ILLUSTRATIVE CASE

A 51-year-old woman with a history of elevated cholesterol and a body mass index (BMI) of 31 presents to your clinic for a scheduled follow-up visit to review recent blood test results. Her A1C was elevated at 5.9%. She wants to know if she should start medication now.

Prediabetes is a high-risk state that ­confers increased risk for type 2 ­diabetes (T2D). It is identified by impaired fasting glucose (fasting plasma glucose [FPG], 100-125 mg/dL), impaired glucose tolerance (2-hour oral glucose tolerance test, 140-199 mg/dL), or an elevated A1C (between 5.7% and 6.4%).²

An estimated 96 million ­Americans—38% of the US adult population—have prediabetes, according to the Centers for Disease Control and Prevention.³ Family physicians frequently encounter this condition when screening for T2D in asymptomatic adults (ages 35 to 70 years) with overweight or obesity, as recommended by the US Preventive Services Task Force (grade “B”).⁴

To treat, or not? Studies have shown that interventions such as lifestyle modification and use of metformin by patients with prediabetes can decrease their risk for T2D.^5,6 In the Diabetes Prevention Program (DPP) study, progression from prediabetes to T2D was reduced to 14% with lifestyle modification and 22% with metformin use, vs 29% with placebo.⁷

However, there is disagreement about whether to treat prediabetes, particularly with medication. Some argue that metformin is a safe, effective, and cost-saving treatment to prevent T2D and its associated health consequences.⁸ The current American Diabetes Association (ADA) guidelines suggest that metformin be considered in certain patients with prediabetes and high-risk factors, especially younger age, obesity or hyperglycemia, or a history of gestational diabetes.⁹ However, only an estimated 1% to 4% of adults with prediabetes are prescribed metformin.¹⁰

Others argue that treating a preclinical condition is not a patient-centered approach, especially since not all patients with prediabetes progress to T2D and the risk for development or progression of retinopathy and microalbuminuria is extremely low if A1C levels remain < 7.0%.¹¹ By this standard, pharmacologic treatment should be initiated only if, or when, a patient develops T2D, with a focus on intensive lifestyle intervention for high-risk patients in the interim.¹¹

Given the conflicting viewpoints, ongoing long-term studies on T2D prevention will help guide treatment decisions for patients with prediabetes. The study by Lee et al¹ was the first to evaluate the effect of metformin or intensive lifestyle modification on all-cause and cause-specific mortality in patients at high risk for T2D.

Continue to: STUDY SUMMARY

No mortality benefit from metformin or lifestyle modification

This secondary analysis evaluated mortality outcomes for patients at risk for T2D who were part of the DPP trial and then were ­followed long term in the Diabetes Prevention Program Outcomes Study (DPPOS).¹ The initial DPP trial included 3234 adult patients at high risk for T2D (defined as having a BMI ≥ 24; an FPG of 95-125 mg/dL; and a 2-hour glucose level of 140-199 mg/dL). Participants were randomized into groups receiving either intensive lifestyle intervention (which focused on achieving ≥ 150 min/wk of exercise and ≥ 7% body weight loss), metformin 850 mg twice daily, or placebo twice daily; the latter 2 groups also received standard exercise and diet recommendations. Mean age was 51 years, mean BMI was 34, and 68% of participants were female.

Both the metformin and lifestyle intervention groups experienced decreases in weight and cardiovascular risk factors but not in mortality.

At the conclusion of the initial 5-year trial, treatment was unmasked and 86% of the patients continued to be followed for long-term outcomes. Patients in the lifestyle group were offered semiannual lifestyle reinforcement, while the metformin group continued to receive the twice-daily 850-mg dose unless a contraindication developed. If FPG levels increased to ≥ 140 mg/dL in the DPP study, or A1C increased to ≥ 7% in the DPPOS, study metformin was discontinued and management of the patient’s diabetes was transferred to their health care provider. By the end of the DPPOS, 53% of patients in the lifestyle group and 55% in the metformin group had progressed to T2D, compared with 60% in the placebo group (P = 0.003).

After a median 21-year follow-up interval, the investigators collected data on cause of death for patients and evaluated hazard ratios (HRs) for overall and cause-specific mortality. In total, 14% of the participants died, with no statistically significant difference in rates between the 3 groups. Cancer (37%) was the leading cause of death in all groups, followed by cardiovascular disease (CVD; 29%).

Compared with the placebo group, patients taking metformin did not have a decreased rate of overall mortality (HR = 0.99; 95% CI, 0.79-1.25), mortality from cancer (HR = 1.04; 95% CI, 0.72-1.52), or mortality due to CVD (HR = 1.08; 95% CI, 0.70-1.66). Similarly, compared with the placebo group, lifestyle intervention did not decrease overall mortality (HR = 1.02; 95% CI, 0.81-1.28), mortality from cancer (HR = 1.07; 95% CI, 0.74-1.55), or mortality due to CVD (HR = 1.18; 95% CI, 0.77-1.81). Results were similar when adjusted for other factors, including out-of-study metformin use, T2D status and duration, BMI change, and other cardiovascular risk factors.

WHAT’S NEW

Long-term data clarifylimits to interventions’ utility

This study looked at long-term follow-up data on mortality outcomes for patients with prediabetes treated with metformin or lifestyle intervention. Although these interventions did support weight loss, reduce the incidence of T2D, and lower cardiovascular risk factors (eg, hypertension, dyslipidemia), the comorbidity benefits did not affect risk for all-cause or cause-specific mortality, which were similar between the treatment and placebo groups.

Continue to: CAVEATS

Exclusion criteria, residual confounding may limit the findings

Patients with significant cardiovascular or renal disease were excluded, so results may not apply to patients with these comorbidities. Additionally, there was a high amount of “drop-in” use of metformin prescribed by physicians once patients developed T2D, which may not have been controlled for completely. And while the intensive lifestyle intervention group had specific goals, the metformin and placebo groups also were encouraged to follow standard diet and lifestyle recommendations—and during a bridge period, all participants were offered a modified group lifestyle intervention. However, multivariable adjustment did not change the study conclusion.

CHALLENGES TO IMPLEMENTATION

Physicians may be unwilling to change their current prescribing habits

Physicians may not be willing to change their practice of prescribing metformin in prediabetes based on a singular study (with residual confounding) that showed no long-term mortality differences between the study groups. However, there may be long-term morbidity differences of interest to patients that were not specifically evaluated in this study—such as quality-of-life benefits from weight loss that may outweigh the risks (eg, gastrointestinal adverse effects such as diarrhea, nausea, and abdominal pain) of metformin for some patients. Therefore, a discussion of the risks and benefits of treatment for prediabetes should be had with patients at high risk who would prefer a pharmacologic intervention.

ILLUSTRATIVE CASE

A 51-year-old woman with a history of elevated cholesterol and a body mass index (BMI) of 31 presents to your clinic for a scheduled follow-up visit to review recent blood test results. Her A1C was elevated at 5.9%. She wants to know if she should start medication now.

Prediabetes is a high-risk state that ­confers increased risk for type 2 ­diabetes (T2D). It is identified by impaired fasting glucose (fasting plasma glucose [FPG], 100-125 mg/dL), impaired glucose tolerance (2-hour oral glucose tolerance test, 140-199 mg/dL), or an elevated A1C (between 5.7% and 6.4%).²

An estimated 96 million ­Americans—38% of the US adult population—have prediabetes, according to the Centers for Disease Control and Prevention.³ Family physicians frequently encounter this condition when screening for T2D in asymptomatic adults (ages 35 to 70 years) with overweight or obesity, as recommended by the US Preventive Services Task Force (grade “B”).⁴

To treat, or not? Studies have shown that interventions such as lifestyle modification and use of metformin by patients with prediabetes can decrease their risk for T2D.^5,6 In the Diabetes Prevention Program (DPP) study, progression from prediabetes to T2D was reduced to 14% with lifestyle modification and 22% with metformin use, vs 29% with placebo.⁷

However, there is disagreement about whether to treat prediabetes, particularly with medication. Some argue that metformin is a safe, effective, and cost-saving treatment to prevent T2D and its associated health consequences.⁸ The current American Diabetes Association (ADA) guidelines suggest that metformin be considered in certain patients with prediabetes and high-risk factors, especially younger age, obesity or hyperglycemia, or a history of gestational diabetes.⁹ However, only an estimated 1% to 4% of adults with prediabetes are prescribed metformin.¹⁰

Others argue that treating a preclinical condition is not a patient-centered approach, especially since not all patients with prediabetes progress to T2D and the risk for development or progression of retinopathy and microalbuminuria is extremely low if A1C levels remain < 7.0%.¹¹ By this standard, pharmacologic treatment should be initiated only if, or when, a patient develops T2D, with a focus on intensive lifestyle intervention for high-risk patients in the interim.¹¹

Given the conflicting viewpoints, ongoing long-term studies on T2D prevention will help guide treatment decisions for patients with prediabetes. The study by Lee et al¹ was the first to evaluate the effect of metformin or intensive lifestyle modification on all-cause and cause-specific mortality in patients at high risk for T2D.

Continue to: STUDY SUMMARY

No mortality benefit from metformin or lifestyle modification

This secondary analysis evaluated mortality outcomes for patients at risk for T2D who were part of the DPP trial and then were ­followed long term in the Diabetes Prevention Program Outcomes Study (DPPOS).¹ The initial DPP trial included 3234 adult patients at high risk for T2D (defined as having a BMI ≥ 24; an FPG of 95-125 mg/dL; and a 2-hour glucose level of 140-199 mg/dL). Participants were randomized into groups receiving either intensive lifestyle intervention (which focused on achieving ≥ 150 min/wk of exercise and ≥ 7% body weight loss), metformin 850 mg twice daily, or placebo twice daily; the latter 2 groups also received standard exercise and diet recommendations. Mean age was 51 years, mean BMI was 34, and 68% of participants were female.

Both the metformin and lifestyle intervention groups experienced decreases in weight and cardiovascular risk factors but not in mortality.

At the conclusion of the initial 5-year trial, treatment was unmasked and 86% of the patients continued to be followed for long-term outcomes. Patients in the lifestyle group were offered semiannual lifestyle reinforcement, while the metformin group continued to receive the twice-daily 850-mg dose unless a contraindication developed. If FPG levels increased to ≥ 140 mg/dL in the DPP study, or A1C increased to ≥ 7% in the DPPOS, study metformin was discontinued and management of the patient’s diabetes was transferred to their health care provider. By the end of the DPPOS, 53% of patients in the lifestyle group and 55% in the metformin group had progressed to T2D, compared with 60% in the placebo group (P = 0.003).

After a median 21-year follow-up interval, the investigators collected data on cause of death for patients and evaluated hazard ratios (HRs) for overall and cause-specific mortality. In total, 14% of the participants died, with no statistically significant difference in rates between the 3 groups. Cancer (37%) was the leading cause of death in all groups, followed by cardiovascular disease (CVD; 29%).

Compared with the placebo group, patients taking metformin did not have a decreased rate of overall mortality (HR = 0.99; 95% CI, 0.79-1.25), mortality from cancer (HR = 1.04; 95% CI, 0.72-1.52), or mortality due to CVD (HR = 1.08; 95% CI, 0.70-1.66). Similarly, compared with the placebo group, lifestyle intervention did not decrease overall mortality (HR = 1.02; 95% CI, 0.81-1.28), mortality from cancer (HR = 1.07; 95% CI, 0.74-1.55), or mortality due to CVD (HR = 1.18; 95% CI, 0.77-1.81). Results were similar when adjusted for other factors, including out-of-study metformin use, T2D status and duration, BMI change, and other cardiovascular risk factors.

WHAT’S NEW

Long-term data clarifylimits to interventions’ utility

This study looked at long-term follow-up data on mortality outcomes for patients with prediabetes treated with metformin or lifestyle intervention. Although these interventions did support weight loss, reduce the incidence of T2D, and lower cardiovascular risk factors (eg, hypertension, dyslipidemia), the comorbidity benefits did not affect risk for all-cause or cause-specific mortality, which were similar between the treatment and placebo groups.

Continue to: CAVEATS

Exclusion criteria, residual confounding may limit the findings

Patients with significant cardiovascular or renal disease were excluded, so results may not apply to patients with these comorbidities. Additionally, there was a high amount of “drop-in” use of metformin prescribed by physicians once patients developed T2D, which may not have been controlled for completely. And while the intensive lifestyle intervention group had specific goals, the metformin and placebo groups also were encouraged to follow standard diet and lifestyle recommendations—and during a bridge period, all participants were offered a modified group lifestyle intervention. However, multivariable adjustment did not change the study conclusion.

CHALLENGES TO IMPLEMENTATION

Physicians may be unwilling to change their current prescribing habits

Physicians may not be willing to change their practice of prescribing metformin in prediabetes based on a singular study (with residual confounding) that showed no long-term mortality differences between the study groups. However, there may be long-term morbidity differences of interest to patients that were not specifically evaluated in this study—such as quality-of-life benefits from weight loss that may outweigh the risks (eg, gastrointestinal adverse effects such as diarrhea, nausea, and abdominal pain) of metformin for some patients. Therefore, a discussion of the risks and benefits of treatment for prediabetes should be had with patients at high risk who would prefer a pharmacologic intervention.

ILLUSTRATIVE CASE

A 51-year-old woman with a history of elevated cholesterol and a body mass index (BMI) of 31 presents to your clinic for a scheduled follow-up visit to review recent blood test results. Her A1C was elevated at 5.9%. She wants to know if she should start medication now.

Prediabetes is a high-risk state that ­confers increased risk for type 2 ­diabetes (T2D). It is identified by impaired fasting glucose (fasting plasma glucose [FPG], 100-125 mg/dL), impaired glucose tolerance (2-hour oral glucose tolerance test, 140-199 mg/dL), or an elevated A1C (between 5.7% and 6.4%).²

An estimated 96 million ­Americans—38% of the US adult population—have prediabetes, according to the Centers for Disease Control and Prevention.³ Family physicians frequently encounter this condition when screening for T2D in asymptomatic adults (ages 35 to 70 years) with overweight or obesity, as recommended by the US Preventive Services Task Force (grade “B”).⁴

To treat, or not? Studies have shown that interventions such as lifestyle modification and use of metformin by patients with prediabetes can decrease their risk for T2D.^5,6 In the Diabetes Prevention Program (DPP) study, progression from prediabetes to T2D was reduced to 14% with lifestyle modification and 22% with metformin use, vs 29% with placebo.⁷

However, there is disagreement about whether to treat prediabetes, particularly with medication. Some argue that metformin is a safe, effective, and cost-saving treatment to prevent T2D and its associated health consequences.⁸ The current American Diabetes Association (ADA) guidelines suggest that metformin be considered in certain patients with prediabetes and high-risk factors, especially younger age, obesity or hyperglycemia, or a history of gestational diabetes.⁹ However, only an estimated 1% to 4% of adults with prediabetes are prescribed metformin.¹⁰

Others argue that treating a preclinical condition is not a patient-centered approach, especially since not all patients with prediabetes progress to T2D and the risk for development or progression of retinopathy and microalbuminuria is extremely low if A1C levels remain < 7.0%.¹¹ By this standard, pharmacologic treatment should be initiated only if, or when, a patient develops T2D, with a focus on intensive lifestyle intervention for high-risk patients in the interim.¹¹

Given the conflicting viewpoints, ongoing long-term studies on T2D prevention will help guide treatment decisions for patients with prediabetes. The study by Lee et al¹ was the first to evaluate the effect of metformin or intensive lifestyle modification on all-cause and cause-specific mortality in patients at high risk for T2D.

Continue to: STUDY SUMMARY

No mortality benefit from metformin or lifestyle modification

This secondary analysis evaluated mortality outcomes for patients at risk for T2D who were part of the DPP trial and then were ­followed long term in the Diabetes Prevention Program Outcomes Study (DPPOS).¹ The initial DPP trial included 3234 adult patients at high risk for T2D (defined as having a BMI ≥ 24; an FPG of 95-125 mg/dL; and a 2-hour glucose level of 140-199 mg/dL). Participants were randomized into groups receiving either intensive lifestyle intervention (which focused on achieving ≥ 150 min/wk of exercise and ≥ 7% body weight loss), metformin 850 mg twice daily, or placebo twice daily; the latter 2 groups also received standard exercise and diet recommendations. Mean age was 51 years, mean BMI was 34, and 68% of participants were female.

Both the metformin and lifestyle intervention groups experienced decreases in weight and cardiovascular risk factors but not in mortality.

At the conclusion of the initial 5-year trial, treatment was unmasked and 86% of the patients continued to be followed for long-term outcomes. Patients in the lifestyle group were offered semiannual lifestyle reinforcement, while the metformin group continued to receive the twice-daily 850-mg dose unless a contraindication developed. If FPG levels increased to ≥ 140 mg/dL in the DPP study, or A1C increased to ≥ 7% in the DPPOS, study metformin was discontinued and management of the patient’s diabetes was transferred to their health care provider. By the end of the DPPOS, 53% of patients in the lifestyle group and 55% in the metformin group had progressed to T2D, compared with 60% in the placebo group (P = 0.003).

After a median 21-year follow-up interval, the investigators collected data on cause of death for patients and evaluated hazard ratios (HRs) for overall and cause-specific mortality. In total, 14% of the participants died, with no statistically significant difference in rates between the 3 groups. Cancer (37%) was the leading cause of death in all groups, followed by cardiovascular disease (CVD; 29%).

Compared with the placebo group, patients taking metformin did not have a decreased rate of overall mortality (HR = 0.99; 95% CI, 0.79-1.25), mortality from cancer (HR = 1.04; 95% CI, 0.72-1.52), or mortality due to CVD (HR = 1.08; 95% CI, 0.70-1.66). Similarly, compared with the placebo group, lifestyle intervention did not decrease overall mortality (HR = 1.02; 95% CI, 0.81-1.28), mortality from cancer (HR = 1.07; 95% CI, 0.74-1.55), or mortality due to CVD (HR = 1.18; 95% CI, 0.77-1.81). Results were similar when adjusted for other factors, including out-of-study metformin use, T2D status and duration, BMI change, and other cardiovascular risk factors.

WHAT’S NEW

Long-term data clarifylimits to interventions’ utility

This study looked at long-term follow-up data on mortality outcomes for patients with prediabetes treated with metformin or lifestyle intervention. Although these interventions did support weight loss, reduce the incidence of T2D, and lower cardiovascular risk factors (eg, hypertension, dyslipidemia), the comorbidity benefits did not affect risk for all-cause or cause-specific mortality, which were similar between the treatment and placebo groups.

Continue to: CAVEATS

Exclusion criteria, residual confounding may limit the findings

Patients with significant cardiovascular or renal disease were excluded, so results may not apply to patients with these comorbidities. Additionally, there was a high amount of “drop-in” use of metformin prescribed by physicians once patients developed T2D, which may not have been controlled for completely. And while the intensive lifestyle intervention group had specific goals, the metformin and placebo groups also were encouraged to follow standard diet and lifestyle recommendations—and during a bridge period, all participants were offered a modified group lifestyle intervention. However, multivariable adjustment did not change the study conclusion.

CHALLENGES TO IMPLEMENTATION

Physicians may be unwilling to change their current prescribing habits

Physicians may not be willing to change their practice of prescribing metformin in prediabetes based on a singular study (with residual confounding) that showed no long-term mortality differences between the study groups. However, there may be long-term morbidity differences of interest to patients that were not specifically evaluated in this study—such as quality-of-life benefits from weight loss that may outweigh the risks (eg, gastrointestinal adverse effects such as diarrhea, nausea, and abdominal pain) of metformin for some patients. Therefore, a discussion of the risks and benefits of treatment for prediabetes should be had with patients at high risk who would prefer a pharmacologic intervention.

This transcript has been edited for clarity.

Michelle L. O’Donoghue, MD, MPH: Hi. This is Dr. Michelle O’Donoghue reporting for Medscape. Joining me today is Dr. Sahil Parikh, who’s a cardiologist and an interventionalist at Columbia University. He’s an associate professor of medicine.

We’ll be discussing two interesting trials that were presented at the ESC Congress here in Amsterdam. They do have the potential to be very practice-changing, so I think it’s worth talking about.
 

The FIRE trial

The first trial we’ll be talking about is the FIRE trial. Perhaps setting the stage, Sahil, I’d love to get your thoughts. We’ve had data in this space to suggest that, for patients with STEMI [ST-segment elevation myocardial infarction], a strategy of complete revascularization – and not only treating the culprit lesion but also treating additional lesions – may be of benefit. Where does that lead us in terms of what we didn’t know?

Sahil A. Parikh, MD: I think that the practice has moved, at least in the United States, over the past two decades, from staging percutaneous coronary interventions over 30 days from index to intervention to now trying to do patients in the same hospitalization whenever possible to achieve complete revascularization.

I think these data support not only that complete revascularization is compulsory now in these patients, but also doing it sooner rather than later, and that the benefit applies to most of the patients that we see in clinical practice. In the earlier data, the patients were relatively youthful – under Medicare age, less than 65 – and now this dataset has a median age of 80. This is more like the real-world clinical practice that most of us are encountering, and it extends the benefit, perhaps, greater than we’ve ever seen before.

O’Donoghue: The FIRE trial is interesting. As you say, it enrolled patients who were over the age of 75, where I think that some proceduralists are probably a little bit hesitant to think about complete revascularization due to concerns about any additional contrast load on their kidneys and other types of comorbidities. Of course, for any trial, there’s going to be some patient selection.

I think it’s very reassuring that even in this older patient group, a strategy of treating all the lesions – and not only in STEMI but also in non-STEMI patients – reduced cardiovascular events and mortality. I was really quite impressed by the mortality benefit.

Parikh: The mortality curve is almost surprising to me. On the other hand, it emboldens us now that we can treat these patients more completely and earlier in their clinical presentation. Certainly, we worried about contrast exposure and the duration of procedures in this older population, but it seems that the benefit that’s derived, which we saw in younger patients where we had a natural inclination to be more aggressive, extends also to this older population.
 

MULTISTARS AMI

O’Donoghue: To the question of timing, as you mentioned, prior to this, we had a study presented earlier this year, the BIOVASC trial, which also was suggestive that maybe earlier complete revascularization was better. But it wasn’t a significant difference, at least for the primary outcome. Now we have MULTISTARS AMI, which is very supportive of what we saw earlier this year, suggesting that complete revascularization really at the time that you’re treating the culprit may be the way to go.

Parikh: All of us, as interventionalists, are circumspect about what we might do in the middle of the night versus what we would do in the light of day. Certainly it seems clear, particularly if it’s straightforward anatomy, that taking care of it in the index procedure is not only saving contrast and fluoroscopy time, but it’s also providing a clinical benefit to the patients. That’s something that will also impact how clinicians interpret these data. Previously, there was always a question about whether we should just do it in the same hospitalization or do it at the same time. I think now, increasingly, we’re emboldened to do more in the index procedure.

O’Donoghue: When you’re thinking about nonculprit lesions and which ones to treat, do you always make that determination based on physiologic guidance of some kind? Are you using instantaneous wave-free ratio? What’s your practice?

Parikh: In the acute setting, imaging is superior for at least the assessment of which is a culprit. If you see a ruptured atherothrombotic situation on optical coherence tomography, for example, that’s fairly convincing and definitive. In the absence of that physiology, we are taught to avoid in the infarct-related artery because of potential spuriously false-negative findings.

