Patients with diabetes and stages 1 to 4 DKD should be treated with a high-intensity statin or a combination of a statin and ezetimibe.^49,50

Tight glycemic control in T1D and T2D can delay the onset, and slow the progression, of albuminuria and a decline in the eGFR.

If a patient is taking a statin and starting dialysis, it’s important to discuss with him or her whether to continue the statin, based on perceived benefits and risks. It is not recommended that statins be initiated in patients on dialysis unless there is a specific cardiovascular indication for doing so. Risk reduction with a statin has been shown to be significantly less in dialysis patients than in patients who are not being treated with dialysis.⁴⁹

Complications of CKD

Anemia is a common complication of CKD. KDIGO recommends measuring the ­hemoglobin concentration annually in DKD stage 3 patients without anemia; at least every 6 months in stage 4 patients; and at least every 3 months in stage 5. DKD patients with anemia should have additional laboratory testing: the absolute reticulocyte count, serum ferritin, serum transferrin saturation, vitamin B12, and folate.⁵¹

Mineral and bone disorder should be screened for in patients with DKD. TABLE 2⁵² outlines when clinical laboratory tests should be ordered to assess for mineral bone disease.

When to refer to a nephrologist

Refer patients with stage 4 or 5 CKD (eGFR, ≤ 30 mL/min/1.73 m²) to a nephrologist for discussion of kidney replacement therapy.⁶ Patients with stage 3a CKD and severely increased albuminuria or with stage 3b CKD and moderately or severely increased albuminuria should also be referred to a nephrologist for intervention to delay disease progression.

Continue to: Identifying the need for early referral...

Nutritional control is important in DKD: A lowsodium diet can slow progression of DKD, and a low-potassium diet can prevent hyperkalemia in end-stage renal disease.

Identifying the need for early referral to a nephrologist has been shown to reduce the cost, and improve the quality, of care.⁵³ Other indications for earlier referral include uncertainty about the etiology of renal disease, persistent or severe albuminuria, persistent hematuria, a rapid decline in eGFR, and acute kidney injury. Additionally, referral at an earlier stage of DKD might be needed to assist with complications associated with DKD, such as anemia, secondary hyperparathyroidism, mineral and bone disorder, resistant hypertension, fluid overload, and electrolyte disturbances.⁶

ACKNOWLEDGEMENT
The authors thank Colleen Colbert, PhD, and Iqbal Ahmad, PhD, for their review and critique of the manuscript of this article. They also thank Christopher Babiuch, MD, for his guidance in the preparation of the manuscript.

CORRESPONDENCE
Faraz Ahmad, MD, MPH, Care Point East Family Medicine, 543 Taylor Avenue, 2nd floor, Columbus, OH 43203; faraz. [email protected].

Primary care physicians (PCPs) generate only a small part of the $75 billion to $100 billion wasted every year on low-value care, according to a brief report published online Jan. 18 in Annals of Internal Medicine.

However, one expert said there are better ways to curb low-value care than focusing on which specialties are guilty of the practice.

Analyzing a 20% random sample of Medicare Part B claims, Aaron Baum, PhD, with the Icahn School of Medicine at Mount Sinai, New York, and colleagues found that the services primary care physicians performed or ordered made up on average 8.3% of the low-value care their patients received (interquartile range, 3.9%-15.1%; 95th percentile, 35.6%) and their referrals made up 15.4% (IQR, 6.3%-26.4%; 95th percentile, 44.6%).

By specialty, cardiology had the worst record with 27% of all spending on low-value services ($1.8 billion) attributed to that specialty. Yet, of the 25 highest-spending specialties in the report, 12 of them were associated with 1% or less than 1% each of all low-value spending, indicating the waste was widely distributed.

Dr. Baum said in an interview that though there are some PCPs guilty of high spending on low-value services, overall, most primary care physicians’ low-value services add up to only 0.3% of Part B spending. He noted that Part B spending is about one-third of all Medicare spending.

Primary care is often thought to be at the core of care management and spending and PCPs are often seen as the gatekeepers, but this analysis suggests that efforts to make big differences in curtailing low-value spending might be more effective elsewhere.

“There’s only so much spending you can reduce by changing primary care physicians’ services that they directly perform,” Dr. Baum said.
 

Low-value care is costly, can be harmful

Mark Fendrick, MD, director of the University of Michigan’s Center for Value-Based Insurance Design in Ann Arbor, said in an interview that the report adds confirmation to previous research that has consistently shown low-value care is “extremely common, very costly, and provided by primary care providers and specialists alike.” He noted that it can also be harmful.

“The math is simple,” he said. “If we want to improve coverage and lower patient costs for essential services like visits, diagnostic tests, and drugs, we have to reduce spending on those services that do not make Americans any healthier.”

The study ranked 31 clinical services judged to be low value by physician societies, Medicare and clinical guidelines, and their use among beneficiaries enrolled between 2007 and 2014. Here’s how the top six low-value services compare.

Dr. Fendrick said a weakness of the paper is the years of the data (2007-2014). Some of the criteria around low-value care have changed since then. The age that a prostate-specific antigen test becomes low-value is now 70 years, for instance, instead of 75. He added that some of the figures attributed to non-PCP providers appear out of date.

Dr. Fendrick said, “I understand that there are Medicare patients who end up at a gastroenterologist or surgeon’s office to get colorectal cancer screening, but it would be very hard for me to believe that half of stress tests and over half of colon cancer screening over [age] 85 [years] and half of PSA for people over 75 did not have some type of referring clinicians involved. I certainly don’t think that would be the case in 2020-2021.”

Dr. Baum said those years were the latest years available for the data points needed for this analysis, but he and his colleagues were working to update the data for future publication.

Dr. Fendrick said not much has changed in recent years in terms of waste on low-value care, even with campaigns such as Choosing Wisely dedicated to identifying low-value services or procedures in each specialty.

“I believe there’s not a particular group of clinicians one way or the other who are actually doing any better now than they were 7 years ago,” he said. He would rather focus less on which specialties are associated with the most low-value care and more on the underlying policies that encourage low-value care.

“If you’re going to get paid for doing a stress test and get paid nothing or significantly less if you don’t, the incentives are in the wrong direction,” he said.

Dr. Fendrick said the pandemic era provides an opportunity to eliminate low-value care because use of those services has dropped drastically as resources have been diverted to COVID-19 patients and many services have been delayed or canceled.

He said he has been pushing an approach that providers should be paid more after the pandemic “to do the things we want them to do.”

As an example, he said, instead of paying $886 million on colonoscopies for people over the age of 85, “why don’t we put a policy in place that would make it better for patients by lowering cost sharing and better for providers by paying them more to do the service on the people who need it as opposed to the people who don’t?”

The research was funded by the American Board of Family Medicine Foundation. Dr. Baum and a coauthor reported receiving personal fees from American Board of Family Medicine Foundation during the conduct of the study. Another coauthor reported receiving personal fees from Collective Health, HealthRight 360, PLOS Medicine, and the New England Journal of Medicine, outside the submitted work. Dr. Fendrick disclosed no relevant financial relationships.

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

Primary care physicians (PCPs) generate only a small part of the $75 billion to $100 billion wasted every year on low-value care, according to a brief report published online Jan. 18 in Annals of Internal Medicine.

However, one expert said there are better ways to curb low-value care than focusing on which specialties are guilty of the practice.

Analyzing a 20% random sample of Medicare Part B claims, Aaron Baum, PhD, with the Icahn School of Medicine at Mount Sinai, New York, and colleagues found that the services primary care physicians performed or ordered made up on average 8.3% of the low-value care their patients received (interquartile range, 3.9%-15.1%; 95th percentile, 35.6%) and their referrals made up 15.4% (IQR, 6.3%-26.4%; 95th percentile, 44.6%).

By specialty, cardiology had the worst record with 27% of all spending on low-value services ($1.8 billion) attributed to that specialty. Yet, of the 25 highest-spending specialties in the report, 12 of them were associated with 1% or less than 1% each of all low-value spending, indicating the waste was widely distributed.

Dr. Baum said in an interview that though there are some PCPs guilty of high spending on low-value services, overall, most primary care physicians’ low-value services add up to only 0.3% of Part B spending. He noted that Part B spending is about one-third of all Medicare spending.

Primary care is often thought to be at the core of care management and spending and PCPs are often seen as the gatekeepers, but this analysis suggests that efforts to make big differences in curtailing low-value spending might be more effective elsewhere.

“There’s only so much spending you can reduce by changing primary care physicians’ services that they directly perform,” Dr. Baum said.
 

Low-value care is costly, can be harmful

Mark Fendrick, MD, director of the University of Michigan’s Center for Value-Based Insurance Design in Ann Arbor, said in an interview that the report adds confirmation to previous research that has consistently shown low-value care is “extremely common, very costly, and provided by primary care providers and specialists alike.” He noted that it can also be harmful.

“The math is simple,” he said. “If we want to improve coverage and lower patient costs for essential services like visits, diagnostic tests, and drugs, we have to reduce spending on those services that do not make Americans any healthier.”

The study ranked 31 clinical services judged to be low value by physician societies, Medicare and clinical guidelines, and their use among beneficiaries enrolled between 2007 and 2014. Here’s how the top six low-value services compare.

Dr. Fendrick said a weakness of the paper is the years of the data (2007-2014). Some of the criteria around low-value care have changed since then. The age that a prostate-specific antigen test becomes low-value is now 70 years, for instance, instead of 75. He added that some of the figures attributed to non-PCP providers appear out of date.

Dr. Fendrick said, “I understand that there are Medicare patients who end up at a gastroenterologist or surgeon’s office to get colorectal cancer screening, but it would be very hard for me to believe that half of stress tests and over half of colon cancer screening over [age] 85 [years] and half of PSA for people over 75 did not have some type of referring clinicians involved. I certainly don’t think that would be the case in 2020-2021.”

Dr. Baum said those years were the latest years available for the data points needed for this analysis, but he and his colleagues were working to update the data for future publication.

Dr. Fendrick said not much has changed in recent years in terms of waste on low-value care, even with campaigns such as Choosing Wisely dedicated to identifying low-value services or procedures in each specialty.

“I believe there’s not a particular group of clinicians one way or the other who are actually doing any better now than they were 7 years ago,” he said. He would rather focus less on which specialties are associated with the most low-value care and more on the underlying policies that encourage low-value care.

“If you’re going to get paid for doing a stress test and get paid nothing or significantly less if you don’t, the incentives are in the wrong direction,” he said.

Dr. Fendrick said the pandemic era provides an opportunity to eliminate low-value care because use of those services has dropped drastically as resources have been diverted to COVID-19 patients and many services have been delayed or canceled.

He said he has been pushing an approach that providers should be paid more after the pandemic “to do the things we want them to do.”

As an example, he said, instead of paying $886 million on colonoscopies for people over the age of 85, “why don’t we put a policy in place that would make it better for patients by lowering cost sharing and better for providers by paying them more to do the service on the people who need it as opposed to the people who don’t?”

The research was funded by the American Board of Family Medicine Foundation. Dr. Baum and a coauthor reported receiving personal fees from American Board of Family Medicine Foundation during the conduct of the study. Another coauthor reported receiving personal fees from Collective Health, HealthRight 360, PLOS Medicine, and the New England Journal of Medicine, outside the submitted work. Dr. Fendrick disclosed no relevant financial relationships.

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

Primary care physicians (PCPs) generate only a small part of the $75 billion to $100 billion wasted every year on low-value care, according to a brief report published online Jan. 18 in Annals of Internal Medicine.

However, one expert said there are better ways to curb low-value care than focusing on which specialties are guilty of the practice.

Analyzing a 20% random sample of Medicare Part B claims, Aaron Baum, PhD, with the Icahn School of Medicine at Mount Sinai, New York, and colleagues found that the services primary care physicians performed or ordered made up on average 8.3% of the low-value care their patients received (interquartile range, 3.9%-15.1%; 95th percentile, 35.6%) and their referrals made up 15.4% (IQR, 6.3%-26.4%; 95th percentile, 44.6%).

By specialty, cardiology had the worst record with 27% of all spending on low-value services ($1.8 billion) attributed to that specialty. Yet, of the 25 highest-spending specialties in the report, 12 of them were associated with 1% or less than 1% each of all low-value spending, indicating the waste was widely distributed.

Dr. Baum said in an interview that though there are some PCPs guilty of high spending on low-value services, overall, most primary care physicians’ low-value services add up to only 0.3% of Part B spending. He noted that Part B spending is about one-third of all Medicare spending.

Primary care is often thought to be at the core of care management and spending and PCPs are often seen as the gatekeepers, but this analysis suggests that efforts to make big differences in curtailing low-value spending might be more effective elsewhere.

“There’s only so much spending you can reduce by changing primary care physicians’ services that they directly perform,” Dr. Baum said.
 

Low-value care is costly, can be harmful

Mark Fendrick, MD, director of the University of Michigan’s Center for Value-Based Insurance Design in Ann Arbor, said in an interview that the report adds confirmation to previous research that has consistently shown low-value care is “extremely common, very costly, and provided by primary care providers and specialists alike.” He noted that it can also be harmful.

“The math is simple,” he said. “If we want to improve coverage and lower patient costs for essential services like visits, diagnostic tests, and drugs, we have to reduce spending on those services that do not make Americans any healthier.”

The study ranked 31 clinical services judged to be low value by physician societies, Medicare and clinical guidelines, and their use among beneficiaries enrolled between 2007 and 2014. Here’s how the top six low-value services compare.

Dr. Fendrick said a weakness of the paper is the years of the data (2007-2014). Some of the criteria around low-value care have changed since then. The age that a prostate-specific antigen test becomes low-value is now 70 years, for instance, instead of 75. He added that some of the figures attributed to non-PCP providers appear out of date.

Dr. Fendrick said, “I understand that there are Medicare patients who end up at a gastroenterologist or surgeon’s office to get colorectal cancer screening, but it would be very hard for me to believe that half of stress tests and over half of colon cancer screening over [age] 85 [years] and half of PSA for people over 75 did not have some type of referring clinicians involved. I certainly don’t think that would be the case in 2020-2021.”

Dr. Baum said those years were the latest years available for the data points needed for this analysis, but he and his colleagues were working to update the data for future publication.

Dr. Fendrick said not much has changed in recent years in terms of waste on low-value care, even with campaigns such as Choosing Wisely dedicated to identifying low-value services or procedures in each specialty.

“I believe there’s not a particular group of clinicians one way or the other who are actually doing any better now than they were 7 years ago,” he said. He would rather focus less on which specialties are associated with the most low-value care and more on the underlying policies that encourage low-value care.

“If you’re going to get paid for doing a stress test and get paid nothing or significantly less if you don’t, the incentives are in the wrong direction,” he said.

Dr. Fendrick said the pandemic era provides an opportunity to eliminate low-value care because use of those services has dropped drastically as resources have been diverted to COVID-19 patients and many services have been delayed or canceled.

He said he has been pushing an approach that providers should be paid more after the pandemic “to do the things we want them to do.”

As an example, he said, instead of paying $886 million on colonoscopies for people over the age of 85, “why don’t we put a policy in place that would make it better for patients by lowering cost sharing and better for providers by paying them more to do the service on the people who need it as opposed to the people who don’t?”

The research was funded by the American Board of Family Medicine Foundation. Dr. Baum and a coauthor reported receiving personal fees from American Board of Family Medicine Foundation during the conduct of the study. Another coauthor reported receiving personal fees from Collective Health, HealthRight 360, PLOS Medicine, and the New England Journal of Medicine, outside the submitted work. Dr. Fendrick disclosed no relevant financial relationships.

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

Medication overuse headache (MOH), a secondary headache diagnosis, is a prevalent phenomenon that complicates headache diagnosis and treatment, increases the cost of care, and reduces quality of life. Effective abortive medication is essential for the headache sufferer; when an abortive is used too frequently, however, headache frequency increases—potentially beginning a cycle in which the patient then takes more medication to abort the headache. Over time, the patient suffers from an ever-­increasing number of headaches, takes even more abortive medication, and so on. In the presence of MOH, there is a reduction in pain response to preventive and abortive treatments; when medication overuse is eliminated, pain response improves.¹

Although MOH is well recognized among headache specialists, the condition is often overlooked in primary care. Since headache is a top complaint in primary care, however, and prevention is a major goal in family medicine, the opportunity for you to recognize, treat, and prevent MOH is significant. In fact, a randomized controlled trial showed that brief patient education about headache care and MOH provided by a primary care physician can lead to a significant reduction in headache frequency among patients with MOH.²

Although medication overuse headache is well recognized among headache specialists, the condition is often overlooked in primary care.

This article reviews the recognition and diagnosis of MOH, based on historical features and current criteria; addresses risk factors for abortive medication overuse and how to withdraw an offending agent; and explores the value of bridging and preventive therapies to reduce the overall frequency of headache.

IMAGE © ROY SCOTT

What defines MOH?