In this situation, certainly, an imaging subgroup probably would be helpful because some of the benefit is almost certainly derived from identifying the infarct-related artery by accident – in other words, doing what you thought was the nonculprit artery, which is, in fact, the culprit. I think that probably is part of this. As somebody who uses imaging in the overwhelming number of my cases, I think that imaging would be an important surrogate to this.
 

Index procedure versus staged

O’Donoghue: For the operator who is coming in to do their STEMI case at 2:00 in the morning, would these data now push you toward doing complete revascularization at that time of night, or do you think that there is wiggle room in terms of interpreting these results regarding timing, where as long as you were doing it before hospital discharge and not, let’s say, 30 days out, that you may be able to derive the same benefit? What are some of the pros and cons?

Parikh: There’s definitely a fatigue factor in the middle of the night if it’s a particularly arduous intervention for the index infarct-related artery. I think there’s a human element where it may make sense just to stop and then bring the patient back in the same hospitalization. It’s clear, though, that doing complete revascularization is better and doing it sooner is better. How soon one actually does it is a judgment call, as ever.

In our practice, we’ve been pushing ourselves to get most of the patients done in their index hospitalization. If you have a left-sided culprit, the left anterior descending artery, for example, and there’s a high-grade stenosis in the circumflex, it may make sense to take care of that in the same index procedure. If, on the other hand, it’s in the right coronary artery where you have to put a new guide in and spend more time, that may be a patient whom you stage. I think those nuances will come up as interventionalists look at the subgroup analysis data more carefully.

O’Donoghue: Those are great points, and I think they also underscore that we always need to think about what type of patient was enrolled in these studies. Certainly, if you have somebody with renal dysfunction, there might be more concern about giving them a large contrast load all in one sitting, albeit hard to know whether they do or not. But spacing that out by just a couple of days would really have a big impact.

Parikh: Very often in the STEMI patient, you don’t have the benefit of knowing the creatinine. The patient will come in immediately, if not directly from the ambulance to the cath lab, and there are no laboratories at all to work with. If the patient has never been seen in the system before, you won’t know. Again, in those situations, one may have pause, particularly if it’s an older patient. I think what’s reassuring, though, is that the data are supportive of being more aggressive earlier, and certainly this is the dataset that we were looking for.

O’Donoghue: To summarize, the two key takeaways are that, one, we now have more data to support a complete revascularization strategy and even extending that now to non-STEMI patients. Two, sooner appears to be better, so ideally, all done at the time of the index procedure. I think this is very interesting science and we’ll see how it changes practice.

Thanks for joining me today. Signing off for Medscape, this is Dr. Michelle O’Donoghue.

Michelle O’Donoghue is a cardiologist at Brigham and Women’s Hospital and senior investigator with the TIMI Study Group.

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

This transcript has been edited for clarity.

Michelle L. O’Donoghue, MD, MPH: Hi. This is Dr. Michelle O’Donoghue reporting for Medscape. Joining me today is Dr. Sahil Parikh, who’s a cardiologist and an interventionalist at Columbia University. He’s an associate professor of medicine.

We’ll be discussing two interesting trials that were presented at the ESC Congress here in Amsterdam. They do have the potential to be very practice-changing, so I think it’s worth talking about.
 

The FIRE trial

The first trial we’ll be talking about is the FIRE trial. Perhaps setting the stage, Sahil, I’d love to get your thoughts. We’ve had data in this space to suggest that, for patients with STEMI [ST-segment elevation myocardial infarction], a strategy of complete revascularization – and not only treating the culprit lesion but also treating additional lesions – may be of benefit. Where does that lead us in terms of what we didn’t know?

Sahil A. Parikh, MD: I think that the practice has moved, at least in the United States, over the past two decades, from staging percutaneous coronary interventions over 30 days from index to intervention to now trying to do patients in the same hospitalization whenever possible to achieve complete revascularization.

I think these data support not only that complete revascularization is compulsory now in these patients, but also doing it sooner rather than later, and that the benefit applies to most of the patients that we see in clinical practice. In the earlier data, the patients were relatively youthful – under Medicare age, less than 65 – and now this dataset has a median age of 80. This is more like the real-world clinical practice that most of us are encountering, and it extends the benefit, perhaps, greater than we’ve ever seen before.

O’Donoghue: The FIRE trial is interesting. As you say, it enrolled patients who were over the age of 75, where I think that some proceduralists are probably a little bit hesitant to think about complete revascularization due to concerns about any additional contrast load on their kidneys and other types of comorbidities. Of course, for any trial, there’s going to be some patient selection.

I think it’s very reassuring that even in this older patient group, a strategy of treating all the lesions – and not only in STEMI but also in non-STEMI patients – reduced cardiovascular events and mortality. I was really quite impressed by the mortality benefit.

Parikh: The mortality curve is almost surprising to me. On the other hand, it emboldens us now that we can treat these patients more completely and earlier in their clinical presentation. Certainly, we worried about contrast exposure and the duration of procedures in this older population, but it seems that the benefit that’s derived, which we saw in younger patients where we had a natural inclination to be more aggressive, extends also to this older population.
 

MULTISTARS AMI

O’Donoghue: To the question of timing, as you mentioned, prior to this, we had a study presented earlier this year, the BIOVASC trial, which also was suggestive that maybe earlier complete revascularization was better. But it wasn’t a significant difference, at least for the primary outcome. Now we have MULTISTARS AMI, which is very supportive of what we saw earlier this year, suggesting that complete revascularization really at the time that you’re treating the culprit may be the way to go.

Parikh: All of us, as interventionalists, are circumspect about what we might do in the middle of the night versus what we would do in the light of day. Certainly it seems clear, particularly if it’s straightforward anatomy, that taking care of it in the index procedure is not only saving contrast and fluoroscopy time, but it’s also providing a clinical benefit to the patients. That’s something that will also impact how clinicians interpret these data. Previously, there was always a question about whether we should just do it in the same hospitalization or do it at the same time. I think now, increasingly, we’re emboldened to do more in the index procedure.

O’Donoghue: When you’re thinking about nonculprit lesions and which ones to treat, do you always make that determination based on physiologic guidance of some kind? Are you using instantaneous wave-free ratio? What’s your practice?

Parikh: In the acute setting, imaging is superior for at least the assessment of which is a culprit. If you see a ruptured atherothrombotic situation on optical coherence tomography, for example, that’s fairly convincing and definitive. In the absence of that physiology, we are taught to avoid in the infarct-related artery because of potential spuriously false-negative findings.

In this situation, certainly, an imaging subgroup probably would be helpful because some of the benefit is almost certainly derived from identifying the infarct-related artery by accident – in other words, doing what you thought was the nonculprit artery, which is, in fact, the culprit. I think that probably is part of this. As somebody who uses imaging in the overwhelming number of my cases, I think that imaging would be an important surrogate to this.
 

Index procedure versus staged

O’Donoghue: For the operator who is coming in to do their STEMI case at 2:00 in the morning, would these data now push you toward doing complete revascularization at that time of night, or do you think that there is wiggle room in terms of interpreting these results regarding timing, where as long as you were doing it before hospital discharge and not, let’s say, 30 days out, that you may be able to derive the same benefit? What are some of the pros and cons?

Parikh: There’s definitely a fatigue factor in the middle of the night if it’s a particularly arduous intervention for the index infarct-related artery. I think there’s a human element where it may make sense just to stop and then bring the patient back in the same hospitalization. It’s clear, though, that doing complete revascularization is better and doing it sooner is better. How soon one actually does it is a judgment call, as ever.

In our practice, we’ve been pushing ourselves to get most of the patients done in their index hospitalization. If you have a left-sided culprit, the left anterior descending artery, for example, and there’s a high-grade stenosis in the circumflex, it may make sense to take care of that in the same index procedure. If, on the other hand, it’s in the right coronary artery where you have to put a new guide in and spend more time, that may be a patient whom you stage. I think those nuances will come up as interventionalists look at the subgroup analysis data more carefully.

O’Donoghue: Those are great points, and I think they also underscore that we always need to think about what type of patient was enrolled in these studies. Certainly, if you have somebody with renal dysfunction, there might be more concern about giving them a large contrast load all in one sitting, albeit hard to know whether they do or not. But spacing that out by just a couple of days would really have a big impact.

Parikh: Very often in the STEMI patient, you don’t have the benefit of knowing the creatinine. The patient will come in immediately, if not directly from the ambulance to the cath lab, and there are no laboratories at all to work with. If the patient has never been seen in the system before, you won’t know. Again, in those situations, one may have pause, particularly if it’s an older patient. I think what’s reassuring, though, is that the data are supportive of being more aggressive earlier, and certainly this is the dataset that we were looking for.

O’Donoghue: To summarize, the two key takeaways are that, one, we now have more data to support a complete revascularization strategy and even extending that now to non-STEMI patients. Two, sooner appears to be better, so ideally, all done at the time of the index procedure. I think this is very interesting science and we’ll see how it changes practice.

Thanks for joining me today. Signing off for Medscape, this is Dr. Michelle O’Donoghue.

Michelle O’Donoghue is a cardiologist at Brigham and Women’s Hospital and senior investigator with the TIMI Study Group.

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

This transcript has been edited for clarity.

Michelle L. O’Donoghue, MD, MPH: Hi. This is Dr. Michelle O’Donoghue reporting for Medscape. Joining me today is Dr. Sahil Parikh, who’s a cardiologist and an interventionalist at Columbia University. He’s an associate professor of medicine.

We’ll be discussing two interesting trials that were presented at the ESC Congress here in Amsterdam. They do have the potential to be very practice-changing, so I think it’s worth talking about.
 

The FIRE trial

The first trial we’ll be talking about is the FIRE trial. Perhaps setting the stage, Sahil, I’d love to get your thoughts. We’ve had data in this space to suggest that, for patients with STEMI [ST-segment elevation myocardial infarction], a strategy of complete revascularization – and not only treating the culprit lesion but also treating additional lesions – may be of benefit. Where does that lead us in terms of what we didn’t know?

Sahil A. Parikh, MD: I think that the practice has moved, at least in the United States, over the past two decades, from staging percutaneous coronary interventions over 30 days from index to intervention to now trying to do patients in the same hospitalization whenever possible to achieve complete revascularization.

I think these data support not only that complete revascularization is compulsory now in these patients, but also doing it sooner rather than later, and that the benefit applies to most of the patients that we see in clinical practice. In the earlier data, the patients were relatively youthful – under Medicare age, less than 65 – and now this dataset has a median age of 80. This is more like the real-world clinical practice that most of us are encountering, and it extends the benefit, perhaps, greater than we’ve ever seen before.

O’Donoghue: The FIRE trial is interesting. As you say, it enrolled patients who were over the age of 75, where I think that some proceduralists are probably a little bit hesitant to think about complete revascularization due to concerns about any additional contrast load on their kidneys and other types of comorbidities. Of course, for any trial, there’s going to be some patient selection.

I think it’s very reassuring that even in this older patient group, a strategy of treating all the lesions – and not only in STEMI but also in non-STEMI patients – reduced cardiovascular events and mortality. I was really quite impressed by the mortality benefit.

Parikh: The mortality curve is almost surprising to me. On the other hand, it emboldens us now that we can treat these patients more completely and earlier in their clinical presentation. Certainly, we worried about contrast exposure and the duration of procedures in this older population, but it seems that the benefit that’s derived, which we saw in younger patients where we had a natural inclination to be more aggressive, extends also to this older population.
 

MULTISTARS AMI

O’Donoghue: To the question of timing, as you mentioned, prior to this, we had a study presented earlier this year, the BIOVASC trial, which also was suggestive that maybe earlier complete revascularization was better. But it wasn’t a significant difference, at least for the primary outcome. Now we have MULTISTARS AMI, which is very supportive of what we saw earlier this year, suggesting that complete revascularization really at the time that you’re treating the culprit may be the way to go.

Parikh: All of us, as interventionalists, are circumspect about what we might do in the middle of the night versus what we would do in the light of day. Certainly it seems clear, particularly if it’s straightforward anatomy, that taking care of it in the index procedure is not only saving contrast and fluoroscopy time, but it’s also providing a clinical benefit to the patients. That’s something that will also impact how clinicians interpret these data. Previously, there was always a question about whether we should just do it in the same hospitalization or do it at the same time. I think now, increasingly, we’re emboldened to do more in the index procedure.

O’Donoghue: When you’re thinking about nonculprit lesions and which ones to treat, do you always make that determination based on physiologic guidance of some kind? Are you using instantaneous wave-free ratio? What’s your practice?

Parikh: In the acute setting, imaging is superior for at least the assessment of which is a culprit. If you see a ruptured atherothrombotic situation on optical coherence tomography, for example, that’s fairly convincing and definitive. In the absence of that physiology, we are taught to avoid in the infarct-related artery because of potential spuriously false-negative findings.

In this situation, certainly, an imaging subgroup probably would be helpful because some of the benefit is almost certainly derived from identifying the infarct-related artery by accident – in other words, doing what you thought was the nonculprit artery, which is, in fact, the culprit. I think that probably is part of this. As somebody who uses imaging in the overwhelming number of my cases, I think that imaging would be an important surrogate to this.
 

Index procedure versus staged

O’Donoghue: For the operator who is coming in to do their STEMI case at 2:00 in the morning, would these data now push you toward doing complete revascularization at that time of night, or do you think that there is wiggle room in terms of interpreting these results regarding timing, where as long as you were doing it before hospital discharge and not, let’s say, 30 days out, that you may be able to derive the same benefit? What are some of the pros and cons?

Parikh: There’s definitely a fatigue factor in the middle of the night if it’s a particularly arduous intervention for the index infarct-related artery. I think there’s a human element where it may make sense just to stop and then bring the patient back in the same hospitalization. It’s clear, though, that doing complete revascularization is better and doing it sooner is better. How soon one actually does it is a judgment call, as ever.

In our practice, we’ve been pushing ourselves to get most of the patients done in their index hospitalization. If you have a left-sided culprit, the left anterior descending artery, for example, and there’s a high-grade stenosis in the circumflex, it may make sense to take care of that in the same index procedure. If, on the other hand, it’s in the right coronary artery where you have to put a new guide in and spend more time, that may be a patient whom you stage. I think those nuances will come up as interventionalists look at the subgroup analysis data more carefully.

O’Donoghue: Those are great points, and I think they also underscore that we always need to think about what type of patient was enrolled in these studies. Certainly, if you have somebody with renal dysfunction, there might be more concern about giving them a large contrast load all in one sitting, albeit hard to know whether they do or not. But spacing that out by just a couple of days would really have a big impact.

Parikh: Very often in the STEMI patient, you don’t have the benefit of knowing the creatinine. The patient will come in immediately, if not directly from the ambulance to the cath lab, and there are no laboratories at all to work with. If the patient has never been seen in the system before, you won’t know. Again, in those situations, one may have pause, particularly if it’s an older patient. I think what’s reassuring, though, is that the data are supportive of being more aggressive earlier, and certainly this is the dataset that we were looking for.

O’Donoghue: To summarize, the two key takeaways are that, one, we now have more data to support a complete revascularization strategy and even extending that now to non-STEMI patients. Two, sooner appears to be better, so ideally, all done at the time of the index procedure. I think this is very interesting science and we’ll see how it changes practice.

Thanks for joining me today. Signing off for Medscape, this is Dr. Michelle O’Donoghue.

Michelle O’Donoghue is a cardiologist at Brigham and Women’s Hospital and senior investigator with the TIMI Study Group.

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

ABSTRACT

Background: We sought to examine whether electrical impedance spectroscopy (EIS), a diagnostic tool approved by the US Food and Drug Administration for the evaluation of pigmented skin lesions (PSLs), is beneficial to primary care providers (PCPs) by comparing the accuracy of PCPs’ management decisions for PSLs based on visual examination alone with those based on concurrent visual and EIS evaluation.

Methods: Physicians and nurse practitioners (NPs) participated in an anonymous online survey in which they viewed clinical images of PSLs and were asked to make 2 clinical decisions before and after being provided an EIS score that indicated the likelihood that the lesion was a melanoma. They were asked (1) if they would biopsy the lesion/refer the patient out and (2) what they expected the pathology results would show.

Results: Forty-four physicians and 17 NPs participated, making clinical decisions for 1354 presented lesions. Overall, with the addition of EIS to visual inspection of clinical images, the sensitivity of biopsy/referral decisions for melanomas and severely dysplastic nevi (SDN) increased from 69.2% to 90.0% (P < .001), while specificity increased from 44.0% to 72.6% (P < .001). Physicians and NPs, regardless of years of experience, each saw significant improvements in sensitivity, specificity, and diagnostic accuracy with the addition of EIS scores.

Conclusions: The incorporation of EIS data into clinical decision-making by PCPs significantly increased the sensitivity and specificity of biopsy/referral decisions for melanomas and SDN and overall diagnostic accuracy compared with visual inspection alone. The results of this study suggest that diagnostic accuracy for PSLs by PCPs may be improved with adjunctive use of EIS with visual inspection.

Primary care providers (PCPs) are often the first line of defense in detecting skin cancers. For patients with concerning skin lesions, PCPs may choose to perform a biopsy or facilitate access to specialty services (eg, Dermatology). Consequently, PCPs play a critical role in the timely detection of skin cancers, and it is paramount to employ continually improving detection methods, such as the application of technologic advances.¹

Differentiating benign nevi from melanoma and severely dysplastic nevi (SDN), both of which warrant excision, poses a unique challenge to clinicians examining pigmented skin lesions (PSLs). PCPs often rely on visual inspection to differentiate benign skin lesions from malignant skin cancers. In some primary care practices, dermoscopy, which involves using a handheld device to evaluate lesions with polarized light and magnification, is used to improve melanoma detection. However, while visual inspection and dermoscopy are valid, effective techniques for the diagnosis of melanocytic lesions, in many instances they still can lead to missed cancers or unnecessary biopsies and specialty referrals. Adjunctive use of dermoscopy with visual inspection has been shown to increase the probability of skin cancer detection, but it fails to achieve a near-100% success rate.² Furthermore, dermoscopy is heavily user-dependent, requiring significant training and experience for appropriate use.³

Another option is an electrical impedance spectroscopy (EIS) device (Nevisense, Scibase, Stockholm, Sweden), which has been approved by the US Food and Drug Administration (FDA) to assist in the detection of melanoma and differentiation from benign PSLs.⁴ EIS is a noninvasive, rapidly applied technology designed to accompany the visual examination of melanocytic lesions in office, with or without dermoscopy. Still relatively new, the technology is employed today by many dermatologists, increasing diagnostic accuracy for PSLs.⁵ The lightweight and portable instrument features a handheld probe, which is held against a lesion to obtain a reading. EIS uses a low-voltage electrode to apply a harmless electrical current to the skin at various frequencies.⁶ As benign and malignant tissues vary in cell shape, size, and composition, EIS distinguishes differential electrical resistance of the tissue to aid in diagnosis.⁷

Continue to: EIS provides high-sensitivity...

EIS provides high-sensitivity melanoma diagnosis vs histopathologic confirmation from biopsies, with 1 study showing a 96.6% sensitivity rating, detecting 256 of 265 melanomas.⁴ The EIS device, by measuring differences in electrical resistance between benign and cancerous cells, outputs a simple integer score ranging from 0 to 10 associated with the likelihood of the lesion being a melanoma.⁸ Based on data from the Nevisense pivotal trial,⁴ Nevisense reports that scores of 0 to 3 carry a negative predictive value of 99% for melanoma, whereas scores of 4 to 10 signify increasingly greater positive predictive values from 7% to 61%.

Findings suggest that the use of electrical impedance spectroscopy is particularly advantageous to clinicians who are less proficient in assessing melanocytic lesions.

We aimed to assess whether EIS may be beneficial to PCPs by comparing the accuracy of clinical decision-making for PSLs based on visual examination alone with that based on concurrent visual and EIS evaluation.

METHODS

A questionnaire was distributed via email to 142 clinicians at clinics affiliated with either of 2 organizations delivering care to the New York City area through a network of community health centers: the Institute for Family Health (IFH) and the Community Healthcare Network (CHN). Of these recipients, 72 were affiliated with IFH across 27 community health centers and 70 were affiliated with CHN across 14 community health centers. Recipients were physicians and nurse practitioners (NPs) practicing at primary health care facilities.

Survey instrument. The first section of the survey instrument (APPENDIX) solicited demographic information and explained how to apply the EIS scores for diagnostic ­decision-making. The second featured images of 12 randomly selected, histologically confirmed, and EIS-evaluated PSLs from a previously published prospective blinded trial of 2416 lesions.⁴ The Institutional Review Board of the Icahn School of Medicine at Mount Sinai reviewed and approved the study and survey instrument.

Clinical images of these lesions, comprising 4 melanocytic nevi, 4 dysplastic nevi (including 3 mild-moderately dysplastic and 1 severely dysplastic nevus), and 4 melanomas, were first presented to respondents with 2 tasks: (1) rate on a scale of 1 to 5 their likelihood to biopsy or refer this lesion to a dermatologist (1: not likely; 5: extremely likely); and (2) select what they expect the pathology results to be: melanocytic nevus, dysplastic nevus, or malignant melanoma. Subsequently, respondents repeated the assessments after being presented with the EIS score for the same lesion in conjunction with the clinical image.

Continue to: Analysis

Analysis. A biopsy or referral rating of 4 or 5 was considered a decision to biopsy or refer (ie, a diagnostic decision consistent with melanoma or SDN warranting excision), whereas a selection of 1 to 3 was considered a decision not to biopsy or refer (ie, a diagnostic decision consistent with a benign PSL). The sensitivity and specificity of biopsy/­referral decisions for melanomas and SDN, the proportion of missed melanomas and SDN, and the proportion of biopsy/referral decisions for benign lesions were separately determined for visual inspection alone and visual inspection with EIS score. Similarly, diagnostic accuracy was calculated for these clinical scenarios. These metrics were further stratified among different subsets of the respondent population. Differences in sensitivity, specificity, biopsy/referral decision proportions, and diagnostic accuracy were calculated using McNemar’s test for paired proportions.

RESULTS

Sixty-one respondents, comprising 44 physicians and 17 NPs, completed the survey, yielding a response rate of 43% (TABLE 1). In total, 1354 clinical decisions (677 based on visual inspection alone and 677 based on visual inspection plus EIS) were made. A biopsy/­referral decision was made after assessing 416 of 677 cases (61%) with visual inspection alone and 360 of 677 cases (53%) when relying on visual inspection plus EIS. None of the respondents reported any prior experience with EIS.

When incorporating EIS scores, respondents’ mean sensitivity for melanomas and SDN increased from 69.2% to 90.0% (P < .001) and specificity from 44.0% to 72.6% (P < .001; TABLE 2). At baseline, physicians demonstrated a sensitivity and specificity of 74.6% and 46.5%, respectively, while NPs demonstrated a sensitivity and specificity of 56.1% and 37.9%, respectively.

All respondent subgroups stratified by occupation and years of experience saw significant increases in both sensitivity and specificity upon the incorporation of EIS scores, with NPs seeing a greater increase in sensitivity (56.1% vs 85.4%; P < .001) and specificity (37.9% vs 69.0%; P < .001) than physicians (sensitivity: 74.6% vs 91.9%; P < .001; specificity: 46.5% vs 74.1%; P < .001). The only difference in diagnostic performance based on years of experience was a greater pre-EIS sensitivity by clinicians who had been in practice for ≥ 15 years, compared with those in practice for shorter periods (TABLE 2).

The improvements, seen in clinicians of varying training and experience, suggest that the learning curve of EIS may not be as steep as that of dermoscopy.