Typically, MOH is a chronification of a primary headache disorder. However, in patients with a history of migraine who are undergoing treatment for another chronic pain condition with an opioid or other analgesic, MOH can be induced.³ An increase in the frequency of headache raises the specter of a concomitant increase in the level of disability⁴; psychiatric comorbidity⁵; and more headache days, with time lost from school and work.

The Migraine Disability Assessment (MIDAS) questionnaire, a validated instrument that helps the provider (1) measure the impact that headache has on a patient’s life and (2) follow treatment progress, also provides information to employers and insurance companies on treatment coverage and the need for work modification. The MIDAS score is 3 times higher in patients with MOH than in patients with episodic migraine.^6,7

The annual associated cost per person of MOH has been estimated at $4000, resulting in billions of dollars in associated costs⁸; most of these costs are related to absenteeism and disability. After detoxification for MOH, annual outpatient medication costs are reduced by approximately 24%.⁹

Efforts to solve a common problem create another

Headache affects nearly 50% of the general population worldwide,¹⁰ accounting for about 4% of primary care visits¹¹ and approximately 20% of outpatient neurology consultations.¹² Although inpatient stays for headache are approximately half the duration of the overall average hospital stay, headache accounts for 3% of admissions.¹³ According to the Global Burden of Disease study, tension-type headache, migraine, and MOH are the 3 most common headache disorders.¹⁰ Headache is the second leading cause of disability among people 15 to 49 years of age.¹⁰

Continue to: The prevalence of MOH...

The prevalence of MOH in the general population is 2%.^7,14,15 A population-based study showed that the rate of progression from episodic headache (< 15 d/mo) to chronic headache (≥ 15 d/mo) in the general population is 2.5% per year¹⁶; however, progression to chronic headache is 14% per year in patients with medication overuse. One-third of the general population with chronic migraine overuses symptomatic medication; in US headache clinics, roughly one-half of patients with chronic headache overuse acute medication.⁶

Definitions and diagnosis

MOH is a secondary headache diagnosis in the third edition of the International Classification of Headache Disorders (ICHD-3) (TABLE 1),¹⁷ which lists diagnostic criteria for recognized headache disorders.

Terminology. MOH has also been called rebound headache, drug-induced headache, and transformed migraine, but these terms are outdated and are not formal diagnoses. Patients sometimes refer to substance-withdrawal headaches (not discussed in this article) as rebound headaches, so clarity is important when discussing headache with patients: namely, that MOH is an exacerbation of an existing headache condition caused by overuse of abortive headache medications, including analgesics, combination analgesics, triptans, barbiturates, and opioids.

The time it takes to develop medication overuse headache is shortest with triptans, followed by ergots, then analgesics.

MOH was recognized in the early 1950s and fully differentiated as a diagnosis in 2005 in the second edition of the ICHD. The disorder is subcategorized by offending abortive agent (TABLE 2¹⁷) because the frequency of analgesic use required to develop MOH differs by agent.

Risk factors for MOH and chronification of a primary headache ­disorder. There are several risk factors for developing MOH, and others that contribute to increasing headache frequency in general (TABLE 3^5,14,18-23). Some risk factors are common to each. All are important to address because some are modifiable.

Continue to: Pathophysiology

Pathophysiology. The pathophysiology and psychology behind MOH are largely unknown. Physiologic changes in pain processing and functional imaging changes have been demonstrated in patients with MOH, both of which are reversible upon withdrawal of medication.²³ Genetic factors and changes in hormone and neurotransmitter levels are found in MOH patients; this is not the case in patients who have an episodic headache pattern only.²⁴

Presentation. Diagnostic criteria for MOH do not include clinical characteristics. Typically, the phenotype of MOH in a given patient is similar to the underlying primary headache²⁵—although this principle can be complicated to tease out because these medications can suppress some symptoms. Diagnosis of a primary headache disorder should be documented along with the diagnosis of MOH.

Medication overuse can exist without MOH: Not every patient who frequently uses an abortive medication develops MOH.

Treatment is multifaceted—and can become complex

Mainstays of treatment of MOH are education about the disorder and detoxification from the overused agent, although specific treatments can differ depending on the agent involved, the frequency and duration of its use, and a patient’s behavioral patterns and psychiatric comorbidities. Often, a daily medication to prevent headache is considered upon, or after, withdrawal of the offending agent. The timing of introducing a preventive might impact its effectiveness. Some refractory cases require more intensive therapy, including hospitalization at a specialized tertiary center.

But before we look at detoxification from an overused agent, it’s important to review one of the best strategies of all in combatting MOH.

Continue to: First and best strategy

Select an appropriate abortive to reduce the risk of MOH. With regard to specific acute headache medications, some nuances other than type of headache should be considered. Nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended as abortive therapy by the American Headache Society for their efficacy, favorable adverse effect profile, and low cost. NSAIDs are protective against development of MOH if a patient’s baseline headache frequency is < 10/mo; at a frequency of 10 to 14 d/mo, however, the risk of MOH increases when using an NSAID.⁶ A similar effect has been seen with triptans.¹⁶ Longer-acting NSAIDs, such as nabumetone and naproxen, have been proposed as less likely to cause MOH, and are even used as bridging therapy sometimes (as long as neither of these was the overused medication).²⁶

The time it takes to develop MOH is shortest with triptans, followed by ergots, then analgesics.²⁷

Prospective cohort studies^6,16 have shown that barbiturates and opioids are more likely to induce MOH; for that reason, agents in these analgesic classes are almost universally avoided unless no other medically acceptable options exist. Using barbiturate-containing compounds or opioids > 4 d/mo exponentially increases the likelihood of MOH.

Promising preclinical data demonstrate that the gepant, or small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, class of medications used as abortive therapy does not induce medication overuse cutaneous allodynia.²⁸

Provide education. Primary prevention of MOH involves (1) increasing patients’ awareness of how to take medications appropriately and (2) restricting intake of over-the-counter abortive medications. Often, the expert recommendation is to limit abortives to approximately 2 d/wk because more frequent use places patients at risk of further increased use and subsequent MOH.

Continue to: A randomized controlled trial in Norway...

A randomized controlled trial in Norway compared outcomes in 2 groups of patients with MOH: One group was given advice on the disorder by a physician; the other group was not provided with advice. In the “business-as-usual” group, there was no significant improvement; however, when general practitioners provided simple advice (lasting roughly 9 minutes) about reducing abortive medication use to a safe level and cautioned patients that they would be “feeling worse before feeling better,” headache days were reduced by approximately 8 per month and medication days, by 16 per month.²

A subsequent, long-term follow-up study²⁹ of patients from the Norway trial² who had been given advice and education showed a relapse rate (ie, into overuse of headache medication) of only 8% and sustained reduction of headache days and medication use at 16 months.

Offer support and other nondrug interventions. A recent review of 3 studies²³ recommended that extra support for patients from a headache nurse, close follow-up, keeping an electronic diary that provides feedback, and undertaking a short course of psychotherapy can reduce medication overuse and prevent relapse.

If MOH develops, initiate withdrawal, introduce a preventive

Withdraw overused medication. Most current evidence suggests that withdrawal of the offending agent is the most effective factor in reducing headache days and improving quality of life. A randomized controlled trial compared the effects of (1) complete and immediate withdrawal of an abortive medication with (2) reducing its use (ie, limiting intake to 2 d/wk), on headache frequency, disability, and quality of life.³⁰ There was a reduction of headache days in both groups; however, reduction was much greater at 2 months in the complete withdrawal group than in the restricted intake group (respectively, a 41% and a 26% reduction in headache days per month). This effect was sustained at 6 and 12 months in both groups. The study confirmed the results of earlier research^2,15: Abrupt withdrawal leads to reversion to an episodic pattern at 2 to 6 months in approximately 40% to 60% of patients.

More studies are needed to determine the most appropriate treatment course for MOH; however, complete withdrawal of the causative drug is the most important intervention.

Continue to: Consider withdrawal plus preventive treatment

Consider withdrawal plus preventive treatment. Use of sodium valproate, in addition to medication overuse detoxification, led to a significant reduction in headache days and improvement in quality of life at 12 weeks but no difference after 24 weeks, compared with detoxification alone in a randomized, double-blind, placebo-controlled study.³¹

A study of 61 patients showed a larger reduction (by 7.2 d/mo) in headache frequency with any preventive medication in addition to medication withdrawal, compared to withdrawal alone (by 4.1 d/mo) after 3 months; however, the relative benefit was gone at 6 months.³²

A study of 98 patients compared immediate and delayed initiation of preventive medication upon withdrawal of overused abortive medication.³³ Response was defined as a > 50% reduction in headache frequency and was similar in both groups; results showed a 28% response with immediate initiation of a preventive; a 23% response with delayed (ie, 2 months after withdrawal) initiation; and a 48% response in both groups at 12 months.