Diagnostic accuracy increased significantly from 48% when based on visual inspection alone to 73% with the addition of EIS scores (P < .001; TABLE 3). Physicians and NPs each significantly increased their diagnostic accuracy upon the incorporation of EIS, with NPs exhibiting the greatest increase (from 36.9% to 65.7%; P < .001). PCPs with 6 to 14 years of experience saw the greatest increase in diagnostic accuracy when adding EIS (45.9% vs 76.4%; P < .001). Overall, the addition of EIS scores resulted in 58 fewer missed melanomas and SDN and 114 fewer benign referrals or biopsies (TABLE 4).

Continue to: DISCUSSION

DISCUSSION

Primary care evaluation plays a significant role in the diagnosis and management of PSLs, ultimately shaping outcomes for patients with melanoma. Improved accuracy of PSL classification could yield greater sensitivity for the diagnosis of melanomas and high-risk melanocytic lesions at earlier stages, while also reducing the number of unnecessary biopsies and referrals—leading to decreased patient morbidity and mortality and reduced health care spending.⁹

Diagnostic tools are valuable insofar as they can improve accuracy and positively impact clinical management and patient outcomes.¹⁰ In this case, increased sensitivity reduced missed melanoma diagnoses, while increased specificity avoided the additional costs and patient toll associated with a biopsy or referral for a benign lesion.

Dermoscopy has been shown to improve the sensitivity and specificity of PSL diagnosis compared with visual inspection alone; however, without substantial training and experience, accuracy with dermoscopy can be no better than examination with the naked eye.^3,11,12 The dropout rates are high for training PCPs in its use, given that several months of training may be needed for competent use.^13,14 To improve the clinical management of PSLs broadly in primary care, a need exists for easy-to-use adjunctive tools that increase diagnostic accuracy.¹⁵

In this study, with only a brief explanation of how to interpret EIS scores, clinicians without any prior experience using EIS demonstrated significantly improved accuracy in deciding appropriate management and classifying melanocytic lesions with the addition of EIS to visual inspection. These improvements, seen in clinicians of varying training and experience, suggest that the learning curve of EIS may not be as steep as that of dermoscopy.

The greater baseline sensitivity, specificity, and diagnostic accuracy of physicians’ clinical decision-making compared with NPs before the incorporation of EIS in the study may be a product of comparatively more extensive medical training. In addition, EIS yielded a greater benefit to NPs than to physicians, with greater increases in sensitivity and specificity noted. This suggests that the use of EIS is particularly advantageous to clinicians who are less proficient in assessing melanocytic lesions. Using visual inspection alone, more experienced respondents made biopsy/referral decisions with greater sensitivity but similar specificity to those with less experience. With the incorporation of EIS scores, the sensitivity and specificity of respondents’ clinical decision-making rose to comparable levels across all experience groups, providing further indication of EIS’s particular value to clinicians who are less proficient in PSL evaluation.

Continue to: This technology holds the potential...

This technology holds the potential to be seamlessly implemented into primary care practice, given that dermatology expertise training is not required to use the EIS device; this could allow for EIS measurement of lesions to be delegated to office staff (eg, nurses, medical assistants).¹⁶ Future studies are needed to assess EIS use among PCPs in a real-world setting, where factors such as its application on nonmelanocytic lesions (eg, seborrheic keratoses) and its pairing with patient historical data could produce varying results.

Limitations. While revealing, this study had its limitations. Respondents did not have access to additional pertinent clinical information, such as patients’ histories and risk factors. Clinical decisions in this survey were made based on digital images rather than in vivo examination. This may not represent a real-life evaluation; there is the potential for minimization of the true consequences of a missed melanoma or unnecessary biopsy in the minds of participants, and this does not factor in the operation of the actual EIS device. The Hawthorne effect may also have influenced PCPs’ diagnostic selections. Also, the limited sample size constitutes another limitation.

The results of this preliminary study suggest that diagnostic accuracy for pigmented skin lesions by PCPs may be improved with the adjunctive use of electrical impedance spectroscopy with visual inspection.

Of note, in this survey format, respondents rated their inclination to biopsy or refer each lesion from 1 to 5. For statistical analyses, lesions rated 1 to 3 were considered as not biopsied/referred and those rated 4 to 5 as biopsied/referred. The sensitivity and specificity values observed, for both visual examination and concurrent visual and EIS evaluation, are therefore based on this classification system of participants’ provided ratings. It is conceivable that differing sensitivity and specificity values might have been detected if clinicians were instead given a binary choice for referral/biopsy decisions.

CONCLUSIONS

Among PCPs tasked with evaluating melanocytic lesions, the incorporation of EIS data into clinical decision-making in this study significantly increased the sensitivity, specificity, and overall diagnostic accuracy of biopsy or referral decisions for melanomas and SDN compared with visual inspection alone. Overall, the results of this preliminary study suggest that diagnostic accuracy for PSLs by PCPs may be improved with the adjunctive use of EIS with visual inspection. This would ultimately improve patient care and reduce the morbidity and mortality of a melanoma diagnosis.

CORRESPONDENCE
Jonathan Ungar, MD, Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai, 5 East 98th Street, 5th Floor, New York, NY 10029; [email protected]

ABSTRACT

Background: We sought to examine whether electrical impedance spectroscopy (EIS), a diagnostic tool approved by the US Food and Drug Administration for the evaluation of pigmented skin lesions (PSLs), is beneficial to primary care providers (PCPs) by comparing the accuracy of PCPs’ management decisions for PSLs based on visual examination alone with those based on concurrent visual and EIS evaluation.

Methods: Physicians and nurse practitioners (NPs) participated in an anonymous online survey in which they viewed clinical images of PSLs and were asked to make 2 clinical decisions before and after being provided an EIS score that indicated the likelihood that the lesion was a melanoma. They were asked (1) if they would biopsy the lesion/refer the patient out and (2) what they expected the pathology results would show.

Results: Forty-four physicians and 17 NPs participated, making clinical decisions for 1354 presented lesions. Overall, with the addition of EIS to visual inspection of clinical images, the sensitivity of biopsy/referral decisions for melanomas and severely dysplastic nevi (SDN) increased from 69.2% to 90.0% (P < .001), while specificity increased from 44.0% to 72.6% (P < .001). Physicians and NPs, regardless of years of experience, each saw significant improvements in sensitivity, specificity, and diagnostic accuracy with the addition of EIS scores.

Conclusions: The incorporation of EIS data into clinical decision-making by PCPs significantly increased the sensitivity and specificity of biopsy/referral decisions for melanomas and SDN and overall diagnostic accuracy compared with visual inspection alone. The results of this study suggest that diagnostic accuracy for PSLs by PCPs may be improved with adjunctive use of EIS with visual inspection.

Primary care providers (PCPs) are often the first line of defense in detecting skin cancers. For patients with concerning skin lesions, PCPs may choose to perform a biopsy or facilitate access to specialty services (eg, Dermatology). Consequently, PCPs play a critical role in the timely detection of skin cancers, and it is paramount to employ continually improving detection methods, such as the application of technologic advances.¹

Differentiating benign nevi from melanoma and severely dysplastic nevi (SDN), both of which warrant excision, poses a unique challenge to clinicians examining pigmented skin lesions (PSLs). PCPs often rely on visual inspection to differentiate benign skin lesions from malignant skin cancers. In some primary care practices, dermoscopy, which involves using a handheld device to evaluate lesions with polarized light and magnification, is used to improve melanoma detection. However, while visual inspection and dermoscopy are valid, effective techniques for the diagnosis of melanocytic lesions, in many instances they still can lead to missed cancers or unnecessary biopsies and specialty referrals. Adjunctive use of dermoscopy with visual inspection has been shown to increase the probability of skin cancer detection, but it fails to achieve a near-100% success rate.² Furthermore, dermoscopy is heavily user-dependent, requiring significant training and experience for appropriate use.³

Another option is an electrical impedance spectroscopy (EIS) device (Nevisense, Scibase, Stockholm, Sweden), which has been approved by the US Food and Drug Administration (FDA) to assist in the detection of melanoma and differentiation from benign PSLs.⁴ EIS is a noninvasive, rapidly applied technology designed to accompany the visual examination of melanocytic lesions in office, with or without dermoscopy. Still relatively new, the technology is employed today by many dermatologists, increasing diagnostic accuracy for PSLs.⁵ The lightweight and portable instrument features a handheld probe, which is held against a lesion to obtain a reading. EIS uses a low-voltage electrode to apply a harmless electrical current to the skin at various frequencies.⁶ As benign and malignant tissues vary in cell shape, size, and composition, EIS distinguishes differential electrical resistance of the tissue to aid in diagnosis.⁷

Continue to: EIS provides high-sensitivity...

EIS provides high-sensitivity melanoma diagnosis vs histopathologic confirmation from biopsies, with 1 study showing a 96.6% sensitivity rating, detecting 256 of 265 melanomas.⁴ The EIS device, by measuring differences in electrical resistance between benign and cancerous cells, outputs a simple integer score ranging from 0 to 10 associated with the likelihood of the lesion being a melanoma.⁸ Based on data from the Nevisense pivotal trial,⁴ Nevisense reports that scores of 0 to 3 carry a negative predictive value of 99% for melanoma, whereas scores of 4 to 10 signify increasingly greater positive predictive values from 7% to 61%.

Findings suggest that the use of electrical impedance spectroscopy is particularly advantageous to clinicians who are less proficient in assessing melanocytic lesions.

We aimed to assess whether EIS may be beneficial to PCPs by comparing the accuracy of clinical decision-making for PSLs based on visual examination alone with that based on concurrent visual and EIS evaluation.

METHODS

A questionnaire was distributed via email to 142 clinicians at clinics affiliated with either of 2 organizations delivering care to the New York City area through a network of community health centers: the Institute for Family Health (IFH) and the Community Healthcare Network (CHN). Of these recipients, 72 were affiliated with IFH across 27 community health centers and 70 were affiliated with CHN across 14 community health centers. Recipients were physicians and nurse practitioners (NPs) practicing at primary health care facilities.

Survey instrument. The first section of the survey instrument (APPENDIX) solicited demographic information and explained how to apply the EIS scores for diagnostic ­decision-making. The second featured images of 12 randomly selected, histologically confirmed, and EIS-evaluated PSLs from a previously published prospective blinded trial of 2416 lesions.⁴ The Institutional Review Board of the Icahn School of Medicine at Mount Sinai reviewed and approved the study and survey instrument.

Clinical images of these lesions, comprising 4 melanocytic nevi, 4 dysplastic nevi (including 3 mild-moderately dysplastic and 1 severely dysplastic nevus), and 4 melanomas, were first presented to respondents with 2 tasks: (1) rate on a scale of 1 to 5 their likelihood to biopsy or refer this lesion to a dermatologist (1: not likely; 5: extremely likely); and (2) select what they expect the pathology results to be: melanocytic nevus, dysplastic nevus, or malignant melanoma. Subsequently, respondents repeated the assessments after being presented with the EIS score for the same lesion in conjunction with the clinical image.

Continue to: Analysis

Analysis. A biopsy or referral rating of 4 or 5 was considered a decision to biopsy or refer (ie, a diagnostic decision consistent with melanoma or SDN warranting excision), whereas a selection of 1 to 3 was considered a decision not to biopsy or refer (ie, a diagnostic decision consistent with a benign PSL). The sensitivity and specificity of biopsy/­referral decisions for melanomas and SDN, the proportion of missed melanomas and SDN, and the proportion of biopsy/referral decisions for benign lesions were separately determined for visual inspection alone and visual inspection with EIS score. Similarly, diagnostic accuracy was calculated for these clinical scenarios. These metrics were further stratified among different subsets of the respondent population. Differences in sensitivity, specificity, biopsy/referral decision proportions, and diagnostic accuracy were calculated using McNemar’s test for paired proportions.

RESULTS

Sixty-one respondents, comprising 44 physicians and 17 NPs, completed the survey, yielding a response rate of 43% (TABLE 1). In total, 1354 clinical decisions (677 based on visual inspection alone and 677 based on visual inspection plus EIS) were made. A biopsy/­referral decision was made after assessing 416 of 677 cases (61%) with visual inspection alone and 360 of 677 cases (53%) when relying on visual inspection plus EIS. None of the respondents reported any prior experience with EIS.

When incorporating EIS scores, respondents’ mean sensitivity for melanomas and SDN increased from 69.2% to 90.0% (P < .001) and specificity from 44.0% to 72.6% (P < .001; TABLE 2). At baseline, physicians demonstrated a sensitivity and specificity of 74.6% and 46.5%, respectively, while NPs demonstrated a sensitivity and specificity of 56.1% and 37.9%, respectively.

All respondent subgroups stratified by occupation and years of experience saw significant increases in both sensitivity and specificity upon the incorporation of EIS scores, with NPs seeing a greater increase in sensitivity (56.1% vs 85.4%; P < .001) and specificity (37.9% vs 69.0%; P < .001) than physicians (sensitivity: 74.6% vs 91.9%; P < .001; specificity: 46.5% vs 74.1%; P < .001). The only difference in diagnostic performance based on years of experience was a greater pre-EIS sensitivity by clinicians who had been in practice for ≥ 15 years, compared with those in practice for shorter periods (TABLE 2).

The improvements, seen in clinicians of varying training and experience, suggest that the learning curve of EIS may not be as steep as that of dermoscopy.

Diagnostic accuracy increased significantly from 48% when based on visual inspection alone to 73% with the addition of EIS scores (P < .001; TABLE 3). Physicians and NPs each significantly increased their diagnostic accuracy upon the incorporation of EIS, with NPs exhibiting the greatest increase (from 36.9% to 65.7%; P < .001). PCPs with 6 to 14 years of experience saw the greatest increase in diagnostic accuracy when adding EIS (45.9% vs 76.4%; P < .001). Overall, the addition of EIS scores resulted in 58 fewer missed melanomas and SDN and 114 fewer benign referrals or biopsies (TABLE 4).

Continue to: DISCUSSION

DISCUSSION

Primary care evaluation plays a significant role in the diagnosis and management of PSLs, ultimately shaping outcomes for patients with melanoma. Improved accuracy of PSL classification could yield greater sensitivity for the diagnosis of melanomas and high-risk melanocytic lesions at earlier stages, while also reducing the number of unnecessary biopsies and referrals—leading to decreased patient morbidity and mortality and reduced health care spending.⁹

Diagnostic tools are valuable insofar as they can improve accuracy and positively impact clinical management and patient outcomes.¹⁰ In this case, increased sensitivity reduced missed melanoma diagnoses, while increased specificity avoided the additional costs and patient toll associated with a biopsy or referral for a benign lesion.

Dermoscopy has been shown to improve the sensitivity and specificity of PSL diagnosis compared with visual inspection alone; however, without substantial training and experience, accuracy with dermoscopy can be no better than examination with the naked eye.^3,11,12 The dropout rates are high for training PCPs in its use, given that several months of training may be needed for competent use.^13,14 To improve the clinical management of PSLs broadly in primary care, a need exists for easy-to-use adjunctive tools that increase diagnostic accuracy.¹⁵

In this study, with only a brief explanation of how to interpret EIS scores, clinicians without any prior experience using EIS demonstrated significantly improved accuracy in deciding appropriate management and classifying melanocytic lesions with the addition of EIS to visual inspection. These improvements, seen in clinicians of varying training and experience, suggest that the learning curve of EIS may not be as steep as that of dermoscopy.

The greater baseline sensitivity, specificity, and diagnostic accuracy of physicians’ clinical decision-making compared with NPs before the incorporation of EIS in the study may be a product of comparatively more extensive medical training. In addition, EIS yielded a greater benefit to NPs than to physicians, with greater increases in sensitivity and specificity noted. This suggests that the use of EIS is particularly advantageous to clinicians who are less proficient in assessing melanocytic lesions. Using visual inspection alone, more experienced respondents made biopsy/referral decisions with greater sensitivity but similar specificity to those with less experience. With the incorporation of EIS scores, the sensitivity and specificity of respondents’ clinical decision-making rose to comparable levels across all experience groups, providing further indication of EIS’s particular value to clinicians who are less proficient in PSL evaluation.

Continue to: This technology holds the potential...

This technology holds the potential to be seamlessly implemented into primary care practice, given that dermatology expertise training is not required to use the EIS device; this could allow for EIS measurement of lesions to be delegated to office staff (eg, nurses, medical assistants).¹⁶ Future studies are needed to assess EIS use among PCPs in a real-world setting, where factors such as its application on nonmelanocytic lesions (eg, seborrheic keratoses) and its pairing with patient historical data could produce varying results.

Limitations. While revealing, this study had its limitations. Respondents did not have access to additional pertinent clinical information, such as patients’ histories and risk factors. Clinical decisions in this survey were made based on digital images rather than in vivo examination. This may not represent a real-life evaluation; there is the potential for minimization of the true consequences of a missed melanoma or unnecessary biopsy in the minds of participants, and this does not factor in the operation of the actual EIS device. The Hawthorne effect may also have influenced PCPs’ diagnostic selections. Also, the limited sample size constitutes another limitation.

The results of this preliminary study suggest that diagnostic accuracy for pigmented skin lesions by PCPs may be improved with the adjunctive use of electrical impedance spectroscopy with visual inspection.

Of note, in this survey format, respondents rated their inclination to biopsy or refer each lesion from 1 to 5. For statistical analyses, lesions rated 1 to 3 were considered as not biopsied/referred and those rated 4 to 5 as biopsied/referred. The sensitivity and specificity values observed, for both visual examination and concurrent visual and EIS evaluation, are therefore based on this classification system of participants’ provided ratings. It is conceivable that differing sensitivity and specificity values might have been detected if clinicians were instead given a binary choice for referral/biopsy decisions.

CONCLUSIONS

Among PCPs tasked with evaluating melanocytic lesions, the incorporation of EIS data into clinical decision-making in this study significantly increased the sensitivity, specificity, and overall diagnostic accuracy of biopsy or referral decisions for melanomas and SDN compared with visual inspection alone. Overall, the results of this preliminary study suggest that diagnostic accuracy for PSLs by PCPs may be improved with the adjunctive use of EIS with visual inspection. This would ultimately improve patient care and reduce the morbidity and mortality of a melanoma diagnosis.

CORRESPONDENCE
Jonathan Ungar, MD, Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai, 5 East 98th Street, 5th Floor, New York, NY 10029; [email protected]

ABSTRACT

Background: We sought to examine whether electrical impedance spectroscopy (EIS), a diagnostic tool approved by the US Food and Drug Administration for the evaluation of pigmented skin lesions (PSLs), is beneficial to primary care providers (PCPs) by comparing the accuracy of PCPs’ management decisions for PSLs based on visual examination alone with those based on concurrent visual and EIS evaluation.

Methods: Physicians and nurse practitioners (NPs) participated in an anonymous online survey in which they viewed clinical images of PSLs and were asked to make 2 clinical decisions before and after being provided an EIS score that indicated the likelihood that the lesion was a melanoma. They were asked (1) if they would biopsy the lesion/refer the patient out and (2) what they expected the pathology results would show.

Results: Forty-four physicians and 17 NPs participated, making clinical decisions for 1354 presented lesions. Overall, with the addition of EIS to visual inspection of clinical images, the sensitivity of biopsy/referral decisions for melanomas and severely dysplastic nevi (SDN) increased from 69.2% to 90.0% (P < .001), while specificity increased from 44.0% to 72.6% (P < .001). Physicians and NPs, regardless of years of experience, each saw significant improvements in sensitivity, specificity, and diagnostic accuracy with the addition of EIS scores.

Conclusions: The incorporation of EIS data into clinical decision-making by PCPs significantly increased the sensitivity and specificity of biopsy/referral decisions for melanomas and SDN and overall diagnostic accuracy compared with visual inspection alone. The results of this study suggest that diagnostic accuracy for PSLs by PCPs may be improved with adjunctive use of EIS with visual inspection.

Primary care providers (PCPs) are often the first line of defense in detecting skin cancers. For patients with concerning skin lesions, PCPs may choose to perform a biopsy or facilitate access to specialty services (eg, Dermatology). Consequently, PCPs play a critical role in the timely detection of skin cancers, and it is paramount to employ continually improving detection methods, such as the application of technologic advances.¹

Differentiating benign nevi from melanoma and severely dysplastic nevi (SDN), both of which warrant excision, poses a unique challenge to clinicians examining pigmented skin lesions (PSLs). PCPs often rely on visual inspection to differentiate benign skin lesions from malignant skin cancers. In some primary care practices, dermoscopy, which involves using a handheld device to evaluate lesions with polarized light and magnification, is used to improve melanoma detection. However, while visual inspection and dermoscopy are valid, effective techniques for the diagnosis of melanocytic lesions, in many instances they still can lead to missed cancers or unnecessary biopsies and specialty referrals. Adjunctive use of dermoscopy with visual inspection has been shown to increase the probability of skin cancer detection, but it fails to achieve a near-100% success rate.² Furthermore, dermoscopy is heavily user-dependent, requiring significant training and experience for appropriate use.³

Another option is an electrical impedance spectroscopy (EIS) device (Nevisense, Scibase, Stockholm, Sweden), which has been approved by the US Food and Drug Administration (FDA) to assist in the detection of melanoma and differentiation from benign PSLs.⁴ EIS is a noninvasive, rapidly applied technology designed to accompany the visual examination of melanocytic lesions in office, with or without dermoscopy. Still relatively new, the technology is employed today by many dermatologists, increasing diagnostic accuracy for PSLs.⁵ The lightweight and portable instrument features a handheld probe, which is held against a lesion to obtain a reading. EIS uses a low-voltage electrode to apply a harmless electrical current to the skin at various frequencies.⁶ As benign and malignant tissues vary in cell shape, size, and composition, EIS distinguishes differential electrical resistance of the tissue to aid in diagnosis.⁷

Continue to: EIS provides high-sensitivity...

EIS provides high-sensitivity melanoma diagnosis vs histopathologic confirmation from biopsies, with 1 study showing a 96.6% sensitivity rating, detecting 256 of 265 melanomas.⁴ The EIS device, by measuring differences in electrical resistance between benign and cancerous cells, outputs a simple integer score ranging from 0 to 10 associated with the likelihood of the lesion being a melanoma.⁸ Based on data from the Nevisense pivotal trial,⁴ Nevisense reports that scores of 0 to 3 carry a negative predictive value of 99% for melanoma, whereas scores of 4 to 10 signify increasingly greater positive predictive values from 7% to 61%.

Findings suggest that the use of electrical impedance spectroscopy is particularly advantageous to clinicians who are less proficient in assessing melanocytic lesions.

We aimed to assess whether EIS may be beneficial to PCPs by comparing the accuracy of clinical decision-making for PSLs based on visual examination alone with that based on concurrent visual and EIS evaluation.

METHODS

A questionnaire was distributed via email to 142 clinicians at clinics affiliated with either of 2 organizations delivering care to the New York City area through a network of community health centers: the Institute for Family Health (IFH) and the Community Healthcare Network (CHN). Of these recipients, 72 were affiliated with IFH across 27 community health centers and 70 were affiliated with CHN across 14 community health centers. Recipients were physicians and nurse practitioners (NPs) practicing at primary health care facilities.

Survey instrument. The first section of the survey instrument (APPENDIX) solicited demographic information and explained how to apply the EIS scores for diagnostic ­decision-making. The second featured images of 12 randomly selected, histologically confirmed, and EIS-evaluated PSLs from a previously published prospective blinded trial of 2416 lesions.⁴ The Institutional Review Board of the Icahn School of Medicine at Mount Sinai reviewed and approved the study and survey instrument.

Clinical images of these lesions, comprising 4 melanocytic nevi, 4 dysplastic nevi (including 3 mild-moderately dysplastic and 1 severely dysplastic nevus), and 4 melanomas, were first presented to respondents with 2 tasks: (1) rate on a scale of 1 to 5 their likelihood to biopsy or refer this lesion to a dermatologist (1: not likely; 5: extremely likely); and (2) select what they expect the pathology results to be: melanocytic nevus, dysplastic nevus, or malignant melanoma. Subsequently, respondents repeated the assessments after being presented with the EIS score for the same lesion in conjunction with the clinical image.

Continue to: Analysis

Analysis. A biopsy or referral rating of 4 or 5 was considered a decision to biopsy or refer (ie, a diagnostic decision consistent with melanoma or SDN warranting excision), whereas a selection of 1 to 3 was considered a decision not to biopsy or refer (ie, a diagnostic decision consistent with a benign PSL). The sensitivity and specificity of biopsy/­referral decisions for melanomas and SDN, the proportion of missed melanomas and SDN, and the proportion of biopsy/referral decisions for benign lesions were separately determined for visual inspection alone and visual inspection with EIS score. Similarly, diagnostic accuracy was calculated for these clinical scenarios. These metrics were further stratified among different subsets of the respondent population. Differences in sensitivity, specificity, biopsy/referral decision proportions, and diagnostic accuracy were calculated using McNemar’s test for paired proportions.

RESULTS

Sixty-one respondents, comprising 44 physicians and 17 NPs, completed the survey, yielding a response rate of 43% (TABLE 1). In total, 1354 clinical decisions (677 based on visual inspection alone and 677 based on visual inspection plus EIS) were made. A biopsy/­referral decision was made after assessing 416 of 677 cases (61%) with visual inspection alone and 360 of 677 cases (53%) when relying on visual inspection plus EIS. None of the respondents reported any prior experience with EIS.

When incorporating EIS scores, respondents’ mean sensitivity for melanomas and SDN increased from 69.2% to 90.0% (P < .001) and specificity from 44.0% to 72.6% (P < .001; TABLE 2). At baseline, physicians demonstrated a sensitivity and specificity of 74.6% and 46.5%, respectively, while NPs demonstrated a sensitivity and specificity of 56.1% and 37.9%, respectively.

All respondent subgroups stratified by occupation and years of experience saw significant increases in both sensitivity and specificity upon the incorporation of EIS scores, with NPs seeing a greater increase in sensitivity (56.1% vs 85.4%; P < .001) and specificity (37.9% vs 69.0%; P < .001) than physicians (sensitivity: 74.6% vs 91.9%; P < .001; specificity: 46.5% vs 74.1%; P < .001). The only difference in diagnostic performance based on years of experience was a greater pre-EIS sensitivity by clinicians who had been in practice for ≥ 15 years, compared with those in practice for shorter periods (TABLE 2).

The improvements, seen in clinicians of varying training and experience, suggest that the learning curve of EIS may not be as steep as that of dermoscopy.

Diagnostic accuracy increased significantly from 48% when based on visual inspection alone to 73% with the addition of EIS scores (P < .001; TABLE 3). Physicians and NPs each significantly increased their diagnostic accuracy upon the incorporation of EIS, with NPs exhibiting the greatest increase (from 36.9% to 65.7%; P < .001). PCPs with 6 to 14 years of experience saw the greatest increase in diagnostic accuracy when adding EIS (45.9% vs 76.4%; P < .001). Overall, the addition of EIS scores resulted in 58 fewer missed melanomas and SDN and 114 fewer benign referrals or biopsies (TABLE 4).

Continue to: DISCUSSION

DISCUSSION

Primary care evaluation plays a significant role in the diagnosis and management of PSLs, ultimately shaping outcomes for patients with melanoma. Improved accuracy of PSL classification could yield greater sensitivity for the diagnosis of melanomas and high-risk melanocytic lesions at earlier stages, while also reducing the number of unnecessary biopsies and referrals—leading to decreased patient morbidity and mortality and reduced health care spending.⁹

Diagnostic tools are valuable insofar as they can improve accuracy and positively impact clinical management and patient outcomes.¹⁰ In this case, increased sensitivity reduced missed melanoma diagnoses, while increased specificity avoided the additional costs and patient toll associated with a biopsy or referral for a benign lesion.

Dermoscopy has been shown to improve the sensitivity and specificity of PSL diagnosis compared with visual inspection alone; however, without substantial training and experience, accuracy with dermoscopy can be no better than examination with the naked eye.^3,11,12 The dropout rates are high for training PCPs in its use, given that several months of training may be needed for competent use.^13,14 To improve the clinical management of PSLs broadly in primary care, a need exists for easy-to-use adjunctive tools that increase diagnostic accuracy.¹⁵

In this study, with only a brief explanation of how to interpret EIS scores, clinicians without any prior experience using EIS demonstrated significantly improved accuracy in deciding appropriate management and classifying melanocytic lesions with the addition of EIS to visual inspection. These improvements, seen in clinicians of varying training and experience, suggest that the learning curve of EIS may not be as steep as that of dermoscopy.

The greater baseline sensitivity, specificity, and diagnostic accuracy of physicians’ clinical decision-making compared with NPs before the incorporation of EIS in the study may be a product of comparatively more extensive medical training. In addition, EIS yielded a greater benefit to NPs than to physicians, with greater increases in sensitivity and specificity noted. This suggests that the use of EIS is particularly advantageous to clinicians who are less proficient in assessing melanocytic lesions. Using visual inspection alone, more experienced respondents made biopsy/referral decisions with greater sensitivity but similar specificity to those with less experience. With the incorporation of EIS scores, the sensitivity and specificity of respondents’ clinical decision-making rose to comparable levels across all experience groups, providing further indication of EIS’s particular value to clinicians who are less proficient in PSL evaluation.

Continue to: This technology holds the potential...

This technology holds the potential to be seamlessly implemented into primary care practice, given that dermatology expertise training is not required to use the EIS device; this could allow for EIS measurement of lesions to be delegated to office staff (eg, nurses, medical assistants).¹⁶ Future studies are needed to assess EIS use among PCPs in a real-world setting, where factors such as its application on nonmelanocytic lesions (eg, seborrheic keratoses) and its pairing with patient historical data could produce varying results.

Limitations. While revealing, this study had its limitations. Respondents did not have access to additional pertinent clinical information, such as patients’ histories and risk factors. Clinical decisions in this survey were made based on digital images rather than in vivo examination. This may not represent a real-life evaluation; there is the potential for minimization of the true consequences of a missed melanoma or unnecessary biopsy in the minds of participants, and this does not factor in the operation of the actual EIS device. The Hawthorne effect may also have influenced PCPs’ diagnostic selections. Also, the limited sample size constitutes another limitation.

The results of this preliminary study suggest that diagnostic accuracy for pigmented skin lesions by PCPs may be improved with the adjunctive use of electrical impedance spectroscopy with visual inspection.

Of note, in this survey format, respondents rated their inclination to biopsy or refer each lesion from 1 to 5. For statistical analyses, lesions rated 1 to 3 were considered as not biopsied/referred and those rated 4 to 5 as biopsied/referred. The sensitivity and specificity values observed, for both visual examination and concurrent visual and EIS evaluation, are therefore based on this classification system of participants’ provided ratings. It is conceivable that differing sensitivity and specificity values might have been detected if clinicians were instead given a binary choice for referral/biopsy decisions.

CONCLUSIONS

Among PCPs tasked with evaluating melanocytic lesions, the incorporation of EIS data into clinical decision-making in this study significantly increased the sensitivity, specificity, and overall diagnostic accuracy of biopsy or referral decisions for melanomas and SDN compared with visual inspection alone. Overall, the results of this preliminary study suggest that diagnostic accuracy for PSLs by PCPs may be improved with the adjunctive use of EIS with visual inspection. This would ultimately improve patient care and reduce the morbidity and mortality of a melanoma diagnosis.

CORRESPONDENCE
Jonathan Ungar, MD, Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai, 5 East 98th Street, 5th Floor, New York, NY 10029; [email protected]

Changing behavior is hard. And at nearly every clinical encounter, we counsel/encourage/remind/help (choose a verb) our patients to make a change—to do something hard. We tell them they need to increase their physical activity, get more sleep, or alter their eating habits. We know that if they make the needed changes, they can improve their health and possibly lengthen their lives. But we also know (from the systematic reviews the US Preventive Services Task Force [USPSTF] uses to make its recommendations) that brief counseling in our offices is largely ineffective unless we connect patients to resources to support the recommended change.

As examples, the USPSTF currently recommends the following (both grade “B”):

• offer or refer adults with cardiovascular disease risk factors to behavioral counseling interventions to promote a healthy diet and physical activity.¹
• offer or refer adults with a body mass index of 30 or higher to intensive, multicomponent behavioral interventions.²

This 2-step rule is tech-free and can be applied by patients in a few seconds to make healthier food choices.

To support our patients when making recommendations such as these, we might refer them to a dietitian for intensive counseling and meal-planning guidance. The American Diabetes Association says that patients seeking to manage their diabetes and prediabetes “can start by working with a registered dietitian nutritionist … to make an eating plan that works for [them].”³ However, this kind of resource is unavailable to many of our patients.

So what else can we do?

We can help patients decide what to buy in the grocery aisle. Nutrition labels are useful, but they are limited by their complexity and requisite level of health literacy.⁴ Even the concept of “calories” is not so intuitive. This challenge with interpreting calories led me (in some of my prior work) to explore a potentially more useful approach: conveying calorie information as physical activity equivalents.⁵

In this issue of The Journal of Family Practice, Dong and colleagues present their findings on whether a simple equation (the Altman Rule) that uses information on nutrition labels may be a reasonable proxy for an even more difficult concept—­glycemic load.⁶ The idea is that consumers (eg, patients with diabetes) can use this rule to help them in their decision-making at the grocery store (or the convenience store or gas station, for that matter, where the high-glycemic-load carbohydrates may be even more tempting). The 2-step rule is tech-free and can be applied in a few seconds. Their research demonstrated that the rule is a reasonable proxy for glycemic load for packaged carbohydrates (eg, chips, cereals, crackers, granola bars). Caveats acknowledged, foods that meet the rule are likely to be healthier choices.

Looking ahead, I would like to see whether counseling patients about the Altman Rule leads to their use of it, and how that translates into healthier eating, lower A1C, and ideally better health. For now, the Altman Rule is worth learning about. It may serve as another tool that you can use to support your patients when you ask them to do the hard work of making healthier food choices. 

Changing behavior is hard. And at nearly every clinical encounter, we counsel/encourage/remind/help (choose a verb) our patients to make a change—to do something hard. We tell them they need to increase their physical activity, get more sleep, or alter their eating habits. We know that if they make the needed changes, they can improve their health and possibly lengthen their lives. But we also know (from the systematic reviews the US Preventive Services Task Force [USPSTF] uses to make its recommendations) that brief counseling in our offices is largely ineffective unless we connect patients to resources to support the recommended change.

As examples, the USPSTF currently recommends the following (both grade “B”):

• offer or refer adults with cardiovascular disease risk factors to behavioral counseling interventions to promote a healthy diet and physical activity.¹
• offer or refer adults with a body mass index of 30 or higher to intensive, multicomponent behavioral interventions.²

This 2-step rule is tech-free and can be applied by patients in a few seconds to make healthier food choices.

To support our patients when making recommendations such as these, we might refer them to a dietitian for intensive counseling and meal-planning guidance. The American Diabetes Association says that patients seeking to manage their diabetes and prediabetes “can start by working with a registered dietitian nutritionist … to make an eating plan that works for [them].”³ However, this kind of resource is unavailable to many of our patients.

So what else can we do?

We can help patients decide what to buy in the grocery aisle. Nutrition labels are useful, but they are limited by their complexity and requisite level of health literacy.⁴ Even the concept of “calories” is not so intuitive. This challenge with interpreting calories led me (in some of my prior work) to explore a potentially more useful approach: conveying calorie information as physical activity equivalents.⁵

In this issue of The Journal of Family Practice, Dong and colleagues present their findings on whether a simple equation (the Altman Rule) that uses information on nutrition labels may be a reasonable proxy for an even more difficult concept—­glycemic load.⁶ The idea is that consumers (eg, patients with diabetes) can use this rule to help them in their decision-making at the grocery store (or the convenience store or gas station, for that matter, where the high-glycemic-load carbohydrates may be even more tempting). The 2-step rule is tech-free and can be applied in a few seconds. Their research demonstrated that the rule is a reasonable proxy for glycemic load for packaged carbohydrates (eg, chips, cereals, crackers, granola bars). Caveats acknowledged, foods that meet the rule are likely to be healthier choices.

Looking ahead, I would like to see whether counseling patients about the Altman Rule leads to their use of it, and how that translates into healthier eating, lower A1C, and ideally better health. For now, the Altman Rule is worth learning about. It may serve as another tool that you can use to support your patients when you ask them to do the hard work of making healthier food choices. 

Changing behavior is hard. And at nearly every clinical encounter, we counsel/encourage/remind/help (choose a verb) our patients to make a change—to do something hard. We tell them they need to increase their physical activity, get more sleep, or alter their eating habits. We know that if they make the needed changes, they can improve their health and possibly lengthen their lives. But we also know (from the systematic reviews the US Preventive Services Task Force [USPSTF] uses to make its recommendations) that brief counseling in our offices is largely ineffective unless we connect patients to resources to support the recommended change.

As examples, the USPSTF currently recommends the following (both grade “B”):

• offer or refer adults with cardiovascular disease risk factors to behavioral counseling interventions to promote a healthy diet and physical activity.¹
• offer or refer adults with a body mass index of 30 or higher to intensive, multicomponent behavioral interventions.²

This 2-step rule is tech-free and can be applied by patients in a few seconds to make healthier food choices.

To support our patients when making recommendations such as these, we might refer them to a dietitian for intensive counseling and meal-planning guidance. The American Diabetes Association says that patients seeking to manage their diabetes and prediabetes “can start by working with a registered dietitian nutritionist … to make an eating plan that works for [them].”³ However, this kind of resource is unavailable to many of our patients.

So what else can we do?

We can help patients decide what to buy in the grocery aisle. Nutrition labels are useful, but they are limited by their complexity and requisite level of health literacy.⁴ Even the concept of “calories” is not so intuitive. This challenge with interpreting calories led me (in some of my prior work) to explore a potentially more useful approach: conveying calorie information as physical activity equivalents.⁵

In this issue of The Journal of Family Practice, Dong and colleagues present their findings on whether a simple equation (the Altman Rule) that uses information on nutrition labels may be a reasonable proxy for an even more difficult concept—­glycemic load.⁶ The idea is that consumers (eg, patients with diabetes) can use this rule to help them in their decision-making at the grocery store (or the convenience store or gas station, for that matter, where the high-glycemic-load carbohydrates may be even more tempting). The 2-step rule is tech-free and can be applied in a few seconds. Their research demonstrated that the rule is a reasonable proxy for glycemic load for packaged carbohydrates (eg, chips, cereals, crackers, granola bars). Caveats acknowledged, foods that meet the rule are likely to be healthier choices.

Looking ahead, I would like to see whether counseling patients about the Altman Rule leads to their use of it, and how that translates into healthier eating, lower A1C, and ideally better health. For now, the Altman Rule is worth learning about. It may serve as another tool that you can use to support your patients when you ask them to do the hard work of making healthier food choices. 

A 75-YEAR-OLD MAN presented to the dermatology clinic for evaluation of localized, persistent burning pain and discomfort attributed to shingles and postherpetic neuralgia. He had received a diagnosis of shingles on his left upper back about 3 years prior to this presentation.

In the ensuing years, the patient had been evaluated and treated by his primary care physician, a pain management team, and a neurologist. These clinicians treated the symptoms as postherpetic neuralgia, with no consensus explanation for the skin findings. The patient reported that his symptoms were unresponsive to trials of gabapentin 800 mg tid, duloxetine 60 mg PO qd, and acetaminophen 1 to 3 g/d PO. He also had undergone several rounds of acupuncture, thoracic and cervical spine steroid injections, and epidurals, without resolution of symptoms. The patient believed the only treatment that helped was a lidocaine 4% patch, which he had used nearly every day for the previous 3 years.

Physical exam by the dermatologist revealed a lidocaine patch applied to the patient’s left upper back. Upon its removal, skin examination showed a well-demarcated, erythematous, hyperpigmented, lichenified plaque with excoriations and erosions where the patch had been (FIGURE).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The patient’s history and skin exam provided enough information to diagnose contact dermatitis. The pruritus, burning, and pain the patient had experienced were due to continuous application of the lidocaine patch to the area rather than postherpetic neuralgia.

There are 2 types of contact dermatitis: irritant and allergic. Irritant contact dermatitis is an inflammatory reaction caused directly by a substance, while allergic contact dermatitis is a delayed hypersensitivity reaction to specific allergens.¹ While data to elucidate the incidence and prevalence of allergic contact dermatitis are unknown, common causes include latex, dyes, oils, resins, and compounds in textiles, rubber, cosmetics, and other products used in daily life.¹

The pruritus, burning, and pain the patient had experienced were due to continuous application of the lidocaine patch to the area rather than postherpetic neuralgia.

Allergic contact dermatitis due to ­lidocaine is becoming more prevalent with increased use and availability of over-the-counter products.² A retrospective chart review of 1819 patch-tested patients from the University of British Columbia Contact Dermatitis Clinic showed a significant proportion of patients (2.4%) were found to have an allergic contact dermatitis to local anesthetics—most commonly benzocaine (45%), followed by lidocaine (32%).³ Therefore, it is important to consider contact dermatitis in patients using topical anesthetics for pain relief.

The differential varies by area affected

The differential diagnosis for contact dermatitis varies by area affected and the distribution of rash. Atopic dermatitis, lichen planus, and psoriasis are a few dermatologic conditions to consider in the differential diagnosis. They can look similar to contact dermatitis, but the patient’s history can help to discern the most likely diagnosis.¹

Atopic dermatitis is a complex dysfunction of the skin barrier and immune factors that often begins in childhood and persists in some patients throughout their lifetime. Atopic dermatitis is associated with other forms of atopy including asthma, allergic rhinitis, and food and contact allergies. Atopic dermatitis in the absence of contact allergies may manifest with chronic, diffuse, scaly patches with poorly defined borders. The patches appear in a symmetrical distribution and favor the flexural surfaces, such as the antecubital fossa, wrists, and neck.

Continue to: Lichen planus

Lichen planus most often manifests in the fourth through sixth decade of life as flat-topped itchy pink-to-purple polygonal papules to plaques. Lesions range from 2 to 10 mm and favor the volar wrists, shins, and lower back, although they may be widespread. Oral lesions manifesting as ulcers or white lacy patches in the buccal mucosa are common and may be a clue to the diagnosis. Unlike more generalized contact dermatitis, lichen planus lesions are discrete.

Psoriasis manifests as well-demarcated scaly plaques distributed symmetrically over extensor surfaces. The plaques commonly are found on the elbows, knees, and scalp. When psoriasis manifests in a very limited form (as just a single plaque or limited number of plaques), it can be hard to confidently exclude other etiologies. In these circumstances, look for psoriasis signs in more unique locations (eg, pitting in the nails or plaques on the scalp or in the gluteal cleft). Adding those findings to an otherwise solitary plaque significantly adds to diagnostic certainty.

Diagnosis entails getting the shape of things

Diagnosis is based on history of exposure to irritating or allergic substances, as well as a clinical exam. Skin examination of contact dermatitis can vary based on how long it has been present: Acute manifestations include erythema, oozing, scale, vesicles, and bullae, while chronic contact dermatitis tends to demonstrate lichenification and scale.¹

Distinctive findings. The most distinctive physical exam findings in patients with contact dermatitis are often shape and distribution of the rash, which reflect points of contact with the offending agent. This clue helped to elucidate the diagnosis in our patient: his rash was perfectly demarcated within the precise area where the patch was applied daily.

Irritant vs allergic. Patch testing can be performed to differentiate irritant vs allergic contact dermatitis.¹ Irritant contact dermatitis usually is apparent when removing a patch and will resolve over a day, whereas allergic contact dermatitis forms over time and the skin rash is most prominent several days after the patch has been removed.¹

Continue to: Treatment

Treatment of both variants of contact dermatitis includes avoidance of the causative substance and symptomatic treatment with topical steroids, antihistamines, and possibly oral steroids depending on the severity.¹

For our patient, a viral swab was taken and submitted for varicella zoster virus polymerase chain reaction testing to rule out persistent herpes zoster infection; the result was negative. The patient was counseled to discontinue use of the lidocaine patch.

Given the severity and protracted duration of the patient’s symptoms, he also was started on high-potency topical steroids (clobetasol 0.05% ointment to be applied twice daily under occlusion for 2 months), a 4-week prednisone taper (60 mg × 1 week, 40 mg × 1 week, 20 mg × 1 week, 10 mg × 1 week, then stop), and hydroxyzine (25 mg nightly as needed for pruritus). The patient’s rash and symptoms improved dramatically within the first few doses of prednisone and completely cleared by Week 4 of the prednisone taper. At his follow-up appointment 1 month after completing the prednisone taper, he stated that the pain on his back had resolved.

A 75-YEAR-OLD MAN presented to the dermatology clinic for evaluation of localized, persistent burning pain and discomfort attributed to shingles and postherpetic neuralgia. He had received a diagnosis of shingles on his left upper back about 3 years prior to this presentation.

In the ensuing years, the patient had been evaluated and treated by his primary care physician, a pain management team, and a neurologist. These clinicians treated the symptoms as postherpetic neuralgia, with no consensus explanation for the skin findings. The patient reported that his symptoms were unresponsive to trials of gabapentin 800 mg tid, duloxetine 60 mg PO qd, and acetaminophen 1 to 3 g/d PO. He also had undergone several rounds of acupuncture, thoracic and cervical spine steroid injections, and epidurals, without resolution of symptoms. The patient believed the only treatment that helped was a lidocaine 4% patch, which he had used nearly every day for the previous 3 years.

Physical exam by the dermatologist revealed a lidocaine patch applied to the patient’s left upper back. Upon its removal, skin examination showed a well-demarcated, erythematous, hyperpigmented, lichenified plaque with excoriations and erosions where the patch had been (FIGURE).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The patient’s history and skin exam provided enough information to diagnose contact dermatitis. The pruritus, burning, and pain the patient had experienced were due to continuous application of the lidocaine patch to the area rather than postherpetic neuralgia.

There are 2 types of contact dermatitis: irritant and allergic. Irritant contact dermatitis is an inflammatory reaction caused directly by a substance, while allergic contact dermatitis is a delayed hypersensitivity reaction to specific allergens.¹ While data to elucidate the incidence and prevalence of allergic contact dermatitis are unknown, common causes include latex, dyes, oils, resins, and compounds in textiles, rubber, cosmetics, and other products used in daily life.¹

The pruritus, burning, and pain the patient had experienced were due to continuous application of the lidocaine patch to the area rather than postherpetic neuralgia.

Allergic contact dermatitis due to ­lidocaine is becoming more prevalent with increased use and availability of over-the-counter products.² A retrospective chart review of 1819 patch-tested patients from the University of British Columbia Contact Dermatitis Clinic showed a significant proportion of patients (2.4%) were found to have an allergic contact dermatitis to local anesthetics—most commonly benzocaine (45%), followed by lidocaine (32%).³ Therefore, it is important to consider contact dermatitis in patients using topical anesthetics for pain relief.