Collectively, these studies suggest that adding a preventive medication at the time of withdrawal has the potential to reduce headache frequency more quickly than withdrawal alone. However, after 3 to 6 months, the outcome of reduced headache frequency is the same whether or not a preventive medication is used—as long as the offending agent has been withdrawn.

Do preventives work without withdrawing overused medication? Patients with MOH often show little or no improvement with addition of a preventive medication only; their response to a preventive improves after withdrawal of the overused medication. Patients without previous headache improvement after addition of a preventive, who also did not improve 2 months after withdrawal, then demonstrated an overall reduction in headache by 26% when a preventive was reintroduced after withdrawal.²

Continue to: The research evidence for preventives

The research evidence for preventives. Medications for headache prevention have not been extensively evaluated specifically for treating MOH. Here is what’s known:

• Flunarizine, amitriptyline, and beta-blockers usually are ineffective for MOH.²⁴
• Results for topiramate are mixed: A small, double-blind, placebo-controlled chronic migraine study in Europe showed that, in a subgroup of patients with MOH, topiramate led to a small but significant reduction (3.5 d/mo) in headache frequency, compared to placebo.²⁷ A similar study done in the United States did not show a significant difference between the active-treatment and placebo groups.³⁴
• Findings regarding onabotulinumtoxinA are intriguing: In a posthoc analysis of onabotulinumtoxinA to treat chronic migraine, patients with MOH who did not undergo detoxification had an 8 d/mo greater reduction in headache, compared to placebo.³⁵ However, when compared to placebo in conjunction with detoxification, onabotulinumtoxinA demonstrated no benefit.³⁶
• Newer CGRP antagonist and CGRP receptor antagonist monoclonal antibodies are successful preventive medications that have demonstrated a reduction in acute medication use days per month and headache days per month³⁷; these compounds have not been compared to withdrawal alone.

Reducing the severity and duration of withdrawal symptoms

Withdrawal from overused abortive headache medications can lead to worsening headache, nausea, vomiting, hypotension, tachycardia, sleep disturbances, restlessness, anxiety, and nervousness. Symptoms usually last 2 to 10 days but can persist for as long as 4 weeks; duration of withdrawal symptoms varies with the medication that is being overused. In patients who have used a triptan, for example, mean duration of withdrawal is 4.1 days; ergotamine, 6.7 days; and NSAIDs, 9.5 days.²³ Tapered withdrawal is sometimes recommended with opioids and barbiturates to reduce withdrawal symptoms. It is unclear whether starting a preventive medication during withdrawal assists in reducing withdrawal symptoms.³⁸

Bridging therapy to reduce symptoms of withdrawal is often provided despite debatable utility. Available evidence does not favor one agent or method but suggests some strategies that could be helpful:

• A prednisone taper has a potential role during the first 6 days of withdrawal by reducing rebound headache and withdrawal symptoms³⁹; however, oral prednisolone has been shown to have no benefit.⁴⁰
• Alone, IV methylprednisolone seems not to be of benefit; however, in a retrospective study of 94 patients, IV methylprednisolone plus diazepam for 5 days led to a significant reduction in headache frequency and drug consumption that was sustained after 3 months.⁴¹
• Celecoxib was compared to prednisone over a 20-day course: a celecoxib dosage of 400 mg/d for the first 5 days, tapered by 100 mg every 5 days, and an oral prednisone dosage of 75 mg/d for the first 5 days, then tapered every 5 days. Patients taking celecoxib had lower headache intensity but there was no difference in headache frequency and acute medication intake between the groups.⁴²

Other strategies. Using antiemetics and NSAIDs to reduce withdrawal symptoms is widely practiced, but no placebo-­controlled trials have been conducted to support this strategy.

Reduce the risk of medication overuse headache by selecting an appropriate abortive; NSAIDs are recommended for their efficacy, favorable adverse effect profile, and low cost.

Patients in withdrawal might be more likely to benefit from inpatient care if they have a severe comorbidity, such as opioid or barbiturate use; failure to respond to, tolerate, or adhere to treatment; or relapse after withdrawal.³⁸

Continue to: Cognitive behavioral therapy...

Cognitive behavioral therapy, exercise, a headache diary, and biofeedback should be considered in every patient’s treatment strategy because a multidisciplinary approach increases adherence and leads to improvement in headache frequency and a decrease in disability and medication use.⁴³

Predictors of Tx success

A prospective cohort study determined that the rate of MOH relapse is 31% at 6 months, 41% at 1 year, and 45% at 4 years, with the highest risk of relapse during the first year.⁴⁴ Looking at the correlation between type of medication overused and relapse rate, the research indicates that

• triptans have the lowest risk of relapse,⁴⁴
• simple analgesics have a higher risk of relapse than triptans,^22,44 and
• opioids have the highest risk of relapse.²²

Where the data don’t agree. Data on combination analgesics and on ergots are conflicting.²² In addition, data on whether the primary type of headache predicts relapse rate conflict; however, migraine might predict a better outcome than tension-type headache.²²

To recap and expand: Management pearls

The major goals of headache management generally are to rule out secondary headache, reach a correct diagnosis, reduce overall headache frequency, and provide effective abortive medication. A large component of reducing headache frequency is addressing and treating medication overuse.

Seek to understand the nature of the patient’s headache disorder. Components of the history are key in identifying the underlying headache diagnosis and ruling out other, more concerning secondary headache diagnoses. The ICHD-3 is an excellent resource for treating headache disorders because the classification lists specific diagnostic criteria for all recognized headache diagnoses.

Continue to: Medication withdrawal...

Medication withdrawal—with or without preventive medication—should reduce the frequency of MOH in 2 or 3 months. If headache does not become less frequent, however, the headache diagnosis might need to be reconsidered. Minimizing the use of abortive medication is generally recommended, but reduction or withdrawal of these medications does not guarantee that patients will revert to an episodic pattern of headache.

Inpatient care of withdrawal might be beneficial when a patient has a severe comorbidity; does not respond to, tolerate, or adhere to treatment; or relapses after withdrawal.

Treating withdrawal symptoms is a reasonable approach in some patients, but evidence does not support routinely providing bridging therapy.

Apply preventives carefully. Abortive medication withdrawal should generally be completed before initiating preventive medication; however, over the short term, starting preventive therapy while withdrawing the overused medication could assist in reducing headache frequency rapidly. This strategy can put patients at risk of medication adverse effects and using the medications longer than necessary, yet might be reasonable in certain patients, given their comorbidities, risk of relapse, and physician and patient preference. A preventive medication for an individual patient should generally be chosen in line with recommendations of the American Academy of Neurology⁴⁵ and on the basis of the history and comorbidities.

Provide education, which is essential to lowering barriers to success. Patients with MOH must be counseled to understand that (1) a headache treatment that is supposed to be making them feel better is, in fact, making them feel worse and (2) they will get worse before they get better. Many patients are afraid to be without medication to use as needed. It is helpful to educate them on the different types of treatments (abortive, preventive); how MOH interferes with headache prophylaxis and medication efficacy; how MOH alters brain function (ie, aforementioned physiologic changes in pain processing and functional imaging changes²³); and that such change is reversible when medication is withdrawn.

ACKNOWLEDGEMENT
The author thanks Jeffrey Curtis, MD, MPH, for his support and editing assistance with the manuscript.

CORRESPONDENCE
Allison Crain, MD, 2927 N 7th Avenue, Phoenix, AZ 85013; [email protected].

Medication overuse headache (MOH), a secondary headache diagnosis, is a prevalent phenomenon that complicates headache diagnosis and treatment, increases the cost of care, and reduces quality of life. Effective abortive medication is essential for the headache sufferer; when an abortive is used too frequently, however, headache frequency increases—potentially beginning a cycle in which the patient then takes more medication to abort the headache. Over time, the patient suffers from an ever-­increasing number of headaches, takes even more abortive medication, and so on. In the presence of MOH, there is a reduction in pain response to preventive and abortive treatments; when medication overuse is eliminated, pain response improves.¹

Although MOH is well recognized among headache specialists, the condition is often overlooked in primary care. Since headache is a top complaint in primary care, however, and prevention is a major goal in family medicine, the opportunity for you to recognize, treat, and prevent MOH is significant. In fact, a randomized controlled trial showed that brief patient education about headache care and MOH provided by a primary care physician can lead to a significant reduction in headache frequency among patients with MOH.²

Although medication overuse headache is well recognized among headache specialists, the condition is often overlooked in primary care.