The differential varies by area affected

The differential diagnosis for contact dermatitis varies by area affected and the distribution of rash. Atopic dermatitis, lichen planus, and psoriasis are a few dermatologic conditions to consider in the differential diagnosis. They can look similar to contact dermatitis, but the patient’s history can help to discern the most likely diagnosis.¹

Atopic dermatitis is a complex dysfunction of the skin barrier and immune factors that often begins in childhood and persists in some patients throughout their lifetime. Atopic dermatitis is associated with other forms of atopy including asthma, allergic rhinitis, and food and contact allergies. Atopic dermatitis in the absence of contact allergies may manifest with chronic, diffuse, scaly patches with poorly defined borders. The patches appear in a symmetrical distribution and favor the flexural surfaces, such as the antecubital fossa, wrists, and neck.

Continue to: Lichen planus

Lichen planus most often manifests in the fourth through sixth decade of life as flat-topped itchy pink-to-purple polygonal papules to plaques. Lesions range from 2 to 10 mm and favor the volar wrists, shins, and lower back, although they may be widespread. Oral lesions manifesting as ulcers or white lacy patches in the buccal mucosa are common and may be a clue to the diagnosis. Unlike more generalized contact dermatitis, lichen planus lesions are discrete.

Psoriasis manifests as well-demarcated scaly plaques distributed symmetrically over extensor surfaces. The plaques commonly are found on the elbows, knees, and scalp. When psoriasis manifests in a very limited form (as just a single plaque or limited number of plaques), it can be hard to confidently exclude other etiologies. In these circumstances, look for psoriasis signs in more unique locations (eg, pitting in the nails or plaques on the scalp or in the gluteal cleft). Adding those findings to an otherwise solitary plaque significantly adds to diagnostic certainty.

Diagnosis entails getting the shape of things

Diagnosis is based on history of exposure to irritating or allergic substances, as well as a clinical exam. Skin examination of contact dermatitis can vary based on how long it has been present: Acute manifestations include erythema, oozing, scale, vesicles, and bullae, while chronic contact dermatitis tends to demonstrate lichenification and scale.¹

Distinctive findings. The most distinctive physical exam findings in patients with contact dermatitis are often shape and distribution of the rash, which reflect points of contact with the offending agent. This clue helped to elucidate the diagnosis in our patient: his rash was perfectly demarcated within the precise area where the patch was applied daily.

Irritant vs allergic. Patch testing can be performed to differentiate irritant vs allergic contact dermatitis.¹ Irritant contact dermatitis usually is apparent when removing a patch and will resolve over a day, whereas allergic contact dermatitis forms over time and the skin rash is most prominent several days after the patch has been removed.¹

Continue to: Treatment

Treatment of both variants of contact dermatitis includes avoidance of the causative substance and symptomatic treatment with topical steroids, antihistamines, and possibly oral steroids depending on the severity.¹

For our patient, a viral swab was taken and submitted for varicella zoster virus polymerase chain reaction testing to rule out persistent herpes zoster infection; the result was negative. The patient was counseled to discontinue use of the lidocaine patch.

Given the severity and protracted duration of the patient’s symptoms, he also was started on high-potency topical steroids (clobetasol 0.05% ointment to be applied twice daily under occlusion for 2 months), a 4-week prednisone taper (60 mg × 1 week, 40 mg × 1 week, 20 mg × 1 week, 10 mg × 1 week, then stop), and hydroxyzine (25 mg nightly as needed for pruritus). The patient’s rash and symptoms improved dramatically within the first few doses of prednisone and completely cleared by Week 4 of the prednisone taper. At his follow-up appointment 1 month after completing the prednisone taper, he stated that the pain on his back had resolved.

A 75-YEAR-OLD MAN presented to the dermatology clinic for evaluation of localized, persistent burning pain and discomfort attributed to shingles and postherpetic neuralgia. He had received a diagnosis of shingles on his left upper back about 3 years prior to this presentation.

In the ensuing years, the patient had been evaluated and treated by his primary care physician, a pain management team, and a neurologist. These clinicians treated the symptoms as postherpetic neuralgia, with no consensus explanation for the skin findings. The patient reported that his symptoms were unresponsive to trials of gabapentin 800 mg tid, duloxetine 60 mg PO qd, and acetaminophen 1 to 3 g/d PO. He also had undergone several rounds of acupuncture, thoracic and cervical spine steroid injections, and epidurals, without resolution of symptoms. The patient believed the only treatment that helped was a lidocaine 4% patch, which he had used nearly every day for the previous 3 years.

Physical exam by the dermatologist revealed a lidocaine patch applied to the patient’s left upper back. Upon its removal, skin examination showed a well-demarcated, erythematous, hyperpigmented, lichenified plaque with excoriations and erosions where the patch had been (FIGURE).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The patient’s history and skin exam provided enough information to diagnose contact dermatitis. The pruritus, burning, and pain the patient had experienced were due to continuous application of the lidocaine patch to the area rather than postherpetic neuralgia.

There are 2 types of contact dermatitis: irritant and allergic. Irritant contact dermatitis is an inflammatory reaction caused directly by a substance, while allergic contact dermatitis is a delayed hypersensitivity reaction to specific allergens.¹ While data to elucidate the incidence and prevalence of allergic contact dermatitis are unknown, common causes include latex, dyes, oils, resins, and compounds in textiles, rubber, cosmetics, and other products used in daily life.¹

The pruritus, burning, and pain the patient had experienced were due to continuous application of the lidocaine patch to the area rather than postherpetic neuralgia.

Allergic contact dermatitis due to ­lidocaine is becoming more prevalent with increased use and availability of over-the-counter products.² A retrospective chart review of 1819 patch-tested patients from the University of British Columbia Contact Dermatitis Clinic showed a significant proportion of patients (2.4%) were found to have an allergic contact dermatitis to local anesthetics—most commonly benzocaine (45%), followed by lidocaine (32%).³ Therefore, it is important to consider contact dermatitis in patients using topical anesthetics for pain relief.

The differential varies by area affected

The differential diagnosis for contact dermatitis varies by area affected and the distribution of rash. Atopic dermatitis, lichen planus, and psoriasis are a few dermatologic conditions to consider in the differential diagnosis. They can look similar to contact dermatitis, but the patient’s history can help to discern the most likely diagnosis.¹

Atopic dermatitis is a complex dysfunction of the skin barrier and immune factors that often begins in childhood and persists in some patients throughout their lifetime. Atopic dermatitis is associated with other forms of atopy including asthma, allergic rhinitis, and food and contact allergies. Atopic dermatitis in the absence of contact allergies may manifest with chronic, diffuse, scaly patches with poorly defined borders. The patches appear in a symmetrical distribution and favor the flexural surfaces, such as the antecubital fossa, wrists, and neck.

Continue to: Lichen planus

Lichen planus most often manifests in the fourth through sixth decade of life as flat-topped itchy pink-to-purple polygonal papules to plaques. Lesions range from 2 to 10 mm and favor the volar wrists, shins, and lower back, although they may be widespread. Oral lesions manifesting as ulcers or white lacy patches in the buccal mucosa are common and may be a clue to the diagnosis. Unlike more generalized contact dermatitis, lichen planus lesions are discrete.

Psoriasis manifests as well-demarcated scaly plaques distributed symmetrically over extensor surfaces. The plaques commonly are found on the elbows, knees, and scalp. When psoriasis manifests in a very limited form (as just a single plaque or limited number of plaques), it can be hard to confidently exclude other etiologies. In these circumstances, look for psoriasis signs in more unique locations (eg, pitting in the nails or plaques on the scalp or in the gluteal cleft). Adding those findings to an otherwise solitary plaque significantly adds to diagnostic certainty.

Diagnosis entails getting the shape of things

Diagnosis is based on history of exposure to irritating or allergic substances, as well as a clinical exam. Skin examination of contact dermatitis can vary based on how long it has been present: Acute manifestations include erythema, oozing, scale, vesicles, and bullae, while chronic contact dermatitis tends to demonstrate lichenification and scale.¹

Distinctive findings. The most distinctive physical exam findings in patients with contact dermatitis are often shape and distribution of the rash, which reflect points of contact with the offending agent. This clue helped to elucidate the diagnosis in our patient: his rash was perfectly demarcated within the precise area where the patch was applied daily.

Irritant vs allergic. Patch testing can be performed to differentiate irritant vs allergic contact dermatitis.¹ Irritant contact dermatitis usually is apparent when removing a patch and will resolve over a day, whereas allergic contact dermatitis forms over time and the skin rash is most prominent several days after the patch has been removed.¹

Continue to: Treatment

Treatment of both variants of contact dermatitis includes avoidance of the causative substance and symptomatic treatment with topical steroids, antihistamines, and possibly oral steroids depending on the severity.¹

For our patient, a viral swab was taken and submitted for varicella zoster virus polymerase chain reaction testing to rule out persistent herpes zoster infection; the result was negative. The patient was counseled to discontinue use of the lidocaine patch.

Given the severity and protracted duration of the patient’s symptoms, he also was started on high-potency topical steroids (clobetasol 0.05% ointment to be applied twice daily under occlusion for 2 months), a 4-week prednisone taper (60 mg × 1 week, 40 mg × 1 week, 20 mg × 1 week, 10 mg × 1 week, then stop), and hydroxyzine (25 mg nightly as needed for pruritus). The patient’s rash and symptoms improved dramatically within the first few doses of prednisone and completely cleared by Week 4 of the prednisone taper. At his follow-up appointment 1 month after completing the prednisone taper, he stated that the pain on his back had resolved.

Evidence summary

Naltrexone is comparable to amitriptyline for diabetic neuropathy pain

A 2021 randomized, double-blind, active-comparator, crossover clinical trial conducted in India examined the efficacy of low-dose naltrexone vs standard-of-care amitriptyline in patients (N = 67) with painful diabetic neuropathy. Participants were adults (ages 18 to 75 years) with painful diabetic neuropathy who had been on a stable dose of nonopioid pain medication for at least 1 month.¹

Patients were randomly assigned to start receiving naltrexone 2 mg (n = 33) or amitriptyline 10 mg (n = 34). They received their starting medication for 6 weeks (with follow-up every 2 weeks), then completed a 2-week washout period, and then switched to the other study medication for 6 weeks (same follow-up schedule). If patients reported < 20% pain reduction on the Visual Analog Scale (VAS; 0-100 scoring system with 0 = no pain and 100 = worst pain) at a follow-up visit, their medication dose was titrated up, to a maximum of 4 mg of naltrexone or 25 to 50 mg of amitriptyline.¹

The primary outcome of interest was the mean change in VAS pain score following 6 weeks of treatment. There was no statistically different change from baseline VAS pain score between the amitriptyline and nal­trexone groups (mean difference [MD] = 1.6; 95% CI, –0.9 to 4.2; P = 0.21). These findings were consistent across the secondary endpoints (Likert 5-point pain scale and McGill Pain Questionnaire scores). There was no statistically significant difference in Hamilton Depression Rating Scale scores (13 in the naltrexone group vs 11 in the amitriptyline group; P = .81), no reports of decreased sleep quality in either group, and no significant difference in Patients’ Global Impression of Change scores at 6-week evaluation.¹

The naltrexone cohort experienced 8 adverse events (most commonly, mild diarrhea), while the amitriptyline cohort experienced 52 adverse events (most commonly, somnolence) (P < .001). The limitations of the study include the lack of a placebo arm and a relatively small sample size.¹

Greater reduction in pain scores with naltrexone

A 2022 retrospective cohort study evaluated the effectiveness of naltrexone for patients treated at a single outpatient integrative pain management practice in Alaska between 2014 and 2019. The exposure group (n = 36) included patients who had completed at least a 2-month continuous regimen of oral naltrexone 4.5 mg. Controls (n = 42) were selected from the remaining practice population receiving standard care and were primarily matched by diagnosis code, followed by gender, then age +/– 5 years. Patients were divided into subgroups for inflammatory and neuropathic pain.²

The primary outcome measured was the mean change in VAS score or numeric rating score (NRS; both used a 1-10 rating system), which was assessed during a patient’s appointment from initiation of treatment to the most recent visit or at the termination of therapy (intervention interquartile range, 12-14 months). There was no statistically significant difference in VAS/NRS between the low-dose naltrexone and control groups at baseline (6.09 vs 6.38; P = .454). The low-dose naltrexone group experienced a greater reduction in VAS/NRS pain scores compared to the control group (–37.8% vs –4.3%; P < .001).²

Compared with control patients in each group, patients in the inflammatory pain subgroup and the neuropathic pain subgroup who received low-dose naltrexone reported reductions in pain scores of 32% (P < .001) and 44% (P = .048), respectively. There was no statistically significant difference in mean change in VAS/NRS scores between the inflammatory and neuropathic subgroups (P = .763). A multivariate linear regression analysis did not identify significant variables other than low-dose naltrexone that correlated with pain improvement. The number needed to treat to observe a ≥ 50% reduction in pain scores was 3.2.²

Continue to: Limitations for this study...

Limitations for this study include its small sample size and open-label design.²

Low-dose naltrexone is effective for fibromyalgia pain

A 2020 single-blind prospective dose-­response study utilized the up-and-down method to identify effective naltrexone dose for patients in a Danish university hospital pain clinic. Patients were White women ages 18 to 60 years (N = 25) who had a diagnosis of fibromyalgia unresponsive to traditional pharmacologic treatment. All patients received treatment with low-dose naltrexone (ranging from 0.75 mg to 6.0 mg) but were blinded to dose.³

Studies show that low-dose naltrexone has some effectiveness in a variety of pain conditions—including diabetic neuropathy and fibromyalgia—with few adverse effects.

Patients were evaluated for improvement in fibromyalgia symptoms using the Patient Global Impression of Improvement (PGI-I) scale—which ranges from 1 (very much improved) to 7 (very much worse), with 4 being “no change”—at baseline and after 2 to 3 weeks of treatment with low-dose naltrexone. A patient was considered a responder if they scored 1 to 3 on the follow-up PGI-I scale or if they experienced a > 30% pain reduction on the VAS. If a patient did not respond to their dose, the next patient began treatment at a dose 0.75 mg higher than the previous patient’s ending dose. If a patient did respond to low-dose naltrexone treatment, the next patient’s starting dose was 0.75 mg less than the previous patient’s. Eleven of 25 patients were considered responders.³

The primary outcomes were effective dose for 50% of fibromyalgia patients (3.88 mg; 95% CI, 3.39-4.35) and effective dose for 95% of fibromyalgia patients (5.4 mg; 95% CI, 4.66-6.13). Secondary outcomes were fibromyalgia symptoms as evaluated on the Fibromyalgia Impact Questionnaire Revised. Five of the 11 responders reported a > 30% improvement in tenderness and 8 of the 11 responders reported a > 30% decrease in waking unrefreshed.³

Limitations of the study include the short time period of treatment before response was assessed and the decision to use low test ­doses, which may have hindered detection of effective doses > 6 mg in fibromyalgia.³

Editor’s takeaway

Low-dose naltrexone, a less-often-used form of pain management, is a welcome option. Studies show some effectiveness in a variety of pain conditions with few adverse effects. The small number of studies, the small sample sizes, and the limited follow-up duration should encourage more investigation into how to best use this intervention.

Evidence summary

Naltrexone is comparable to amitriptyline for diabetic neuropathy pain

A 2021 randomized, double-blind, active-comparator, crossover clinical trial conducted in India examined the efficacy of low-dose naltrexone vs standard-of-care amitriptyline in patients (N = 67) with painful diabetic neuropathy. Participants were adults (ages 18 to 75 years) with painful diabetic neuropathy who had been on a stable dose of nonopioid pain medication for at least 1 month.¹

Patients were randomly assigned to start receiving naltrexone 2 mg (n = 33) or amitriptyline 10 mg (n = 34). They received their starting medication for 6 weeks (with follow-up every 2 weeks), then completed a 2-week washout period, and then switched to the other study medication for 6 weeks (same follow-up schedule). If patients reported < 20% pain reduction on the Visual Analog Scale (VAS; 0-100 scoring system with 0 = no pain and 100 = worst pain) at a follow-up visit, their medication dose was titrated up, to a maximum of 4 mg of naltrexone or 25 to 50 mg of amitriptyline.¹

The primary outcome of interest was the mean change in VAS pain score following 6 weeks of treatment. There was no statistically different change from baseline VAS pain score between the amitriptyline and nal­trexone groups (mean difference [MD] = 1.6; 95% CI, –0.9 to 4.2; P = 0.21). These findings were consistent across the secondary endpoints (Likert 5-point pain scale and McGill Pain Questionnaire scores). There was no statistically significant difference in Hamilton Depression Rating Scale scores (13 in the naltrexone group vs 11 in the amitriptyline group; P = .81), no reports of decreased sleep quality in either group, and no significant difference in Patients’ Global Impression of Change scores at 6-week evaluation.¹

The naltrexone cohort experienced 8 adverse events (most commonly, mild diarrhea), while the amitriptyline cohort experienced 52 adverse events (most commonly, somnolence) (P < .001). The limitations of the study include the lack of a placebo arm and a relatively small sample size.¹

Greater reduction in pain scores with naltrexone

A 2022 retrospective cohort study evaluated the effectiveness of naltrexone for patients treated at a single outpatient integrative pain management practice in Alaska between 2014 and 2019. The exposure group (n = 36) included patients who had completed at least a 2-month continuous regimen of oral naltrexone 4.5 mg. Controls (n = 42) were selected from the remaining practice population receiving standard care and were primarily matched by diagnosis code, followed by gender, then age +/– 5 years. Patients were divided into subgroups for inflammatory and neuropathic pain.²

The primary outcome measured was the mean change in VAS score or numeric rating score (NRS; both used a 1-10 rating system), which was assessed during a patient’s appointment from initiation of treatment to the most recent visit or at the termination of therapy (intervention interquartile range, 12-14 months). There was no statistically significant difference in VAS/NRS between the low-dose naltrexone and control groups at baseline (6.09 vs 6.38; P = .454). The low-dose naltrexone group experienced a greater reduction in VAS/NRS pain scores compared to the control group (–37.8% vs –4.3%; P < .001).²

Compared with control patients in each group, patients in the inflammatory pain subgroup and the neuropathic pain subgroup who received low-dose naltrexone reported reductions in pain scores of 32% (P < .001) and 44% (P = .048), respectively. There was no statistically significant difference in mean change in VAS/NRS scores between the inflammatory and neuropathic subgroups (P = .763). A multivariate linear regression analysis did not identify significant variables other than low-dose naltrexone that correlated with pain improvement. The number needed to treat to observe a ≥ 50% reduction in pain scores was 3.2.²

Continue to: Limitations for this study...

Limitations for this study include its small sample size and open-label design.²

Low-dose naltrexone is effective for fibromyalgia pain

A 2020 single-blind prospective dose-­response study utilized the up-and-down method to identify effective naltrexone dose for patients in a Danish university hospital pain clinic. Patients were White women ages 18 to 60 years (N = 25) who had a diagnosis of fibromyalgia unresponsive to traditional pharmacologic treatment. All patients received treatment with low-dose naltrexone (ranging from 0.75 mg to 6.0 mg) but were blinded to dose.³

Studies show that low-dose naltrexone has some effectiveness in a variety of pain conditions—including diabetic neuropathy and fibromyalgia—with few adverse effects.

Patients were evaluated for improvement in fibromyalgia symptoms using the Patient Global Impression of Improvement (PGI-I) scale—which ranges from 1 (very much improved) to 7 (very much worse), with 4 being “no change”—at baseline and after 2 to 3 weeks of treatment with low-dose naltrexone. A patient was considered a responder if they scored 1 to 3 on the follow-up PGI-I scale or if they experienced a > 30% pain reduction on the VAS. If a patient did not respond to their dose, the next patient began treatment at a dose 0.75 mg higher than the previous patient’s ending dose. If a patient did respond to low-dose naltrexone treatment, the next patient’s starting dose was 0.75 mg less than the previous patient’s. Eleven of 25 patients were considered responders.³

The primary outcomes were effective dose for 50% of fibromyalgia patients (3.88 mg; 95% CI, 3.39-4.35) and effective dose for 95% of fibromyalgia patients (5.4 mg; 95% CI, 4.66-6.13). Secondary outcomes were fibromyalgia symptoms as evaluated on the Fibromyalgia Impact Questionnaire Revised. Five of the 11 responders reported a > 30% improvement in tenderness and 8 of the 11 responders reported a > 30% decrease in waking unrefreshed.³

Limitations of the study include the short time period of treatment before response was assessed and the decision to use low test ­doses, which may have hindered detection of effective doses > 6 mg in fibromyalgia.³

Editor’s takeaway

Low-dose naltrexone, a less-often-used form of pain management, is a welcome option. Studies show some effectiveness in a variety of pain conditions with few adverse effects. The small number of studies, the small sample sizes, and the limited follow-up duration should encourage more investigation into how to best use this intervention.

Evidence summary

Naltrexone is comparable to amitriptyline for diabetic neuropathy pain

A 2021 randomized, double-blind, active-comparator, crossover clinical trial conducted in India examined the efficacy of low-dose naltrexone vs standard-of-care amitriptyline in patients (N = 67) with painful diabetic neuropathy. Participants were adults (ages 18 to 75 years) with painful diabetic neuropathy who had been on a stable dose of nonopioid pain medication for at least 1 month.¹

Patients were randomly assigned to start receiving naltrexone 2 mg (n = 33) or amitriptyline 10 mg (n = 34). They received their starting medication for 6 weeks (with follow-up every 2 weeks), then completed a 2-week washout period, and then switched to the other study medication for 6 weeks (same follow-up schedule). If patients reported < 20% pain reduction on the Visual Analog Scale (VAS; 0-100 scoring system with 0 = no pain and 100 = worst pain) at a follow-up visit, their medication dose was titrated up, to a maximum of 4 mg of naltrexone or 25 to 50 mg of amitriptyline.¹

The primary outcome of interest was the mean change in VAS pain score following 6 weeks of treatment. There was no statistically different change from baseline VAS pain score between the amitriptyline and nal­trexone groups (mean difference [MD] = 1.6; 95% CI, –0.9 to 4.2; P = 0.21). These findings were consistent across the secondary endpoints (Likert 5-point pain scale and McGill Pain Questionnaire scores). There was no statistically significant difference in Hamilton Depression Rating Scale scores (13 in the naltrexone group vs 11 in the amitriptyline group; P = .81), no reports of decreased sleep quality in either group, and no significant difference in Patients’ Global Impression of Change scores at 6-week evaluation.¹

The naltrexone cohort experienced 8 adverse events (most commonly, mild diarrhea), while the amitriptyline cohort experienced 52 adverse events (most commonly, somnolence) (P < .001). The limitations of the study include the lack of a placebo arm and a relatively small sample size.¹

Greater reduction in pain scores with naltrexone

A 2022 retrospective cohort study evaluated the effectiveness of naltrexone for patients treated at a single outpatient integrative pain management practice in Alaska between 2014 and 2019. The exposure group (n = 36) included patients who had completed at least a 2-month continuous regimen of oral naltrexone 4.5 mg. Controls (n = 42) were selected from the remaining practice population receiving standard care and were primarily matched by diagnosis code, followed by gender, then age +/– 5 years. Patients were divided into subgroups for inflammatory and neuropathic pain.²

The primary outcome measured was the mean change in VAS score or numeric rating score (NRS; both used a 1-10 rating system), which was assessed during a patient’s appointment from initiation of treatment to the most recent visit or at the termination of therapy (intervention interquartile range, 12-14 months). There was no statistically significant difference in VAS/NRS between the low-dose naltrexone and control groups at baseline (6.09 vs 6.38; P = .454). The low-dose naltrexone group experienced a greater reduction in VAS/NRS pain scores compared to the control group (–37.8% vs –4.3%; P < .001).²

Compared with control patients in each group, patients in the inflammatory pain subgroup and the neuropathic pain subgroup who received low-dose naltrexone reported reductions in pain scores of 32% (P < .001) and 44% (P = .048), respectively. There was no statistically significant difference in mean change in VAS/NRS scores between the inflammatory and neuropathic subgroups (P = .763). A multivariate linear regression analysis did not identify significant variables other than low-dose naltrexone that correlated with pain improvement. The number needed to treat to observe a ≥ 50% reduction in pain scores was 3.2.²

Continue to: Limitations for this study...

Limitations for this study include its small sample size and open-label design.²

Low-dose naltrexone is effective for fibromyalgia pain

A 2020 single-blind prospective dose-­response study utilized the up-and-down method to identify effective naltrexone dose for patients in a Danish university hospital pain clinic. Patients were White women ages 18 to 60 years (N = 25) who had a diagnosis of fibromyalgia unresponsive to traditional pharmacologic treatment. All patients received treatment with low-dose naltrexone (ranging from 0.75 mg to 6.0 mg) but were blinded to dose.³

Studies show that low-dose naltrexone has some effectiveness in a variety of pain conditions—including diabetic neuropathy and fibromyalgia—with few adverse effects.

Patients were evaluated for improvement in fibromyalgia symptoms using the Patient Global Impression of Improvement (PGI-I) scale—which ranges from 1 (very much improved) to 7 (very much worse), with 4 being “no change”—at baseline and after 2 to 3 weeks of treatment with low-dose naltrexone. A patient was considered a responder if they scored 1 to 3 on the follow-up PGI-I scale or if they experienced a > 30% pain reduction on the VAS. If a patient did not respond to their dose, the next patient began treatment at a dose 0.75 mg higher than the previous patient’s ending dose. If a patient did respond to low-dose naltrexone treatment, the next patient’s starting dose was 0.75 mg less than the previous patient’s. Eleven of 25 patients were considered responders.³

The primary outcomes were effective dose for 50% of fibromyalgia patients (3.88 mg; 95% CI, 3.39-4.35) and effective dose for 95% of fibromyalgia patients (5.4 mg; 95% CI, 4.66-6.13). Secondary outcomes were fibromyalgia symptoms as evaluated on the Fibromyalgia Impact Questionnaire Revised. Five of the 11 responders reported a > 30% improvement in tenderness and 8 of the 11 responders reported a > 30% decrease in waking unrefreshed.³

Limitations of the study include the short time period of treatment before response was assessed and the decision to use low test ­doses, which may have hindered detection of effective doses > 6 mg in fibromyalgia.³

Editor’s takeaway

Low-dose naltrexone, a less-often-used form of pain management, is a welcome option. Studies show some effectiveness in a variety of pain conditions with few adverse effects. The small number of studies, the small sample sizes, and the limited follow-up duration should encourage more investigation into how to best use this intervention.

THE CASE

Juana*, a 10-year-old who identifies as a cisgender, Hispanic female, was referred to our integrated behavioral health program by her primary care physician. Her mother was concerned because Juana had been refusing to attend school due to complaints of gastrointestinal upset. This concern began when Juana was in first grade but had increased in severity over the past few months.

Upon further questioning, the patient reported that she initially did not want to attend school due to academic difficulties and bullying. However, since COVID-19, her fears of attending school had significantly worsened. Juana’s mother’s primary language was Spanish and she had limited English proficiency; she reported difficulty communicating with school personnel about Juana’s poor attendance.

Juana had recently had a complete medical work-up for her gastrointestinal concerns, with negative results. Since the negative work-up, Juana’s mother had told her daughter that she would be punished if she didn’t go to school.

● How would you proceed with this patient?

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

School avoidance, also referred to as school refusal, is a symptom of an emotional condition that manifests as a child refusing to go to school or having difficulty going to school or remaining in the classroom for the entire day. School avoidance is not a clinical diagnosis but often is related to an underlying disorder.¹

School avoidance is common, affecting 5% to 28% of youth sometime in their school career.² Available data are not specific to school avoidance but focus on chronic absenteeism (missing ≥ 15 days per school year). Rates of chronic absenteeism are high in elementary and middle school (about 14% each) and tend to increase in high school (about 21%).³ Students with disabilities are 1.5 times more likely to be chronically absent than students without disabilities.³ Compared to White students, American Indian and Pacific Islander students are > 50% more likely, Black students 40% more likely, and Hispanic students 17% more likely to miss ≥ 3 weeks of school.³ Rates of chronic absenteeism are similar (about 16%) for males and females.³

Absenteeism can have immediate and long-term negative effects.⁴ School attendance issues are correlated to negative life outcomes, such as delinquency, teen pregnancy, substance use, and poor academic achievement.⁵ According to the US Department of Education, individuals who chronically miss school are less likely to achieve educational milestones (particularly in younger years) and may be more likely to drop out of school.³

What school avoidance is (and what it isn’t)

It is important to distinguish school avoidance from truancy. Truancy often is associated with antisocial behavior such as lying and stealing, while school avoidance occurs in the absence of significant antisocial disorders.⁶ With truancy, the absence usually is hidden from the parent. In contrast, with school avoidance, the parents usually know where their child is; the child often spends the day secluded in their bedroom. Students who engage in truancy do not demonstrate excessive anxiety about attending school but may have decreased interest in schoolwork and academic performance.⁶ With school avoidance, the child exhibits severe emotional distress about attending school but is willing to complete schoolwork at home.

Why children may avoid school

School avoidance is a biopsychosocial condition with a multitude of underlying causes.⁴ It is associated most commonly with anxiety disorders and neurodevelopmental disorders, including but not limited to learning disabilities and attention-deficit/hyperactivity disorder.¹ Depressive disorders also have been associated with school avoidance.⁷ Social concerns related to changes with school personnel or classes, academic challenges, bullying, health emergencies, and family stressors also can result in symptoms of school avoidance.¹

Continue to: A child seeking to avoid...

A child seeking to avoid school may be motivated by potential negative and/or positive effects of doing so. Kearney and Silverman⁸ identified 4 primary functions of school refusal behaviors:

• avoiding stimuli at school that lend to negative affect (depression, anxiety)
• escaping the social interactions and/or situations for evaluation that occur at school
• gaining more attention from caregivers, and
• obtaining tangible rewards or benefits outside the school environment.

How school avoidance manifests

School avoidance has attributes of internalizing (depression, anxiety, somatic complaints) and externalizing (aggression, tantrums, running away, clinginess) behaviors. It can cause distress for the student, parents and caregivers, and school personnel.

With school avoidance, the child exhibits severe emotional distress about attending school but is willing to complete schoolwork at home.

The avoidance may manifest with behaviors such as crying, hiding, emotional outbursts, and refusing to move prior to the start of the school day. Additionally, the child may beg their parents not to make them go to school or, when at school, they may leave the classroom to go to a safe place such as the nurse’s or counselor’s office.

The avoidance may occur abruptly, such as after a break in the school schedule or a change of school. Or it may be the final result of the student’s gradual inability to cope with the underlying issue.

How to assess for school avoidance

Due to the multifactorial nature of this presenting concern, a comprehensive evaluation is recommended when school avoidance is reported.⁴ Often the child will present with physical symptoms, such as abdominal pain, nausea, vomiting, diarrhea, headaches, shortness of breath, dizziness, chest pain, and palpitations. A thorough medical examination should be performed to rule out a physiological cause. The medical visit should include clinical interviews with the patient and family members or guardians.

Continue to: To identify school avoidance...

To identify school avoidance in pediatric and adolescent populations, medical history and physical ­examination—along with social history to better understand familial, social, and academic concerns—should be a regular part of the medical encounter. The School Refusal Assessment Scale-Revised (SRAS-R) for both parents and their children was developed to assess for school avoidance and can be utilized within the primary care setting. Additional psychiatric history for both the family and patient may be beneficial, due to associations between parental mental health concerns and school avoidance in their children.^9,10

More than onethird of children with behavioral problems, such as school avoidance, have been diagnosed with anxiety.

Assessment for an underlying mental health condition, such as an anxiety or depressive disorder, should be completed when a patient presents with school avoidance.⁴ More than one-third of children with behavioral problems, such as school avoidance, have been diagnosed with anxiety.¹¹ The 2020 National Survey of Children’s Health found that 7.8% of children and adolescents ages 3 to 17 years had a current anxiety disorder, leading the US Preventive Services Task Force to recommend screening for anxiety in children and adolescents ages 8 to 18 years.^12,13 Furthermore, if academic achievement is of concern, then consideration of further assessment for neurodevelopmental disorders is warranted.¹

Treatment is multimodal and multidisciplinary

Treatment for school avoidance is often multimodal and may involve interdisciplinary, team-based care including the medical provider, school system (eg, Child Study Team), family, and mental health care provider.^1,4

Cognitive behavioral therapy (CBT) is the most-studied intervention for school avoidance, with behavioral, exposure-based interventions often central to therapeutic gains in treatment.^1,14,15 The goals of treatment are to increase school attendance while decreasing emotional distress through various strategies, including exposure-based interventions, contingency management with parents and school staff, relaxation training, and/or social skills training.^14,16 Collaborative involvement between the medical provider and the school system is key to successful treatment.

Medication may be considered alone or in combination with CBT when comorbid mental health conditions have been identified. Selective serotonin reuptake inhibitors (SSRIs)—including fluoxetine, sertraline, and escitalopram—are considered first-line treatment for anxiety in children and adolescents.¹⁷ Serotonin-norepinephrine reuptake inhibitors (SNRIs), such as duloxetine and venlafaxine, also have been shown to be effective. Duloxetine is the only medication approved by the US Food and Drug Administration (FDA) for treatment of generalized anxiety disorder in children ages 7 years and older.¹⁷

Continue to: SSRIs and SNRIs have a boxed warning...

SSRIs and SNRIs have a boxed warning from the FDA for increased suicidal thoughts and behaviors in children and adolescents. Although this risk is rare, it should be discussed with the patient and parent/guardian in order to obtain informed consent prior to treatment initiation.

Medication should be started at the lowest possible dose and increased gradually. Patients should remain on the medication for 6 to 12 months after symptom resolution and should be tapered during a nonstressful time, such as the summer break.

THE CASE

Based on the concerns of continued school refusal after negative gastrointestinal work-up, Juana’s physician screened her for anxiety and conducted a clinical interview to better understand any psychosocial concerns. Juana’s score of 10 on the General Anxiety Disorder-7 scale indicated moderate anxiety. She reported symptoms consistent with social anxiety disorder contributing to school avoidance.

The physician consulted with the clinic’s behavioral health consultant (BHC) to confirm the multimodal treatment plan, which was then discussed with Juana and her mother. The physician discussed medication options (SSRIs) and provided documentation (in both English and Spanish) from the visit to Juana’s mother so she could initiate a school-based intervention with the Child Study Team at Juana’s school. A plan for CBT—including a collaborative contingency management plan between the patient and her parent (eg, a reward chart for attending school) and exposure interventions (eg, a graduated plan to participate in school-based activities with the end goal to resume full school attendance)—was developed with the BHC. Biweekly follow-up appointments were scheduled with the BHC and monthly appointments were scheduled with the physician to reinforce the interventions.

CORRESPONDENCE
Meredith L. C. Williamson, PhD, 2900 East 29th Street, Suite 100, Bryan, TX 77840; [email protected]

THE CASE

Juana*, a 10-year-old who identifies as a cisgender, Hispanic female, was referred to our integrated behavioral health program by her primary care physician. Her mother was concerned because Juana had been refusing to attend school due to complaints of gastrointestinal upset. This concern began when Juana was in first grade but had increased in severity over the past few months.

Upon further questioning, the patient reported that she initially did not want to attend school due to academic difficulties and bullying. However, since COVID-19, her fears of attending school had significantly worsened. Juana’s mother’s primary language was Spanish and she had limited English proficiency; she reported difficulty communicating with school personnel about Juana’s poor attendance.

Juana had recently had a complete medical work-up for her gastrointestinal concerns, with negative results. Since the negative work-up, Juana’s mother had told her daughter that she would be punished if she didn’t go to school.

● How would you proceed with this patient?

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

School avoidance, also referred to as school refusal, is a symptom of an emotional condition that manifests as a child refusing to go to school or having difficulty going to school or remaining in the classroom for the entire day. School avoidance is not a clinical diagnosis but often is related to an underlying disorder.¹

School avoidance is common, affecting 5% to 28% of youth sometime in their school career.² Available data are not specific to school avoidance but focus on chronic absenteeism (missing ≥ 15 days per school year). Rates of chronic absenteeism are high in elementary and middle school (about 14% each) and tend to increase in high school (about 21%).³ Students with disabilities are 1.5 times more likely to be chronically absent than students without disabilities.³ Compared to White students, American Indian and Pacific Islander students are > 50% more likely, Black students 40% more likely, and Hispanic students 17% more likely to miss ≥ 3 weeks of school.³ Rates of chronic absenteeism are similar (about 16%) for males and females.³

Absenteeism can have immediate and long-term negative effects.⁴ School attendance issues are correlated to negative life outcomes, such as delinquency, teen pregnancy, substance use, and poor academic achievement.⁵ According to the US Department of Education, individuals who chronically miss school are less likely to achieve educational milestones (particularly in younger years) and may be more likely to drop out of school.³

What school avoidance is (and what it isn’t)

It is important to distinguish school avoidance from truancy. Truancy often is associated with antisocial behavior such as lying and stealing, while school avoidance occurs in the absence of significant antisocial disorders.⁶ With truancy, the absence usually is hidden from the parent. In contrast, with school avoidance, the parents usually know where their child is; the child often spends the day secluded in their bedroom. Students who engage in truancy do not demonstrate excessive anxiety about attending school but may have decreased interest in schoolwork and academic performance.⁶ With school avoidance, the child exhibits severe emotional distress about attending school but is willing to complete schoolwork at home.

Why children may avoid school

School avoidance is a biopsychosocial condition with a multitude of underlying causes.⁴ It is associated most commonly with anxiety disorders and neurodevelopmental disorders, including but not limited to learning disabilities and attention-deficit/hyperactivity disorder.¹ Depressive disorders also have been associated with school avoidance.⁷ Social concerns related to changes with school personnel or classes, academic challenges, bullying, health emergencies, and family stressors also can result in symptoms of school avoidance.¹

Continue to: A child seeking to avoid...

A child seeking to avoid school may be motivated by potential negative and/or positive effects of doing so. Kearney and Silverman⁸ identified 4 primary functions of school refusal behaviors:

• avoiding stimuli at school that lend to negative affect (depression, anxiety)
• escaping the social interactions and/or situations for evaluation that occur at school
• gaining more attention from caregivers, and
• obtaining tangible rewards or benefits outside the school environment.

How school avoidance manifests

School avoidance has attributes of internalizing (depression, anxiety, somatic complaints) and externalizing (aggression, tantrums, running away, clinginess) behaviors. It can cause distress for the student, parents and caregivers, and school personnel.

With school avoidance, the child exhibits severe emotional distress about attending school but is willing to complete schoolwork at home.

The avoidance may manifest with behaviors such as crying, hiding, emotional outbursts, and refusing to move prior to the start of the school day. Additionally, the child may beg their parents not to make them go to school or, when at school, they may leave the classroom to go to a safe place such as the nurse’s or counselor’s office.

The avoidance may occur abruptly, such as after a break in the school schedule or a change of school. Or it may be the final result of the student’s gradual inability to cope with the underlying issue.

How to assess for school avoidance

Due to the multifactorial nature of this presenting concern, a comprehensive evaluation is recommended when school avoidance is reported.⁴ Often the child will present with physical symptoms, such as abdominal pain, nausea, vomiting, diarrhea, headaches, shortness of breath, dizziness, chest pain, and palpitations. A thorough medical examination should be performed to rule out a physiological cause. The medical visit should include clinical interviews with the patient and family members or guardians.

Continue to: To identify school avoidance...

To identify school avoidance in pediatric and adolescent populations, medical history and physical ­examination—along with social history to better understand familial, social, and academic concerns—should be a regular part of the medical encounter. The School Refusal Assessment Scale-Revised (SRAS-R) for both parents and their children was developed to assess for school avoidance and can be utilized within the primary care setting. Additional psychiatric history for both the family and patient may be beneficial, due to associations between parental mental health concerns and school avoidance in their children.^9,10

More than onethird of children with behavioral problems, such as school avoidance, have been diagnosed with anxiety.

Assessment for an underlying mental health condition, such as an anxiety or depressive disorder, should be completed when a patient presents with school avoidance.⁴ More than one-third of children with behavioral problems, such as school avoidance, have been diagnosed with anxiety.¹¹ The 2020 National Survey of Children’s Health found that 7.8% of children and adolescents ages 3 to 17 years had a current anxiety disorder, leading the US Preventive Services Task Force to recommend screening for anxiety in children and adolescents ages 8 to 18 years.^12,13 Furthermore, if academic achievement is of concern, then consideration of further assessment for neurodevelopmental disorders is warranted.¹

Treatment is multimodal and multidisciplinary

Treatment for school avoidance is often multimodal and may involve interdisciplinary, team-based care including the medical provider, school system (eg, Child Study Team), family, and mental health care provider.^1,4

Cognitive behavioral therapy (CBT) is the most-studied intervention for school avoidance, with behavioral, exposure-based interventions often central to therapeutic gains in treatment.^1,14,15 The goals of treatment are to increase school attendance while decreasing emotional distress through various strategies, including exposure-based interventions, contingency management with parents and school staff, relaxation training, and/or social skills training.^14,16 Collaborative involvement between the medical provider and the school system is key to successful treatment.

Medication may be considered alone or in combination with CBT when comorbid mental health conditions have been identified. Selective serotonin reuptake inhibitors (SSRIs)—including fluoxetine, sertraline, and escitalopram—are considered first-line treatment for anxiety in children and adolescents.¹⁷ Serotonin-norepinephrine reuptake inhibitors (SNRIs), such as duloxetine and venlafaxine, also have been shown to be effective. Duloxetine is the only medication approved by the US Food and Drug Administration (FDA) for treatment of generalized anxiety disorder in children ages 7 years and older.¹⁷

Continue to: SSRIs and SNRIs have a boxed warning...

SSRIs and SNRIs have a boxed warning from the FDA for increased suicidal thoughts and behaviors in children and adolescents. Although this risk is rare, it should be discussed with the patient and parent/guardian in order to obtain informed consent prior to treatment initiation.

Medication should be started at the lowest possible dose and increased gradually. Patients should remain on the medication for 6 to 12 months after symptom resolution and should be tapered during a nonstressful time, such as the summer break.

THE CASE

Based on the concerns of continued school refusal after negative gastrointestinal work-up, Juana’s physician screened her for anxiety and conducted a clinical interview to better understand any psychosocial concerns. Juana’s score of 10 on the General Anxiety Disorder-7 scale indicated moderate anxiety. She reported symptoms consistent with social anxiety disorder contributing to school avoidance.

The physician consulted with the clinic’s behavioral health consultant (BHC) to confirm the multimodal treatment plan, which was then discussed with Juana and her mother. The physician discussed medication options (SSRIs) and provided documentation (in both English and Spanish) from the visit to Juana’s mother so she could initiate a school-based intervention with the Child Study Team at Juana’s school. A plan for CBT—including a collaborative contingency management plan between the patient and her parent (eg, a reward chart for attending school) and exposure interventions (eg, a graduated plan to participate in school-based activities with the end goal to resume full school attendance)—was developed with the BHC. Biweekly follow-up appointments were scheduled with the BHC and monthly appointments were scheduled with the physician to reinforce the interventions.

CORRESPONDENCE
Meredith L. C. Williamson, PhD, 2900 East 29th Street, Suite 100, Bryan, TX 77840; [email protected]

THE CASE

Juana*, a 10-year-old who identifies as a cisgender, Hispanic female, was referred to our integrated behavioral health program by her primary care physician. Her mother was concerned because Juana had been refusing to attend school due to complaints of gastrointestinal upset. This concern began when Juana was in first grade but had increased in severity over the past few months.

Upon further questioning, the patient reported that she initially did not want to attend school due to academic difficulties and bullying. However, since COVID-19, her fears of attending school had significantly worsened. Juana’s mother’s primary language was Spanish and she had limited English proficiency; she reported difficulty communicating with school personnel about Juana’s poor attendance.

Juana had recently had a complete medical work-up for her gastrointestinal concerns, with negative results. Since the negative work-up, Juana’s mother had told her daughter that she would be punished if she didn’t go to school.

● How would you proceed with this patient?

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

School avoidance, also referred to as school refusal, is a symptom of an emotional condition that manifests as a child refusing to go to school or having difficulty going to school or remaining in the classroom for the entire day. School avoidance is not a clinical diagnosis but often is related to an underlying disorder.¹

School avoidance is common, affecting 5% to 28% of youth sometime in their school career.² Available data are not specific to school avoidance but focus on chronic absenteeism (missing ≥ 15 days per school year). Rates of chronic absenteeism are high in elementary and middle school (about 14% each) and tend to increase in high school (about 21%).³ Students with disabilities are 1.5 times more likely to be chronically absent than students without disabilities.³ Compared to White students, American Indian and Pacific Islander students are > 50% more likely, Black students 40% more likely, and Hispanic students 17% more likely to miss ≥ 3 weeks of school.³ Rates of chronic absenteeism are similar (about 16%) for males and females.³

Absenteeism can have immediate and long-term negative effects.⁴ School attendance issues are correlated to negative life outcomes, such as delinquency, teen pregnancy, substance use, and poor academic achievement.⁵ According to the US Department of Education, individuals who chronically miss school are less likely to achieve educational milestones (particularly in younger years) and may be more likely to drop out of school.³

What school avoidance is (and what it isn’t)

It is important to distinguish school avoidance from truancy. Truancy often is associated with antisocial behavior such as lying and stealing, while school avoidance occurs in the absence of significant antisocial disorders.⁶ With truancy, the absence usually is hidden from the parent. In contrast, with school avoidance, the parents usually know where their child is; the child often spends the day secluded in their bedroom. Students who engage in truancy do not demonstrate excessive anxiety about attending school but may have decreased interest in schoolwork and academic performance.⁶ With school avoidance, the child exhibits severe emotional distress about attending school but is willing to complete schoolwork at home.

Why children may avoid school

School avoidance is a biopsychosocial condition with a multitude of underlying causes.⁴ It is associated most commonly with anxiety disorders and neurodevelopmental disorders, including but not limited to learning disabilities and attention-deficit/hyperactivity disorder.¹ Depressive disorders also have been associated with school avoidance.⁷ Social concerns related to changes with school personnel or classes, academic challenges, bullying, health emergencies, and family stressors also can result in symptoms of school avoidance.¹

Continue to: A child seeking to avoid...

A child seeking to avoid school may be motivated by potential negative and/or positive effects of doing so. Kearney and Silverman⁸ identified 4 primary functions of school refusal behaviors:

• avoiding stimuli at school that lend to negative affect (depression, anxiety)
• escaping the social interactions and/or situations for evaluation that occur at school
• gaining more attention from caregivers, and
• obtaining tangible rewards or benefits outside the school environment.