This article reviews the recognition and diagnosis of MOH, based on historical features and current criteria; addresses risk factors for abortive medication overuse and how to withdraw an offending agent; and explores the value of bridging and preventive therapies to reduce the overall frequency of headache.

IMAGE © ROY SCOTT

What defines MOH?

Typically, MOH is a chronification of a primary headache disorder. However, in patients with a history of migraine who are undergoing treatment for another chronic pain condition with an opioid or other analgesic, MOH can be induced.³ An increase in the frequency of headache raises the specter of a concomitant increase in the level of disability⁴; psychiatric comorbidity⁵; and more headache days, with time lost from school and work.

The Migraine Disability Assessment (MIDAS) questionnaire, a validated instrument that helps the provider (1) measure the impact that headache has on a patient’s life and (2) follow treatment progress, also provides information to employers and insurance companies on treatment coverage and the need for work modification. The MIDAS score is 3 times higher in patients with MOH than in patients with episodic migraine.^6,7

The annual associated cost per person of MOH has been estimated at $4000, resulting in billions of dollars in associated costs⁸; most of these costs are related to absenteeism and disability. After detoxification for MOH, annual outpatient medication costs are reduced by approximately 24%.⁹

Efforts to solve a common problem create another

Headache affects nearly 50% of the general population worldwide,¹⁰ accounting for about 4% of primary care visits¹¹ and approximately 20% of outpatient neurology consultations.¹² Although inpatient stays for headache are approximately half the duration of the overall average hospital stay, headache accounts for 3% of admissions.¹³ According to the Global Burden of Disease study, tension-type headache, migraine, and MOH are the 3 most common headache disorders.¹⁰ Headache is the second leading cause of disability among people 15 to 49 years of age.¹⁰

Continue to: The prevalence of MOH...

The prevalence of MOH in the general population is 2%.^7,14,15 A population-based study showed that the rate of progression from episodic headache (< 15 d/mo) to chronic headache (≥ 15 d/mo) in the general population is 2.5% per year¹⁶; however, progression to chronic headache is 14% per year in patients with medication overuse. One-third of the general population with chronic migraine overuses symptomatic medication; in US headache clinics, roughly one-half of patients with chronic headache overuse acute medication.⁶

Definitions and diagnosis

MOH is a secondary headache diagnosis in the third edition of the International Classification of Headache Disorders (ICHD-3) (TABLE 1),¹⁷ which lists diagnostic criteria for recognized headache disorders.

Terminology. MOH has also been called rebound headache, drug-induced headache, and transformed migraine, but these terms are outdated and are not formal diagnoses. Patients sometimes refer to substance-withdrawal headaches (not discussed in this article) as rebound headaches, so clarity is important when discussing headache with patients: namely, that MOH is an exacerbation of an existing headache condition caused by overuse of abortive headache medications, including analgesics, combination analgesics, triptans, barbiturates, and opioids.

The time it takes to develop medication overuse headache is shortest with triptans, followed by ergots, then analgesics.

MOH was recognized in the early 1950s and fully differentiated as a diagnosis in 2005 in the second edition of the ICHD. The disorder is subcategorized by offending abortive agent (TABLE 2¹⁷) because the frequency of analgesic use required to develop MOH differs by agent.

Risk factors for MOH and chronification of a primary headache ­disorder. There are several risk factors for developing MOH, and others that contribute to increasing headache frequency in general (TABLE 3^5,14,18-23). Some risk factors are common to each. All are important to address because some are modifiable.

Continue to: Pathophysiology

Pathophysiology. The pathophysiology and psychology behind MOH are largely unknown. Physiologic changes in pain processing and functional imaging changes have been demonstrated in patients with MOH, both of which are reversible upon withdrawal of medication.²³ Genetic factors and changes in hormone and neurotransmitter levels are found in MOH patients; this is not the case in patients who have an episodic headache pattern only.²⁴

Presentation. Diagnostic criteria for MOH do not include clinical characteristics. Typically, the phenotype of MOH in a given patient is similar to the underlying primary headache²⁵—although this principle can be complicated to tease out because these medications can suppress some symptoms. Diagnosis of a primary headache disorder should be documented along with the diagnosis of MOH.

Medication overuse can exist without MOH: Not every patient who frequently uses an abortive medication develops MOH.

Treatment is multifaceted—and can become complex

Mainstays of treatment of MOH are education about the disorder and detoxification from the overused agent, although specific treatments can differ depending on the agent involved, the frequency and duration of its use, and a patient’s behavioral patterns and psychiatric comorbidities. Often, a daily medication to prevent headache is considered upon, or after, withdrawal of the offending agent. The timing of introducing a preventive might impact its effectiveness. Some refractory cases require more intensive therapy, including hospitalization at a specialized tertiary center.

But before we look at detoxification from an overused agent, it’s important to review one of the best strategies of all in combatting MOH.

Continue to: First and best strategy

Select an appropriate abortive to reduce the risk of MOH. With regard to specific acute headache medications, some nuances other than type of headache should be considered. Nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended as abortive therapy by the American Headache Society for their efficacy, favorable adverse effect profile, and low cost. NSAIDs are protective against development of MOH if a patient’s baseline headache frequency is < 10/mo; at a frequency of 10 to 14 d/mo, however, the risk of MOH increases when using an NSAID.⁶ A similar effect has been seen with triptans.¹⁶ Longer-acting NSAIDs, such as nabumetone and naproxen, have been proposed as less likely to cause MOH, and are even used as bridging therapy sometimes (as long as neither of these was the overused medication).²⁶

The time it takes to develop MOH is shortest with triptans, followed by ergots, then analgesics.²⁷

Prospective cohort studies^6,16 have shown that barbiturates and opioids are more likely to induce MOH; for that reason, agents in these analgesic classes are almost universally avoided unless no other medically acceptable options exist. Using barbiturate-containing compounds or opioids > 4 d/mo exponentially increases the likelihood of MOH.

Promising preclinical data demonstrate that the gepant, or small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, class of medications used as abortive therapy does not induce medication overuse cutaneous allodynia.²⁸

Provide education. Primary prevention of MOH involves (1) increasing patients’ awareness of how to take medications appropriately and (2) restricting intake of over-the-counter abortive medications. Often, the expert recommendation is to limit abortives to approximately 2 d/wk because more frequent use places patients at risk of further increased use and subsequent MOH.

Continue to: A randomized controlled trial in Norway...

A randomized controlled trial in Norway compared outcomes in 2 groups of patients with MOH: One group was given advice on the disorder by a physician; the other group was not provided with advice. In the “business-as-usual” group, there was no significant improvement; however, when general practitioners provided simple advice (lasting roughly 9 minutes) about reducing abortive medication use to a safe level and cautioned patients that they would be “feeling worse before feeling better,” headache days were reduced by approximately 8 per month and medication days, by 16 per month.²

A subsequent, long-term follow-up study²⁹ of patients from the Norway trial² who had been given advice and education showed a relapse rate (ie, into overuse of headache medication) of only 8% and sustained reduction of headache days and medication use at 16 months.

Offer support and other nondrug interventions. A recent review of 3 studies²³ recommended that extra support for patients from a headache nurse, close follow-up, keeping an electronic diary that provides feedback, and undertaking a short course of psychotherapy can reduce medication overuse and prevent relapse.

If MOH develops, initiate withdrawal, introduce a preventive

Withdraw overused medication. Most current evidence suggests that withdrawal of the offending agent is the most effective factor in reducing headache days and improving quality of life. A randomized controlled trial compared the effects of (1) complete and immediate withdrawal of an abortive medication with (2) reducing its use (ie, limiting intake to 2 d/wk), on headache frequency, disability, and quality of life.³⁰ There was a reduction of headache days in both groups; however, reduction was much greater at 2 months in the complete withdrawal group than in the restricted intake group (respectively, a 41% and a 26% reduction in headache days per month). This effect was sustained at 6 and 12 months in both groups. The study confirmed the results of earlier research^2,15: Abrupt withdrawal leads to reversion to an episodic pattern at 2 to 6 months in approximately 40% to 60% of patients.

More studies are needed to determine the most appropriate treatment course for MOH; however, complete withdrawal of the causative drug is the most important intervention.