How school avoidance manifests

School avoidance has attributes of internalizing (depression, anxiety, somatic complaints) and externalizing (aggression, tantrums, running away, clinginess) behaviors. It can cause distress for the student, parents and caregivers, and school personnel.

With school avoidance, the child exhibits severe emotional distress about attending school but is willing to complete schoolwork at home.

The avoidance may manifest with behaviors such as crying, hiding, emotional outbursts, and refusing to move prior to the start of the school day. Additionally, the child may beg their parents not to make them go to school or, when at school, they may leave the classroom to go to a safe place such as the nurse’s or counselor’s office.

The avoidance may occur abruptly, such as after a break in the school schedule or a change of school. Or it may be the final result of the student’s gradual inability to cope with the underlying issue.

How to assess for school avoidance

Due to the multifactorial nature of this presenting concern, a comprehensive evaluation is recommended when school avoidance is reported.⁴ Often the child will present with physical symptoms, such as abdominal pain, nausea, vomiting, diarrhea, headaches, shortness of breath, dizziness, chest pain, and palpitations. A thorough medical examination should be performed to rule out a physiological cause. The medical visit should include clinical interviews with the patient and family members or guardians.

Continue to: To identify school avoidance...

To identify school avoidance in pediatric and adolescent populations, medical history and physical ­examination—along with social history to better understand familial, social, and academic concerns—should be a regular part of the medical encounter. The School Refusal Assessment Scale-Revised (SRAS-R) for both parents and their children was developed to assess for school avoidance and can be utilized within the primary care setting. Additional psychiatric history for both the family and patient may be beneficial, due to associations between parental mental health concerns and school avoidance in their children.^9,10

More than onethird of children with behavioral problems, such as school avoidance, have been diagnosed with anxiety.

Assessment for an underlying mental health condition, such as an anxiety or depressive disorder, should be completed when a patient presents with school avoidance.⁴ More than one-third of children with behavioral problems, such as school avoidance, have been diagnosed with anxiety.¹¹ The 2020 National Survey of Children’s Health found that 7.8% of children and adolescents ages 3 to 17 years had a current anxiety disorder, leading the US Preventive Services Task Force to recommend screening for anxiety in children and adolescents ages 8 to 18 years.^12,13 Furthermore, if academic achievement is of concern, then consideration of further assessment for neurodevelopmental disorders is warranted.¹

Treatment is multimodal and multidisciplinary

Treatment for school avoidance is often multimodal and may involve interdisciplinary, team-based care including the medical provider, school system (eg, Child Study Team), family, and mental health care provider.^1,4

Cognitive behavioral therapy (CBT) is the most-studied intervention for school avoidance, with behavioral, exposure-based interventions often central to therapeutic gains in treatment.^1,14,15 The goals of treatment are to increase school attendance while decreasing emotional distress through various strategies, including exposure-based interventions, contingency management with parents and school staff, relaxation training, and/or social skills training.^14,16 Collaborative involvement between the medical provider and the school system is key to successful treatment.

Medication may be considered alone or in combination with CBT when comorbid mental health conditions have been identified. Selective serotonin reuptake inhibitors (SSRIs)—including fluoxetine, sertraline, and escitalopram—are considered first-line treatment for anxiety in children and adolescents.¹⁷ Serotonin-norepinephrine reuptake inhibitors (SNRIs), such as duloxetine and venlafaxine, also have been shown to be effective. Duloxetine is the only medication approved by the US Food and Drug Administration (FDA) for treatment of generalized anxiety disorder in children ages 7 years and older.¹⁷

Continue to: SSRIs and SNRIs have a boxed warning...

SSRIs and SNRIs have a boxed warning from the FDA for increased suicidal thoughts and behaviors in children and adolescents. Although this risk is rare, it should be discussed with the patient and parent/guardian in order to obtain informed consent prior to treatment initiation.

Medication should be started at the lowest possible dose and increased gradually. Patients should remain on the medication for 6 to 12 months after symptom resolution and should be tapered during a nonstressful time, such as the summer break.

THE CASE

Based on the concerns of continued school refusal after negative gastrointestinal work-up, Juana’s physician screened her for anxiety and conducted a clinical interview to better understand any psychosocial concerns. Juana’s score of 10 on the General Anxiety Disorder-7 scale indicated moderate anxiety. She reported symptoms consistent with social anxiety disorder contributing to school avoidance.

The physician consulted with the clinic’s behavioral health consultant (BHC) to confirm the multimodal treatment plan, which was then discussed with Juana and her mother. The physician discussed medication options (SSRIs) and provided documentation (in both English and Spanish) from the visit to Juana’s mother so she could initiate a school-based intervention with the Child Study Team at Juana’s school. A plan for CBT—including a collaborative contingency management plan between the patient and her parent (eg, a reward chart for attending school) and exposure interventions (eg, a graduated plan to participate in school-based activities with the end goal to resume full school attendance)—was developed with the BHC. Biweekly follow-up appointments were scheduled with the BHC and monthly appointments were scheduled with the physician to reinforce the interventions.

CORRESPONDENCE
Meredith L. C. Williamson, PhD, 2900 East 29th Street, Suite 100, Bryan, TX 77840; [email protected]

ABSTRACT

Background: The Altman Rule, a simple tool for consumers seeking to make healthier packaged food choices at the point of sale, applies to packaged carbohydrates. According to the Altman Rule, a food is a healthier option if it has at least 3 g of fiber per serving and the grams of fiber plus the grams of protein exceed the grams of sugar per serving. This study sought to evaluate whether the Altman Rule is a valid proxy for glycemic load (GL).

Methods: We compared the binary outcome of whether a food item meets the Altman Rule with the GL of all foods categorized as cereals, chips, crackers, and granola bars in the Nutrition Data System for Research Database (University of Minnesota, Version 2010). We examined the percentage of foods in low-, medium-, and high-GL categories that met the Altman Rule.

Results: There were 1235 foods (342 cereals, 305 chips, 379 crackers, and 209 granola bars) in this analysis. There was a significant relationship between the GL of foods and the Altman Rule (P < .001) in that most low-GL (68%), almost half of medium-GL (48%), and very few high-GL (7%) foods met the criteria of the rule.

Conclusions: The Altman Rule is a reasonable proxy for GL and can be a useful and accessible tool for consumers interested in buying healthier packaged carbohydrate foods.

Nutrition can be complicated for consumers interested in making healthier choices at the grocery store. Consumers may have difficulty identifying more nutritious options, especially when food labels are adorned with claims such as “Good Source of Fiber” or “Heart Healthy.”¹ In addition, when reading food labels, consumers may find it difficult to decipher which data to prioritize when carbohydrates, total sugars, added sugars, total dietary fiber, soluble fiber, and insoluble fiber are all listed.

The concept of glycemic load (GL) is an important consideration, especially for people with diabetes. GL approximates the blood sugar response to different foods. A food with a high GL is digested quickly, and its carbohydrates are taken into the bloodstream rapidly. This leads to a spike and subsequent drop in blood sugars, which can cause symptoms of hyperglycemia and hypoglycemia in a person with diabetes.^2,3 Despite its usefulness, GL may be too complicated for a consumer to understand, and it does not appear anywhere on the food label. Since GL is calculated using pooled blood sugar response from individuals after the ingestion of the particular food, estimation of the GL is not intuitable.⁴

Point-of-sale tools. People seeking to lose weight, control diabetes, improve dyslipidemia and/or blood pressure, and/or decrease their risk for heart disease may benefit from point-of-sale tools such as the Altman Rule, which simplifies and encourages the selection of more nutritious foods.¹ Other tools—such as Guiding Stars (https://guidingstars.com), NuVal (www.nuval.com), and different variations of traffic lights—have been created to help consumers make more informed and healthier food choices.^5-8 However, Guiding Stars and NuVal are based on complicated algorithms that are not entirely transparent and not accessible to the average consumer.^6,7 Evaluations of these nutrition tools indicate that consumers tend to underrate the healthiness of some foods, such as raw almonds and salmon, and overrate the healthiness of others, such as fruit punch and diet soda, when using traffic light systems.⁶ Furthermore, these nutrition tools are not available in many supermarkets. Previous research suggests that the use of point-of-sale nutrition apps decreases with the time and effort involved in using an app.⁹

Continue to: The Altman Rule

The Altman Rule was developed by a family physician (author WA) to provide a more accessible tool for people interested in choosing healthier prepackaged carbohydrate foods while shopping. Since the user does not need to have a smartphone, and they are not required to download or understand an app for each purchase, the Altman Rule may be more usable compared with more complicated alternatives.

The Altman Rule can be used with nutrition labels that feature serving information and calories in enlarged and bold type, in compliance with the most recent US Food and Drug Administration (FDA) guideline from 2016. Many foods with high fiber also have high amounts of sugar, so the criteria of the Altman Rule includes a 2-step process requiring (1) a minimum of 3 g of total dietary fiber per serving and (2) the sum of the grams of fiber plus the grams of protein per serving to be greater than the total grams of sugar (not grams of added sugar or grams of carbohydrate) per serving (FIGURE 1A). Unlike the relatively complicated formula related to GL, this 2-part rule can be applied in seconds while shopping (FIGURE 1B).

The rule is intended only to be used for packaged carbohydrate products, such as bread, muffins, bagels, pasta, rice, oatmeal, cereals, snack bars, chips, and crackers. It does not apply to whole foods, such as meat, dairy, fruits, or vegetables. These foods are excluded to prevent any consumer confusion related to the nutritional content of whole foods (eg, an apple may have more sugar than fiber and protein combined, but it is still a nutritious option).

Since the user does not need to have a smartphone, the Altman Rule may be more usable compared with more complicated alternatives.

This study aimed to determine if the Altman Rule is a reasonable proxy for the more complicated concept of GL. We calculated the relationship between the GL of commercially available packaged carbohydrate foods and whether those foods met the Altman Rule.

METHODS

The Altman Rule was tested by comparing the binary outcome of the rule (meets/does not meet) with data on all foods categorized as cereals, chips, crackers, and granola bars in the Nutrition Data System for Research (NDSR) Database (University of Minnesota, Version 2010).

Continue to: To account for differences...

To account for differences in serving size, we used the standard of 50 g for each product as 1 serving. We used 50 g (about 1.7 oz) to help compare the different foods and between foods within the same group. Additionally, 50 g is close to 1 serving for most foods in these groups; it is about the size of a typical granola bar, three-quarters to 2 cups of cereal, 10 to 12 crackers, and 15 to 25 chips. We determined the GL for each product by multiplying the number of available carbohydrates (total carbohydrate – dietary fiber) by the product’s glycemic index/100. In general, GL is categorized as low (≤ 10), medium (11-19), or high (≥ 20).

We applied the Altman Rule to categorize each product as meeting or not meeting the rule. We compared the proportion of foods meeting the Altman Rule, stratified by GL and by specific foods, and used chi-square to determine if differences were statistically significant. These data were collected and analyzed in the summer of 2019.

RESULTS

There were 1235 foods (342 breakfast cereals, 305 chips, 379 crackers, and 209 granola bars) used for this analysis. There is a significant relationship between the GL of foods and the Altman Rule in that most low-GL (68%), almost half of medium-GL (48%), and only a few high-GL foods (7%) met the rule (P < .001) (TABLE 1). There was also a significant relationship between “meeting the ­Altman Rule” and GL within each food type (P < .001) (TABLE 2).

The medium-GL foods were the second largest category of foods we calculated; thus we further broke them into binary categories of low-medium GL (values 11-14) and high-medium GL (values 15-19) to explore the results of the Altman Rule. About half of the foods in medium-GL category met the Altman Rule. About eighty-five percent of the foods with low-medium GL passed the Altman Rule, while only 39% of the foods with high-medium GL did.

Foods that met the rule were more likely to be low GL and foods that did not pass the rule were more likely high GL. Within the medium-GL category, foods that met the rule were more likely to be low-medium GL. 

Continue to: The findings within food categories...

The findings within food categories showed that very few cereals, chips, crackers, and granola bars were low GL. For every food category, except granola bars, far more low-GL foods met the Altman Rule than those that did not. At the same time, very few high-GL foods met the Altman Rule. The category with the most individual high-GL food items meeting the Altman Rule was cereal. This was also the subcategory with the largest percentage of high-GL food items meeting the Altman Rule. Thirty-nine cereals that were high GL met the rule, but more than 4 times as many high-GL cereals did not (n = 190).

DISCUSSION

Marketing and nutrition messaging create consumer confusion that makes it challenging to identify packaged food items that are more nutrient dense. The Altman Rule simplifies food choices that have become unnecessarily complex. Our findings suggest this 2-step rule is a reasonable proxy for the more complicated and less accessible GL for packaged carbohydrates, such as cereals, chips, crackers, and snack bars. Foods that meet the rule are likely low or low-medium GL and thus are foods that are likely to be healthier choices.

Our findings suggest this 2-step rule is a reasonable proxy for the more complicated and less accessible glycemic load for packaged carbohydrates.

Of note, only 9% of chips (n = 27) passed the Altman Rule, likely due to their low dietary fiber content, which was typical of chips. If a food item does not have at least 3 grams of total dietary fiber per serving, it does not pass the Altman Rule, regardless of how much protein or sugar is in the product. This may be considered a strength or a weakness of the Altman Rule. Few nutrition-dense foods are low in fiber, but some foods could be nutritious but do not meet the Altman Rule due to having < 3 g of fiber.

With the high prevalence of chronic diseases such as hypertension, diabetes, hyperlipidemia, and cardiovascular disease, it is essential to help consumers prevent chronic disease altogether or manage their chronic disease by providing tools to identify healthier food choices. The tool also has a place in clinical medicine for use by physicians and other health care professionals. Research shows that physicians find both time and lack of ­knowledge/resources to be a barrier to providing nutritional counseling to patients.¹⁰ Since the Altman Rule can be shared and explained with very little time and without extensive nutritional knowledge, it meets these needs.

Limitations

Glycemic load. We acknowledge that the Altman Rule is not foolproof and that assessing this rule based on GL has some limitations. GL is not a perfect or comprehensive way to measure the nutritional value of a food. For example, fruits such as watermelon and grapes are nutritionally dense. However, they contain high amounts of natural sugars—and as such, their GL is relatively high, which could lead a consumer to perceive them as unhealthy. Nevertheless, GL is both a useful and accepted tool and a reasonable way to assess the validity of the rule, specifically when assessing packaged carbohydrates. The simplicity of the Altman Rule and its relationship with GL makes it such that consumers are more likely to make a healthier food choice using it.⁹

Continue to: Specificity and sensitivity

Specificity and sensitivity. There are other limitations to the Altman Rule, given that a small number of high-GL foods meet the rule. For example, some granola bars had high dietary protein, which offset a high sugar content just enough to pass the rule despite a higher GL. As such, concluding that a snack bar is a healthier choice because it meets the Altman Rule when it has high amounts of sugar may not be appropriate. This limitation could be considered a lack of specificity (the rule includes food it ought not to include). Another limitation to consider would be a lack of sensitivity, given that only 68% of low-GL foods passed the Altman Rule. Since GL is associated with carbohydrate content, foods with a low carbohydrate count often have little to no fiber and thus would fall into the category of foods that did not meet the Altman Rule but had low GL. In this case, however, the low amount of fiber may render the Altman Rule a better indicator of a healthier food choice than the GL.

Hidden sugars. Foods with sugar alcohols and artificial sweeteners may be as deleterious as caloric alternatives while not being accounted for when reporting the grams of sugar per serving on the nutrition label.⁷ This may represent an exception to the Altman Rule, as foods that are not healthier choices may pass the rule because the sugar content on the nutrition label is, in a sense, artificially lowered. Future research may investigate the hypothesis that these foods are nutritionally inferior despite meeting the Altman Rule.

The sample. Our study also was limited to working only with foods that were included in the NDSR database up to 2010. This limitation is mitigated by the fact that the sample size was large (> 1000 packaged food items were included in our analyses). The study also could be limited by the food categories that were analyzed; food categories such as bread, rice, pasta, and bagels were not included.

The objective of this research was to investigate the relationship between GL and the Altman Rule, rather than to conduct an exhaustive analysis of the Altman Rule for every possible food category. Studying the relationship between the Altman Rule and GL in other categories of food is an objective for future research. The data so far support a relationship between these entities. The likelihood of the nutrition facts of foods changing without the GL changing (or vice versa) is very low. As such, the Altman Rule still seems to be a reasonable proxy of GL.

CONCLUSIONS

Research indicates that point-of-sale tools, such as Guiding Stars, NuVal, and other stoplight tools, can successfully alter consumers’ behaviors.⁹ These tools can be helpful but are not available in many supermarkets. Despite the limitations, the Altman Rule is a useful decision aid that is accessible to all consumers no matter where they live or shop and is easy to use and remember.

The Altman rule can be used in clinical practice by health care professionals, such as physicians, nurse practitioners, physician assistants, dietitians, and health coaches. It also has the potential to be used in commercial settings, such as grocery stores, to help consumers easily identify healthier convenience foods. This has public health implications, as the rule can both empower consumers and potentially incentivize food manufacturers to upgrade their products nutritionally.

Additional research would be useful to evaluate consumers’ preferences and perceptions about how user-friendly the Altman Rule is at the point of sale with packaged carbohydrate foods. This would help to further understand how the use of information on food packaging can motivate healthier decisions—thereby helping to alleviate the burden of chronic disease.

CORRESPONDENCE
Kimberly R. Dong, DrPH, MS, RDN, Tufts University School of Medicine, Department of Public Health and Community Medicine, 136 Harrison Avenue, MV Building, Boston, MA 02111; [email protected]

ABSTRACT

Background: The Altman Rule, a simple tool for consumers seeking to make healthier packaged food choices at the point of sale, applies to packaged carbohydrates. According to the Altman Rule, a food is a healthier option if it has at least 3 g of fiber per serving and the grams of fiber plus the grams of protein exceed the grams of sugar per serving. This study sought to evaluate whether the Altman Rule is a valid proxy for glycemic load (GL).

Methods: We compared the binary outcome of whether a food item meets the Altman Rule with the GL of all foods categorized as cereals, chips, crackers, and granola bars in the Nutrition Data System for Research Database (University of Minnesota, Version 2010). We examined the percentage of foods in low-, medium-, and high-GL categories that met the Altman Rule.

Results: There were 1235 foods (342 cereals, 305 chips, 379 crackers, and 209 granola bars) in this analysis. There was a significant relationship between the GL of foods and the Altman Rule (P < .001) in that most low-GL (68%), almost half of medium-GL (48%), and very few high-GL (7%) foods met the criteria of the rule.

Conclusions: The Altman Rule is a reasonable proxy for GL and can be a useful and accessible tool for consumers interested in buying healthier packaged carbohydrate foods.

Nutrition can be complicated for consumers interested in making healthier choices at the grocery store. Consumers may have difficulty identifying more nutritious options, especially when food labels are adorned with claims such as “Good Source of Fiber” or “Heart Healthy.”¹ In addition, when reading food labels, consumers may find it difficult to decipher which data to prioritize when carbohydrates, total sugars, added sugars, total dietary fiber, soluble fiber, and insoluble fiber are all listed.

The concept of glycemic load (GL) is an important consideration, especially for people with diabetes. GL approximates the blood sugar response to different foods. A food with a high GL is digested quickly, and its carbohydrates are taken into the bloodstream rapidly. This leads to a spike and subsequent drop in blood sugars, which can cause symptoms of hyperglycemia and hypoglycemia in a person with diabetes.^2,3 Despite its usefulness, GL may be too complicated for a consumer to understand, and it does not appear anywhere on the food label. Since GL is calculated using pooled blood sugar response from individuals after the ingestion of the particular food, estimation of the GL is not intuitable.⁴

Point-of-sale tools. People seeking to lose weight, control diabetes, improve dyslipidemia and/or blood pressure, and/or decrease their risk for heart disease may benefit from point-of-sale tools such as the Altman Rule, which simplifies and encourages the selection of more nutritious foods.¹ Other tools—such as Guiding Stars (https://guidingstars.com), NuVal (www.nuval.com), and different variations of traffic lights—have been created to help consumers make more informed and healthier food choices.^5-8 However, Guiding Stars and NuVal are based on complicated algorithms that are not entirely transparent and not accessible to the average consumer.^6,7 Evaluations of these nutrition tools indicate that consumers tend to underrate the healthiness of some foods, such as raw almonds and salmon, and overrate the healthiness of others, such as fruit punch and diet soda, when using traffic light systems.⁶ Furthermore, these nutrition tools are not available in many supermarkets. Previous research suggests that the use of point-of-sale nutrition apps decreases with the time and effort involved in using an app.⁹

Continue to: The Altman Rule

The Altman Rule was developed by a family physician (author WA) to provide a more accessible tool for people interested in choosing healthier prepackaged carbohydrate foods while shopping. Since the user does not need to have a smartphone, and they are not required to download or understand an app for each purchase, the Altman Rule may be more usable compared with more complicated alternatives.

The Altman Rule can be used with nutrition labels that feature serving information and calories in enlarged and bold type, in compliance with the most recent US Food and Drug Administration (FDA) guideline from 2016. Many foods with high fiber also have high amounts of sugar, so the criteria of the Altman Rule includes a 2-step process requiring (1) a minimum of 3 g of total dietary fiber per serving and (2) the sum of the grams of fiber plus the grams of protein per serving to be greater than the total grams of sugar (not grams of added sugar or grams of carbohydrate) per serving (FIGURE 1A). Unlike the relatively complicated formula related to GL, this 2-part rule can be applied in seconds while shopping (FIGURE 1B).

The rule is intended only to be used for packaged carbohydrate products, such as bread, muffins, bagels, pasta, rice, oatmeal, cereals, snack bars, chips, and crackers. It does not apply to whole foods, such as meat, dairy, fruits, or vegetables. These foods are excluded to prevent any consumer confusion related to the nutritional content of whole foods (eg, an apple may have more sugar than fiber and protein combined, but it is still a nutritious option).

Since the user does not need to have a smartphone, the Altman Rule may be more usable compared with more complicated alternatives.

This study aimed to determine if the Altman Rule is a reasonable proxy for the more complicated concept of GL. We calculated the relationship between the GL of commercially available packaged carbohydrate foods and whether those foods met the Altman Rule.

METHODS

The Altman Rule was tested by comparing the binary outcome of the rule (meets/does not meet) with data on all foods categorized as cereals, chips, crackers, and granola bars in the Nutrition Data System for Research (NDSR) Database (University of Minnesota, Version 2010).

Continue to: To account for differences...

To account for differences in serving size, we used the standard of 50 g for each product as 1 serving. We used 50 g (about 1.7 oz) to help compare the different foods and between foods within the same group. Additionally, 50 g is close to 1 serving for most foods in these groups; it is about the size of a typical granola bar, three-quarters to 2 cups of cereal, 10 to 12 crackers, and 15 to 25 chips. We determined the GL for each product by multiplying the number of available carbohydrates (total carbohydrate – dietary fiber) by the product’s glycemic index/100. In general, GL is categorized as low (≤ 10), medium (11-19), or high (≥ 20).

We applied the Altman Rule to categorize each product as meeting or not meeting the rule. We compared the proportion of foods meeting the Altman Rule, stratified by GL and by specific foods, and used chi-square to determine if differences were statistically significant. These data were collected and analyzed in the summer of 2019.