Continue to: Consider withdrawal plus preventive treatment

Consider withdrawal plus preventive treatment. Use of sodium valproate, in addition to medication overuse detoxification, led to a significant reduction in headache days and improvement in quality of life at 12 weeks but no difference after 24 weeks, compared with detoxification alone in a randomized, double-blind, placebo-controlled study.³¹

A study of 61 patients showed a larger reduction (by 7.2 d/mo) in headache frequency with any preventive medication in addition to medication withdrawal, compared to withdrawal alone (by 4.1 d/mo) after 3 months; however, the relative benefit was gone at 6 months.³²

A study of 98 patients compared immediate and delayed initiation of preventive medication upon withdrawal of overused abortive medication.³³ Response was defined as a > 50% reduction in headache frequency and was similar in both groups; results showed a 28% response with immediate initiation of a preventive; a 23% response with delayed (ie, 2 months after withdrawal) initiation; and a 48% response in both groups at 12 months.

Collectively, these studies suggest that adding a preventive medication at the time of withdrawal has the potential to reduce headache frequency more quickly than withdrawal alone. However, after 3 to 6 months, the outcome of reduced headache frequency is the same whether or not a preventive medication is used—as long as the offending agent has been withdrawn.

Do preventives work without withdrawing overused medication? Patients with MOH often show little or no improvement with addition of a preventive medication only; their response to a preventive improves after withdrawal of the overused medication. Patients without previous headache improvement after addition of a preventive, who also did not improve 2 months after withdrawal, then demonstrated an overall reduction in headache by 26% when a preventive was reintroduced after withdrawal.²

Continue to: The research evidence for preventives

The research evidence for preventives. Medications for headache prevention have not been extensively evaluated specifically for treating MOH. Here is what’s known:

• Flunarizine, amitriptyline, and beta-blockers usually are ineffective for MOH.²⁴
• Results for topiramate are mixed: A small, double-blind, placebo-controlled chronic migraine study in Europe showed that, in a subgroup of patients with MOH, topiramate led to a small but significant reduction (3.5 d/mo) in headache frequency, compared to placebo.²⁷ A similar study done in the United States did not show a significant difference between the active-treatment and placebo groups.³⁴
• Findings regarding onabotulinumtoxinA are intriguing: In a posthoc analysis of onabotulinumtoxinA to treat chronic migraine, patients with MOH who did not undergo detoxification had an 8 d/mo greater reduction in headache, compared to placebo.³⁵ However, when compared to placebo in conjunction with detoxification, onabotulinumtoxinA demonstrated no benefit.³⁶
• Newer CGRP antagonist and CGRP receptor antagonist monoclonal antibodies are successful preventive medications that have demonstrated a reduction in acute medication use days per month and headache days per month³⁷; these compounds have not been compared to withdrawal alone.

Reducing the severity and duration of withdrawal symptoms

Withdrawal from overused abortive headache medications can lead to worsening headache, nausea, vomiting, hypotension, tachycardia, sleep disturbances, restlessness, anxiety, and nervousness. Symptoms usually last 2 to 10 days but can persist for as long as 4 weeks; duration of withdrawal symptoms varies with the medication that is being overused. In patients who have used a triptan, for example, mean duration of withdrawal is 4.1 days; ergotamine, 6.7 days; and NSAIDs, 9.5 days.²³ Tapered withdrawal is sometimes recommended with opioids and barbiturates to reduce withdrawal symptoms. It is unclear whether starting a preventive medication during withdrawal assists in reducing withdrawal symptoms.³⁸

Bridging therapy to reduce symptoms of withdrawal is often provided despite debatable utility. Available evidence does not favor one agent or method but suggests some strategies that could be helpful:

• A prednisone taper has a potential role during the first 6 days of withdrawal by reducing rebound headache and withdrawal symptoms³⁹; however, oral prednisolone has been shown to have no benefit.⁴⁰
• Alone, IV methylprednisolone seems not to be of benefit; however, in a retrospective study of 94 patients, IV methylprednisolone plus diazepam for 5 days led to a significant reduction in headache frequency and drug consumption that was sustained after 3 months.⁴¹
• Celecoxib was compared to prednisone over a 20-day course: a celecoxib dosage of 400 mg/d for the first 5 days, tapered by 100 mg every 5 days, and an oral prednisone dosage of 75 mg/d for the first 5 days, then tapered every 5 days. Patients taking celecoxib had lower headache intensity but there was no difference in headache frequency and acute medication intake between the groups.⁴²

Other strategies. Using antiemetics and NSAIDs to reduce withdrawal symptoms is widely practiced, but no placebo-­controlled trials have been conducted to support this strategy.

Reduce the risk of medication overuse headache by selecting an appropriate abortive; NSAIDs are recommended for their efficacy, favorable adverse effect profile, and low cost.

Patients in withdrawal might be more likely to benefit from inpatient care if they have a severe comorbidity, such as opioid or barbiturate use; failure to respond to, tolerate, or adhere to treatment; or relapse after withdrawal.³⁸

Continue to: Cognitive behavioral therapy...

Cognitive behavioral therapy, exercise, a headache diary, and biofeedback should be considered in every patient’s treatment strategy because a multidisciplinary approach increases adherence and leads to improvement in headache frequency and a decrease in disability and medication use.⁴³

Predictors of Tx success

A prospective cohort study determined that the rate of MOH relapse is 31% at 6 months, 41% at 1 year, and 45% at 4 years, with the highest risk of relapse during the first year.⁴⁴ Looking at the correlation between type of medication overused and relapse rate, the research indicates that

• triptans have the lowest risk of relapse,⁴⁴
• simple analgesics have a higher risk of relapse than triptans,^22,44 and
• opioids have the highest risk of relapse.²²

Where the data don’t agree. Data on combination analgesics and on ergots are conflicting.²² In addition, data on whether the primary type of headache predicts relapse rate conflict; however, migraine might predict a better outcome than tension-type headache.²²

To recap and expand: Management pearls

The major goals of headache management generally are to rule out secondary headache, reach a correct diagnosis, reduce overall headache frequency, and provide effective abortive medication. A large component of reducing headache frequency is addressing and treating medication overuse.

Seek to understand the nature of the patient’s headache disorder. Components of the history are key in identifying the underlying headache diagnosis and ruling out other, more concerning secondary headache diagnoses. The ICHD-3 is an excellent resource for treating headache disorders because the classification lists specific diagnostic criteria for all recognized headache diagnoses.

Continue to: Medication withdrawal...

Medication withdrawal—with or without preventive medication—should reduce the frequency of MOH in 2 or 3 months. If headache does not become less frequent, however, the headache diagnosis might need to be reconsidered. Minimizing the use of abortive medication is generally recommended, but reduction or withdrawal of these medications does not guarantee that patients will revert to an episodic pattern of headache.

Inpatient care of withdrawal might be beneficial when a patient has a severe comorbidity; does not respond to, tolerate, or adhere to treatment; or relapses after withdrawal.

Treating withdrawal symptoms is a reasonable approach in some patients, but evidence does not support routinely providing bridging therapy.

Apply preventives carefully. Abortive medication withdrawal should generally be completed before initiating preventive medication; however, over the short term, starting preventive therapy while withdrawing the overused medication could assist in reducing headache frequency rapidly. This strategy can put patients at risk of medication adverse effects and using the medications longer than necessary, yet might be reasonable in certain patients, given their comorbidities, risk of relapse, and physician and patient preference. A preventive medication for an individual patient should generally be chosen in line with recommendations of the American Academy of Neurology⁴⁵ and on the basis of the history and comorbidities.

Provide education, which is essential to lowering barriers to success. Patients with MOH must be counseled to understand that (1) a headache treatment that is supposed to be making them feel better is, in fact, making them feel worse and (2) they will get worse before they get better. Many patients are afraid to be without medication to use as needed. It is helpful to educate them on the different types of treatments (abortive, preventive); how MOH interferes with headache prophylaxis and medication efficacy; how MOH alters brain function (ie, aforementioned physiologic changes in pain processing and functional imaging changes²³); and that such change is reversible when medication is withdrawn.

ACKNOWLEDGEMENT
The author thanks Jeffrey Curtis, MD, MPH, for his support and editing assistance with the manuscript.

CORRESPONDENCE
Allison Crain, MD, 2927 N 7th Avenue, Phoenix, AZ 85013; [email protected].

Medication overuse headache (MOH), a secondary headache diagnosis, is a prevalent phenomenon that complicates headache diagnosis and treatment, increases the cost of care, and reduces quality of life. Effective abortive medication is essential for the headache sufferer; when an abortive is used too frequently, however, headache frequency increases—potentially beginning a cycle in which the patient then takes more medication to abort the headache. Over time, the patient suffers from an ever-­increasing number of headaches, takes even more abortive medication, and so on. In the presence of MOH, there is a reduction in pain response to preventive and abortive treatments; when medication overuse is eliminated, pain response improves.¹

Although MOH is well recognized among headache specialists, the condition is often overlooked in primary care. Since headache is a top complaint in primary care, however, and prevention is a major goal in family medicine, the opportunity for you to recognize, treat, and prevent MOH is significant. In fact, a randomized controlled trial showed that brief patient education about headache care and MOH provided by a primary care physician can lead to a significant reduction in headache frequency among patients with MOH.²

Although medication overuse headache is well recognized among headache specialists, the condition is often overlooked in primary care.

This article reviews the recognition and diagnosis of MOH, based on historical features and current criteria; addresses risk factors for abortive medication overuse and how to withdraw an offending agent; and explores the value of bridging and preventive therapies to reduce the overall frequency of headache.

IMAGE © ROY SCOTT

What defines MOH?

Typically, MOH is a chronification of a primary headache disorder. However, in patients with a history of migraine who are undergoing treatment for another chronic pain condition with an opioid or other analgesic, MOH can be induced.³ An increase in the frequency of headache raises the specter of a concomitant increase in the level of disability⁴; psychiatric comorbidity⁵; and more headache days, with time lost from school and work.

The Migraine Disability Assessment (MIDAS) questionnaire, a validated instrument that helps the provider (1) measure the impact that headache has on a patient’s life and (2) follow treatment progress, also provides information to employers and insurance companies on treatment coverage and the need for work modification. The MIDAS score is 3 times higher in patients with MOH than in patients with episodic migraine.^6,7

The annual associated cost per person of MOH has been estimated at $4000, resulting in billions of dollars in associated costs⁸; most of these costs are related to absenteeism and disability. After detoxification for MOH, annual outpatient medication costs are reduced by approximately 24%.⁹

Efforts to solve a common problem create another

Headache affects nearly 50% of the general population worldwide,¹⁰ accounting for about 4% of primary care visits¹¹ and approximately 20% of outpatient neurology consultations.¹² Although inpatient stays for headache are approximately half the duration of the overall average hospital stay, headache accounts for 3% of admissions.¹³ According to the Global Burden of Disease study, tension-type headache, migraine, and MOH are the 3 most common headache disorders.¹⁰ Headache is the second leading cause of disability among people 15 to 49 years of age.¹⁰

Continue to: The prevalence of MOH...

The prevalence of MOH in the general population is 2%.^7,14,15 A population-based study showed that the rate of progression from episodic headache (< 15 d/mo) to chronic headache (≥ 15 d/mo) in the general population is 2.5% per year¹⁶; however, progression to chronic headache is 14% per year in patients with medication overuse. One-third of the general population with chronic migraine overuses symptomatic medication; in US headache clinics, roughly one-half of patients with chronic headache overuse acute medication.⁶

Definitions and diagnosis

MOH is a secondary headache diagnosis in the third edition of the International Classification of Headache Disorders (ICHD-3) (TABLE 1),¹⁷ which lists diagnostic criteria for recognized headache disorders.

Terminology. MOH has also been called rebound headache, drug-induced headache, and transformed migraine, but these terms are outdated and are not formal diagnoses. Patients sometimes refer to substance-withdrawal headaches (not discussed in this article) as rebound headaches, so clarity is important when discussing headache with patients: namely, that MOH is an exacerbation of an existing headache condition caused by overuse of abortive headache medications, including analgesics, combination analgesics, triptans, barbiturates, and opioids.

The time it takes to develop medication overuse headache is shortest with triptans, followed by ergots, then analgesics.

MOH was recognized in the early 1950s and fully differentiated as a diagnosis in 2005 in the second edition of the ICHD. The disorder is subcategorized by offending abortive agent (TABLE 2¹⁷) because the frequency of analgesic use required to develop MOH differs by agent.

Risk factors for MOH and chronification of a primary headache ­disorder. There are several risk factors for developing MOH, and others that contribute to increasing headache frequency in general (TABLE 3^5,14,18-23). Some risk factors are common to each. All are important to address because some are modifiable.

Continue to: Pathophysiology

Pathophysiology. The pathophysiology and psychology behind MOH are largely unknown. Physiologic changes in pain processing and functional imaging changes have been demonstrated in patients with MOH, both of which are reversible upon withdrawal of medication.²³ Genetic factors and changes in hormone and neurotransmitter levels are found in MOH patients; this is not the case in patients who have an episodic headache pattern only.²⁴

Presentation. Diagnostic criteria for MOH do not include clinical characteristics. Typically, the phenotype of MOH in a given patient is similar to the underlying primary headache²⁵—although this principle can be complicated to tease out because these medications can suppress some symptoms. Diagnosis of a primary headache disorder should be documented along with the diagnosis of MOH.

Medication overuse can exist without MOH: Not every patient who frequently uses an abortive medication develops MOH.

Treatment is multifaceted—and can become complex

Mainstays of treatment of MOH are education about the disorder and detoxification from the overused agent, although specific treatments can differ depending on the agent involved, the frequency and duration of its use, and a patient’s behavioral patterns and psychiatric comorbidities. Often, a daily medication to prevent headache is considered upon, or after, withdrawal of the offending agent. The timing of introducing a preventive might impact its effectiveness. Some refractory cases require more intensive therapy, including hospitalization at a specialized tertiary center.

But before we look at detoxification from an overused agent, it’s important to review one of the best strategies of all in combatting MOH.

Continue to: First and best strategy

Select an appropriate abortive to reduce the risk of MOH. With regard to specific acute headache medications, some nuances other than type of headache should be considered. Nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended as abortive therapy by the American Headache Society for their efficacy, favorable adverse effect profile, and low cost. NSAIDs are protective against development of MOH if a patient’s baseline headache frequency is < 10/mo; at a frequency of 10 to 14 d/mo, however, the risk of MOH increases when using an NSAID.⁶ A similar effect has been seen with triptans.¹⁶ Longer-acting NSAIDs, such as nabumetone and naproxen, have been proposed as less likely to cause MOH, and are even used as bridging therapy sometimes (as long as neither of these was the overused medication).²⁶

The time it takes to develop MOH is shortest with triptans, followed by ergots, then analgesics.²⁷

Prospective cohort studies^6,16 have shown that barbiturates and opioids are more likely to induce MOH; for that reason, agents in these analgesic classes are almost universally avoided unless no other medically acceptable options exist. Using barbiturate-containing compounds or opioids > 4 d/mo exponentially increases the likelihood of MOH.

Promising preclinical data demonstrate that the gepant, or small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, class of medications used as abortive therapy does not induce medication overuse cutaneous allodynia.²⁸

Provide education. Primary prevention of MOH involves (1) increasing patients’ awareness of how to take medications appropriately and (2) restricting intake of over-the-counter abortive medications. Often, the expert recommendation is to limit abortives to approximately 2 d/wk because more frequent use places patients at risk of further increased use and subsequent MOH.

Continue to: A randomized controlled trial in Norway...

A randomized controlled trial in Norway compared outcomes in 2 groups of patients with MOH: One group was given advice on the disorder by a physician; the other group was not provided with advice. In the “business-as-usual” group, there was no significant improvement; however, when general practitioners provided simple advice (lasting roughly 9 minutes) about reducing abortive medication use to a safe level and cautioned patients that they would be “feeling worse before feeling better,” headache days were reduced by approximately 8 per month and medication days, by 16 per month.²

A subsequent, long-term follow-up study²⁹ of patients from the Norway trial² who had been given advice and education showed a relapse rate (ie, into overuse of headache medication) of only 8% and sustained reduction of headache days and medication use at 16 months.

Offer support and other nondrug interventions. A recent review of 3 studies²³ recommended that extra support for patients from a headache nurse, close follow-up, keeping an electronic diary that provides feedback, and undertaking a short course of psychotherapy can reduce medication overuse and prevent relapse.

If MOH develops, initiate withdrawal, introduce a preventive

Withdraw overused medication. Most current evidence suggests that withdrawal of the offending agent is the most effective factor in reducing headache days and improving quality of life. A randomized controlled trial compared the effects of (1) complete and immediate withdrawal of an abortive medication with (2) reducing its use (ie, limiting intake to 2 d/wk), on headache frequency, disability, and quality of life.³⁰ There was a reduction of headache days in both groups; however, reduction was much greater at 2 months in the complete withdrawal group than in the restricted intake group (respectively, a 41% and a 26% reduction in headache days per month). This effect was sustained at 6 and 12 months in both groups. The study confirmed the results of earlier research^2,15: Abrupt withdrawal leads to reversion to an episodic pattern at 2 to 6 months in approximately 40% to 60% of patients.

More studies are needed to determine the most appropriate treatment course for MOH; however, complete withdrawal of the causative drug is the most important intervention.

Continue to: Consider withdrawal plus preventive treatment

Consider withdrawal plus preventive treatment. Use of sodium valproate, in addition to medication overuse detoxification, led to a significant reduction in headache days and improvement in quality of life at 12 weeks but no difference after 24 weeks, compared with detoxification alone in a randomized, double-blind, placebo-controlled study.³¹

A study of 61 patients showed a larger reduction (by 7.2 d/mo) in headache frequency with any preventive medication in addition to medication withdrawal, compared to withdrawal alone (by 4.1 d/mo) after 3 months; however, the relative benefit was gone at 6 months.³²

A study of 98 patients compared immediate and delayed initiation of preventive medication upon withdrawal of overused abortive medication.³³ Response was defined as a > 50% reduction in headache frequency and was similar in both groups; results showed a 28% response with immediate initiation of a preventive; a 23% response with delayed (ie, 2 months after withdrawal) initiation; and a 48% response in both groups at 12 months.

Collectively, these studies suggest that adding a preventive medication at the time of withdrawal has the potential to reduce headache frequency more quickly than withdrawal alone. However, after 3 to 6 months, the outcome of reduced headache frequency is the same whether or not a preventive medication is used—as long as the offending agent has been withdrawn.

Do preventives work without withdrawing overused medication? Patients with MOH often show little or no improvement with addition of a preventive medication only; their response to a preventive improves after withdrawal of the overused medication. Patients without previous headache improvement after addition of a preventive, who also did not improve 2 months after withdrawal, then demonstrated an overall reduction in headache by 26% when a preventive was reintroduced after withdrawal.²

Continue to: The research evidence for preventives

The research evidence for preventives. Medications for headache prevention have not been extensively evaluated specifically for treating MOH. Here is what’s known:

• Flunarizine, amitriptyline, and beta-blockers usually are ineffective for MOH.²⁴
• Results for topiramate are mixed: A small, double-blind, placebo-controlled chronic migraine study in Europe showed that, in a subgroup of patients with MOH, topiramate led to a small but significant reduction (3.5 d/mo) in headache frequency, compared to placebo.²⁷ A similar study done in the United States did not show a significant difference between the active-treatment and placebo groups.³⁴
• Findings regarding onabotulinumtoxinA are intriguing: In a posthoc analysis of onabotulinumtoxinA to treat chronic migraine, patients with MOH who did not undergo detoxification had an 8 d/mo greater reduction in headache, compared to placebo.³⁵ However, when compared to placebo in conjunction with detoxification, onabotulinumtoxinA demonstrated no benefit.³⁶
• Newer CGRP antagonist and CGRP receptor antagonist monoclonal antibodies are successful preventive medications that have demonstrated a reduction in acute medication use days per month and headache days per month³⁷; these compounds have not been compared to withdrawal alone.

Reducing the severity and duration of withdrawal symptoms

Withdrawal from overused abortive headache medications can lead to worsening headache, nausea, vomiting, hypotension, tachycardia, sleep disturbances, restlessness, anxiety, and nervousness. Symptoms usually last 2 to 10 days but can persist for as long as 4 weeks; duration of withdrawal symptoms varies with the medication that is being overused. In patients who have used a triptan, for example, mean duration of withdrawal is 4.1 days; ergotamine, 6.7 days; and NSAIDs, 9.5 days.²³ Tapered withdrawal is sometimes recommended with opioids and barbiturates to reduce withdrawal symptoms. It is unclear whether starting a preventive medication during withdrawal assists in reducing withdrawal symptoms.³⁸

Bridging therapy to reduce symptoms of withdrawal is often provided despite debatable utility. Available evidence does not favor one agent or method but suggests some strategies that could be helpful:

• A prednisone taper has a potential role during the first 6 days of withdrawal by reducing rebound headache and withdrawal symptoms³⁹; however, oral prednisolone has been shown to have no benefit.⁴⁰
• Alone, IV methylprednisolone seems not to be of benefit; however, in a retrospective study of 94 patients, IV methylprednisolone plus diazepam for 5 days led to a significant reduction in headache frequency and drug consumption that was sustained after 3 months.⁴¹
• Celecoxib was compared to prednisone over a 20-day course: a celecoxib dosage of 400 mg/d for the first 5 days, tapered by 100 mg every 5 days, and an oral prednisone dosage of 75 mg/d for the first 5 days, then tapered every 5 days. Patients taking celecoxib had lower headache intensity but there was no difference in headache frequency and acute medication intake between the groups.⁴²

Other strategies. Using antiemetics and NSAIDs to reduce withdrawal symptoms is widely practiced, but no placebo-­controlled trials have been conducted to support this strategy.

Reduce the risk of medication overuse headache by selecting an appropriate abortive; NSAIDs are recommended for their efficacy, favorable adverse effect profile, and low cost.

Patients in withdrawal might be more likely to benefit from inpatient care if they have a severe comorbidity, such as opioid or barbiturate use; failure to respond to, tolerate, or adhere to treatment; or relapse after withdrawal.³⁸

Continue to: Cognitive behavioral therapy...

Cognitive behavioral therapy, exercise, a headache diary, and biofeedback should be considered in every patient’s treatment strategy because a multidisciplinary approach increases adherence and leads to improvement in headache frequency and a decrease in disability and medication use.⁴³

Predictors of Tx success

A prospective cohort study determined that the rate of MOH relapse is 31% at 6 months, 41% at 1 year, and 45% at 4 years, with the highest risk of relapse during the first year.⁴⁴ Looking at the correlation between type of medication overused and relapse rate, the research indicates that

• triptans have the lowest risk of relapse,⁴⁴
• simple analgesics have a higher risk of relapse than triptans,^22,44 and
• opioids have the highest risk of relapse.²²

Where the data don’t agree. Data on combination analgesics and on ergots are conflicting.²² In addition, data on whether the primary type of headache predicts relapse rate conflict; however, migraine might predict a better outcome than tension-type headache.²²

To recap and expand: Management pearls

The major goals of headache management generally are to rule out secondary headache, reach a correct diagnosis, reduce overall headache frequency, and provide effective abortive medication. A large component of reducing headache frequency is addressing and treating medication overuse.

Seek to understand the nature of the patient’s headache disorder. Components of the history are key in identifying the underlying headache diagnosis and ruling out other, more concerning secondary headache diagnoses. The ICHD-3 is an excellent resource for treating headache disorders because the classification lists specific diagnostic criteria for all recognized headache diagnoses.

Continue to: Medication withdrawal...

Medication withdrawal—with or without preventive medication—should reduce the frequency of MOH in 2 or 3 months. If headache does not become less frequent, however, the headache diagnosis might need to be reconsidered. Minimizing the use of abortive medication is generally recommended, but reduction or withdrawal of these medications does not guarantee that patients will revert to an episodic pattern of headache.

Inpatient care of withdrawal might be beneficial when a patient has a severe comorbidity; does not respond to, tolerate, or adhere to treatment; or relapses after withdrawal.

Treating withdrawal symptoms is a reasonable approach in some patients, but evidence does not support routinely providing bridging therapy.

Apply preventives carefully. Abortive medication withdrawal should generally be completed before initiating preventive medication; however, over the short term, starting preventive therapy while withdrawing the overused medication could assist in reducing headache frequency rapidly. This strategy can put patients at risk of medication adverse effects and using the medications longer than necessary, yet might be reasonable in certain patients, given their comorbidities, risk of relapse, and physician and patient preference. A preventive medication for an individual patient should generally be chosen in line with recommendations of the American Academy of Neurology⁴⁵ and on the basis of the history and comorbidities.

Provide education, which is essential to lowering barriers to success. Patients with MOH must be counseled to understand that (1) a headache treatment that is supposed to be making them feel better is, in fact, making them feel worse and (2) they will get worse before they get better. Many patients are afraid to be without medication to use as needed. It is helpful to educate them on the different types of treatments (abortive, preventive); how MOH interferes with headache prophylaxis and medication efficacy; how MOH alters brain function (ie, aforementioned physiologic changes in pain processing and functional imaging changes²³); and that such change is reversible when medication is withdrawn.

ACKNOWLEDGEMENT
The author thanks Jeffrey Curtis, MD, MPH, for his support and editing assistance with the manuscript.

CORRESPONDENCE
Allison Crain, MD, 2927 N 7th Avenue, Phoenix, AZ 85013; [email protected].