RESULTS

There were 1235 foods (342 breakfast cereals, 305 chips, 379 crackers, and 209 granola bars) used for this analysis. There is a significant relationship between the GL of foods and the Altman Rule in that most low-GL (68%), almost half of medium-GL (48%), and only a few high-GL foods (7%) met the rule (P < .001) (TABLE 1). There was also a significant relationship between “meeting the ­Altman Rule” and GL within each food type (P < .001) (TABLE 2).

The medium-GL foods were the second largest category of foods we calculated; thus we further broke them into binary categories of low-medium GL (values 11-14) and high-medium GL (values 15-19) to explore the results of the Altman Rule. About half of the foods in medium-GL category met the Altman Rule. About eighty-five percent of the foods with low-medium GL passed the Altman Rule, while only 39% of the foods with high-medium GL did.

Foods that met the rule were more likely to be low GL and foods that did not pass the rule were more likely high GL. Within the medium-GL category, foods that met the rule were more likely to be low-medium GL. 

Continue to: The findings within food categories...

The findings within food categories showed that very few cereals, chips, crackers, and granola bars were low GL. For every food category, except granola bars, far more low-GL foods met the Altman Rule than those that did not. At the same time, very few high-GL foods met the Altman Rule. The category with the most individual high-GL food items meeting the Altman Rule was cereal. This was also the subcategory with the largest percentage of high-GL food items meeting the Altman Rule. Thirty-nine cereals that were high GL met the rule, but more than 4 times as many high-GL cereals did not (n = 190).

DISCUSSION

Marketing and nutrition messaging create consumer confusion that makes it challenging to identify packaged food items that are more nutrient dense. The Altman Rule simplifies food choices that have become unnecessarily complex. Our findings suggest this 2-step rule is a reasonable proxy for the more complicated and less accessible GL for packaged carbohydrates, such as cereals, chips, crackers, and snack bars. Foods that meet the rule are likely low or low-medium GL and thus are foods that are likely to be healthier choices.

Our findings suggest this 2-step rule is a reasonable proxy for the more complicated and less accessible glycemic load for packaged carbohydrates.

Of note, only 9% of chips (n = 27) passed the Altman Rule, likely due to their low dietary fiber content, which was typical of chips. If a food item does not have at least 3 grams of total dietary fiber per serving, it does not pass the Altman Rule, regardless of how much protein or sugar is in the product. This may be considered a strength or a weakness of the Altman Rule. Few nutrition-dense foods are low in fiber, but some foods could be nutritious but do not meet the Altman Rule due to having < 3 g of fiber.

With the high prevalence of chronic diseases such as hypertension, diabetes, hyperlipidemia, and cardiovascular disease, it is essential to help consumers prevent chronic disease altogether or manage their chronic disease by providing tools to identify healthier food choices. The tool also has a place in clinical medicine for use by physicians and other health care professionals. Research shows that physicians find both time and lack of ­knowledge/resources to be a barrier to providing nutritional counseling to patients.¹⁰ Since the Altman Rule can be shared and explained with very little time and without extensive nutritional knowledge, it meets these needs.

Limitations

Glycemic load. We acknowledge that the Altman Rule is not foolproof and that assessing this rule based on GL has some limitations. GL is not a perfect or comprehensive way to measure the nutritional value of a food. For example, fruits such as watermelon and grapes are nutritionally dense. However, they contain high amounts of natural sugars—and as such, their GL is relatively high, which could lead a consumer to perceive them as unhealthy. Nevertheless, GL is both a useful and accepted tool and a reasonable way to assess the validity of the rule, specifically when assessing packaged carbohydrates. The simplicity of the Altman Rule and its relationship with GL makes it such that consumers are more likely to make a healthier food choice using it.⁹

Continue to: Specificity and sensitivity

Specificity and sensitivity. There are other limitations to the Altman Rule, given that a small number of high-GL foods meet the rule. For example, some granola bars had high dietary protein, which offset a high sugar content just enough to pass the rule despite a higher GL. As such, concluding that a snack bar is a healthier choice because it meets the Altman Rule when it has high amounts of sugar may not be appropriate. This limitation could be considered a lack of specificity (the rule includes food it ought not to include). Another limitation to consider would be a lack of sensitivity, given that only 68% of low-GL foods passed the Altman Rule. Since GL is associated with carbohydrate content, foods with a low carbohydrate count often have little to no fiber and thus would fall into the category of foods that did not meet the Altman Rule but had low GL. In this case, however, the low amount of fiber may render the Altman Rule a better indicator of a healthier food choice than the GL.

Hidden sugars. Foods with sugar alcohols and artificial sweeteners may be as deleterious as caloric alternatives while not being accounted for when reporting the grams of sugar per serving on the nutrition label.⁷ This may represent an exception to the Altman Rule, as foods that are not healthier choices may pass the rule because the sugar content on the nutrition label is, in a sense, artificially lowered. Future research may investigate the hypothesis that these foods are nutritionally inferior despite meeting the Altman Rule.

The sample. Our study also was limited to working only with foods that were included in the NDSR database up to 2010. This limitation is mitigated by the fact that the sample size was large (> 1000 packaged food items were included in our analyses). The study also could be limited by the food categories that were analyzed; food categories such as bread, rice, pasta, and bagels were not included.

The objective of this research was to investigate the relationship between GL and the Altman Rule, rather than to conduct an exhaustive analysis of the Altman Rule for every possible food category. Studying the relationship between the Altman Rule and GL in other categories of food is an objective for future research. The data so far support a relationship between these entities. The likelihood of the nutrition facts of foods changing without the GL changing (or vice versa) is very low. As such, the Altman Rule still seems to be a reasonable proxy of GL.

CONCLUSIONS

Research indicates that point-of-sale tools, such as Guiding Stars, NuVal, and other stoplight tools, can successfully alter consumers’ behaviors.⁹ These tools can be helpful but are not available in many supermarkets. Despite the limitations, the Altman Rule is a useful decision aid that is accessible to all consumers no matter where they live or shop and is easy to use and remember.

The Altman rule can be used in clinical practice by health care professionals, such as physicians, nurse practitioners, physician assistants, dietitians, and health coaches. It also has the potential to be used in commercial settings, such as grocery stores, to help consumers easily identify healthier convenience foods. This has public health implications, as the rule can both empower consumers and potentially incentivize food manufacturers to upgrade their products nutritionally.

Additional research would be useful to evaluate consumers’ preferences and perceptions about how user-friendly the Altman Rule is at the point of sale with packaged carbohydrate foods. This would help to further understand how the use of information on food packaging can motivate healthier decisions—thereby helping to alleviate the burden of chronic disease.

CORRESPONDENCE
Kimberly R. Dong, DrPH, MS, RDN, Tufts University School of Medicine, Department of Public Health and Community Medicine, 136 Harrison Avenue, MV Building, Boston, MA 02111; [email protected]

ABSTRACT

Background: The Altman Rule, a simple tool for consumers seeking to make healthier packaged food choices at the point of sale, applies to packaged carbohydrates. According to the Altman Rule, a food is a healthier option if it has at least 3 g of fiber per serving and the grams of fiber plus the grams of protein exceed the grams of sugar per serving. This study sought to evaluate whether the Altman Rule is a valid proxy for glycemic load (GL).

Methods: We compared the binary outcome of whether a food item meets the Altman Rule with the GL of all foods categorized as cereals, chips, crackers, and granola bars in the Nutrition Data System for Research Database (University of Minnesota, Version 2010). We examined the percentage of foods in low-, medium-, and high-GL categories that met the Altman Rule.

Results: There were 1235 foods (342 cereals, 305 chips, 379 crackers, and 209 granola bars) in this analysis. There was a significant relationship between the GL of foods and the Altman Rule (P < .001) in that most low-GL (68%), almost half of medium-GL (48%), and very few high-GL (7%) foods met the criteria of the rule.

Conclusions: The Altman Rule is a reasonable proxy for GL and can be a useful and accessible tool for consumers interested in buying healthier packaged carbohydrate foods.

Nutrition can be complicated for consumers interested in making healthier choices at the grocery store. Consumers may have difficulty identifying more nutritious options, especially when food labels are adorned with claims such as “Good Source of Fiber” or “Heart Healthy.”¹ In addition, when reading food labels, consumers may find it difficult to decipher which data to prioritize when carbohydrates, total sugars, added sugars, total dietary fiber, soluble fiber, and insoluble fiber are all listed.

The concept of glycemic load (GL) is an important consideration, especially for people with diabetes. GL approximates the blood sugar response to different foods. A food with a high GL is digested quickly, and its carbohydrates are taken into the bloodstream rapidly. This leads to a spike and subsequent drop in blood sugars, which can cause symptoms of hyperglycemia and hypoglycemia in a person with diabetes.^2,3 Despite its usefulness, GL may be too complicated for a consumer to understand, and it does not appear anywhere on the food label. Since GL is calculated using pooled blood sugar response from individuals after the ingestion of the particular food, estimation of the GL is not intuitable.⁴

Point-of-sale tools. People seeking to lose weight, control diabetes, improve dyslipidemia and/or blood pressure, and/or decrease their risk for heart disease may benefit from point-of-sale tools such as the Altman Rule, which simplifies and encourages the selection of more nutritious foods.¹ Other tools—such as Guiding Stars (https://guidingstars.com), NuVal (www.nuval.com), and different variations of traffic lights—have been created to help consumers make more informed and healthier food choices.^5-8 However, Guiding Stars and NuVal are based on complicated algorithms that are not entirely transparent and not accessible to the average consumer.^6,7 Evaluations of these nutrition tools indicate that consumers tend to underrate the healthiness of some foods, such as raw almonds and salmon, and overrate the healthiness of others, such as fruit punch and diet soda, when using traffic light systems.⁶ Furthermore, these nutrition tools are not available in many supermarkets. Previous research suggests that the use of point-of-sale nutrition apps decreases with the time and effort involved in using an app.⁹

Continue to: The Altman Rule

The Altman Rule was developed by a family physician (author WA) to provide a more accessible tool for people interested in choosing healthier prepackaged carbohydrate foods while shopping. Since the user does not need to have a smartphone, and they are not required to download or understand an app for each purchase, the Altman Rule may be more usable compared with more complicated alternatives.

The Altman Rule can be used with nutrition labels that feature serving information and calories in enlarged and bold type, in compliance with the most recent US Food and Drug Administration (FDA) guideline from 2016. Many foods with high fiber also have high amounts of sugar, so the criteria of the Altman Rule includes a 2-step process requiring (1) a minimum of 3 g of total dietary fiber per serving and (2) the sum of the grams of fiber plus the grams of protein per serving to be greater than the total grams of sugar (not grams of added sugar or grams of carbohydrate) per serving (FIGURE 1A). Unlike the relatively complicated formula related to GL, this 2-part rule can be applied in seconds while shopping (FIGURE 1B).

The rule is intended only to be used for packaged carbohydrate products, such as bread, muffins, bagels, pasta, rice, oatmeal, cereals, snack bars, chips, and crackers. It does not apply to whole foods, such as meat, dairy, fruits, or vegetables. These foods are excluded to prevent any consumer confusion related to the nutritional content of whole foods (eg, an apple may have more sugar than fiber and protein combined, but it is still a nutritious option).

Since the user does not need to have a smartphone, the Altman Rule may be more usable compared with more complicated alternatives.

This study aimed to determine if the Altman Rule is a reasonable proxy for the more complicated concept of GL. We calculated the relationship between the GL of commercially available packaged carbohydrate foods and whether those foods met the Altman Rule.

METHODS

The Altman Rule was tested by comparing the binary outcome of the rule (meets/does not meet) with data on all foods categorized as cereals, chips, crackers, and granola bars in the Nutrition Data System for Research (NDSR) Database (University of Minnesota, Version 2010).

Continue to: To account for differences...

To account for differences in serving size, we used the standard of 50 g for each product as 1 serving. We used 50 g (about 1.7 oz) to help compare the different foods and between foods within the same group. Additionally, 50 g is close to 1 serving for most foods in these groups; it is about the size of a typical granola bar, three-quarters to 2 cups of cereal, 10 to 12 crackers, and 15 to 25 chips. We determined the GL for each product by multiplying the number of available carbohydrates (total carbohydrate – dietary fiber) by the product’s glycemic index/100. In general, GL is categorized as low (≤ 10), medium (11-19), or high (≥ 20).

We applied the Altman Rule to categorize each product as meeting or not meeting the rule. We compared the proportion of foods meeting the Altman Rule, stratified by GL and by specific foods, and used chi-square to determine if differences were statistically significant. These data were collected and analyzed in the summer of 2019.

RESULTS

There were 1235 foods (342 breakfast cereals, 305 chips, 379 crackers, and 209 granola bars) used for this analysis. There is a significant relationship between the GL of foods and the Altman Rule in that most low-GL (68%), almost half of medium-GL (48%), and only a few high-GL foods (7%) met the rule (P < .001) (TABLE 1). There was also a significant relationship between “meeting the ­Altman Rule” and GL within each food type (P < .001) (TABLE 2).

The medium-GL foods were the second largest category of foods we calculated; thus we further broke them into binary categories of low-medium GL (values 11-14) and high-medium GL (values 15-19) to explore the results of the Altman Rule. About half of the foods in medium-GL category met the Altman Rule. About eighty-five percent of the foods with low-medium GL passed the Altman Rule, while only 39% of the foods with high-medium GL did.

Foods that met the rule were more likely to be low GL and foods that did not pass the rule were more likely high GL. Within the medium-GL category, foods that met the rule were more likely to be low-medium GL. 

Continue to: The findings within food categories...

The findings within food categories showed that very few cereals, chips, crackers, and granola bars were low GL. For every food category, except granola bars, far more low-GL foods met the Altman Rule than those that did not. At the same time, very few high-GL foods met the Altman Rule. The category with the most individual high-GL food items meeting the Altman Rule was cereal. This was also the subcategory with the largest percentage of high-GL food items meeting the Altman Rule. Thirty-nine cereals that were high GL met the rule, but more than 4 times as many high-GL cereals did not (n = 190).

DISCUSSION

Marketing and nutrition messaging create consumer confusion that makes it challenging to identify packaged food items that are more nutrient dense. The Altman Rule simplifies food choices that have become unnecessarily complex. Our findings suggest this 2-step rule is a reasonable proxy for the more complicated and less accessible GL for packaged carbohydrates, such as cereals, chips, crackers, and snack bars. Foods that meet the rule are likely low or low-medium GL and thus are foods that are likely to be healthier choices.

Our findings suggest this 2-step rule is a reasonable proxy for the more complicated and less accessible glycemic load for packaged carbohydrates.

Of note, only 9% of chips (n = 27) passed the Altman Rule, likely due to their low dietary fiber content, which was typical of chips. If a food item does not have at least 3 grams of total dietary fiber per serving, it does not pass the Altman Rule, regardless of how much protein or sugar is in the product. This may be considered a strength or a weakness of the Altman Rule. Few nutrition-dense foods are low in fiber, but some foods could be nutritious but do not meet the Altman Rule due to having < 3 g of fiber.

With the high prevalence of chronic diseases such as hypertension, diabetes, hyperlipidemia, and cardiovascular disease, it is essential to help consumers prevent chronic disease altogether or manage their chronic disease by providing tools to identify healthier food choices. The tool also has a place in clinical medicine for use by physicians and other health care professionals. Research shows that physicians find both time and lack of ­knowledge/resources to be a barrier to providing nutritional counseling to patients.¹⁰ Since the Altman Rule can be shared and explained with very little time and without extensive nutritional knowledge, it meets these needs.

Limitations

Glycemic load. We acknowledge that the Altman Rule is not foolproof and that assessing this rule based on GL has some limitations. GL is not a perfect or comprehensive way to measure the nutritional value of a food. For example, fruits such as watermelon and grapes are nutritionally dense. However, they contain high amounts of natural sugars—and as such, their GL is relatively high, which could lead a consumer to perceive them as unhealthy. Nevertheless, GL is both a useful and accepted tool and a reasonable way to assess the validity of the rule, specifically when assessing packaged carbohydrates. The simplicity of the Altman Rule and its relationship with GL makes it such that consumers are more likely to make a healthier food choice using it.⁹

Continue to: Specificity and sensitivity

Specificity and sensitivity. There are other limitations to the Altman Rule, given that a small number of high-GL foods meet the rule. For example, some granola bars had high dietary protein, which offset a high sugar content just enough to pass the rule despite a higher GL. As such, concluding that a snack bar is a healthier choice because it meets the Altman Rule when it has high amounts of sugar may not be appropriate. This limitation could be considered a lack of specificity (the rule includes food it ought not to include). Another limitation to consider would be a lack of sensitivity, given that only 68% of low-GL foods passed the Altman Rule. Since GL is associated with carbohydrate content, foods with a low carbohydrate count often have little to no fiber and thus would fall into the category of foods that did not meet the Altman Rule but had low GL. In this case, however, the low amount of fiber may render the Altman Rule a better indicator of a healthier food choice than the GL.

Hidden sugars. Foods with sugar alcohols and artificial sweeteners may be as deleterious as caloric alternatives while not being accounted for when reporting the grams of sugar per serving on the nutrition label.⁷ This may represent an exception to the Altman Rule, as foods that are not healthier choices may pass the rule because the sugar content on the nutrition label is, in a sense, artificially lowered. Future research may investigate the hypothesis that these foods are nutritionally inferior despite meeting the Altman Rule.

The sample. Our study also was limited to working only with foods that were included in the NDSR database up to 2010. This limitation is mitigated by the fact that the sample size was large (> 1000 packaged food items were included in our analyses). The study also could be limited by the food categories that were analyzed; food categories such as bread, rice, pasta, and bagels were not included.

The objective of this research was to investigate the relationship between GL and the Altman Rule, rather than to conduct an exhaustive analysis of the Altman Rule for every possible food category. Studying the relationship between the Altman Rule and GL in other categories of food is an objective for future research. The data so far support a relationship between these entities. The likelihood of the nutrition facts of foods changing without the GL changing (or vice versa) is very low. As such, the Altman Rule still seems to be a reasonable proxy of GL.

CONCLUSIONS

Research indicates that point-of-sale tools, such as Guiding Stars, NuVal, and other stoplight tools, can successfully alter consumers’ behaviors.⁹ These tools can be helpful but are not available in many supermarkets. Despite the limitations, the Altman Rule is a useful decision aid that is accessible to all consumers no matter where they live or shop and is easy to use and remember.

The Altman rule can be used in clinical practice by health care professionals, such as physicians, nurse practitioners, physician assistants, dietitians, and health coaches. It also has the potential to be used in commercial settings, such as grocery stores, to help consumers easily identify healthier convenience foods. This has public health implications, as the rule can both empower consumers and potentially incentivize food manufacturers to upgrade their products nutritionally.

Additional research would be useful to evaluate consumers’ preferences and perceptions about how user-friendly the Altman Rule is at the point of sale with packaged carbohydrate foods. This would help to further understand how the use of information on food packaging can motivate healthier decisions—thereby helping to alleviate the burden of chronic disease.

CORRESPONDENCE
Kimberly R. Dong, DrPH, MS, RDN, Tufts University School of Medicine, Department of Public Health and Community Medicine, 136 Harrison Avenue, MV Building, Boston, MA 02111; [email protected]

Migraine is a headache disorder that often causes unilateral pain, photophobia, phonophobia, nausea, and vomiting. More than 70% of office visits for migraine are made to primary care physicians.¹ Recent data suggest migraine may be caused primarily by neuronal dysfunction and only secondarily by vasodilation.² Although there are numerous classes of drugs used for migraine prevention and treatment, their success has been limited by inadequate efficacy, tolerability, and patient adherence.³ The discovery of pro-inflammatory markers such as calcitonin gene-related peptide (CGRP) has led to the development of new medications to prevent and treat migraine.⁴

IMAGE: © SCOTT BODELL

Pathophysiology, Dx and triggers, indications for pharmacotherapy

Pathophysiology. A migraine is thought to be caused by cortical spreading depression (CSD), a depolarization of glial and neuronal cell membranes.⁵This results in increased cortical excitability, central trigeminal-thalamic sensitization, and defective descending pain modulatory activity.⁶The activation of the trigeminal sensory pathways, primarily the ophthalmic branch, sends nociceptive signals to second-order neurons mediated by the release of neurotransmitters, such as CGRPs.⁵ This activation explains in part the primary location for a migraine, which is around the eye and the neighboring cranial regions. The pain perceived by the patient is caused by these second-order neurons.

It has been theorized that gepants bind to calcitonin gene-related peptide receptors, resulting in decreased blood flow to the brain, inhibition of neurogenic inflammation, and reduced pain signaling.

Dx and triggers. In 2018, the International Headache Society revised its guidelines for the diagnosis of migraine.⁷ According to the 3rd edition of The International Classification of Headache Disorders (ICHD-3), the diagnosis of migraine is made when a patient has at least 5 headache attacks that last 4 to 72 hours and have at least 2 of the following characteristics: (1) unilateral location, (2) pulsating quality, (3) moderate-to-severe pain intensity, and (4) aggravated by or causing avoidance of routine physical activity.⁷ The headache attacks also should have (1) associated nausea or vomiting or (2) photophobia and phonophobia.⁷ The presence of atypical signs or symptoms as indicated by the SNNOOP10 mnemonic raises concerns for secondary headaches and the need for further investigation into the cause of the headache (TABLE 1).⁸ It is not possible to detect every secondary headache with standard neuroimaging, but the SNNOOP10 red flags can help determine when imaging may be indicated.⁸ Potential triggers for migraine can be found in TABLE 2.⁹

Indications for pharmacotherapy. All patients receiving a diagnosis of migraine should be offered acute pharmacologic treatment. Consider preventive therapy anytime there are ≥ 4 headache days per month, debilitating attacks despite acute therapy, overuse of acute medication (> 2 d/wk), difficulty tolerating acute medication, patient preference, or presence of certain migraine subtypes.^7,10

Acute treatments

Abortive therapies for migraine include analgesics such as nonsteroidal anti-­inflammatory drugs (NSAIDs) and acetaminophen, and ergot alkaloids, triptans, or small-molecule CGRP receptor antagonists (gepants). Prompt administration increases the chance of success with acute therapy. Medications with the highest levels of efficacy based on the 2015 guidelines from the American Headache Society (AHS) are given in TABLE 3.¹¹ Lasmiditan (Reyvow) is not included in the 2015 guidelines, as it was approved after publication of the guidelines.

Non-CGRP first-line therapies

NSAIDs and acetaminophen. NSAIDs such as aspirin, diclofenac, ibuprofen, and naproxen have a high level of evidence to support their use as first-line treatments for mild-to-moderate migraine attacks. Trials consistently demonstrate their superiority to placebo in headache relief and complete pain relief at 2 hours. There is no recommendation for selecting one NSAID over another; however, consider their frequency of dosing and ­adverse effect profiles. The number needed to treat for complete pain relief at 2 hours ranges from 7 to 10 for most NSAIDs.^11,12 In some placebo-controlled studies, acetaminophen was less effective than NSAIDs, but was safer because it did not cause gastric irritation or antiplatelet effects.¹²

Triptans inhibit 5-HT_1B/1D receptors. Consider formulation, route of administration, cost, and pharmacokinetics when selecting a triptan. Patients who do not respond well to one triptan may respond favorably to another. A meta-analysis of the effectiveness of the 7 available agents found that triptans at standard doses provided pain relief within 2 hours in 42% to 76% of patients, and sustained freedom from pain for 2 hours in 18% to 50% of patients.¹³ Lasmiditan is a selective serotonin receptor (5-HT_1F) agonist that lacks vasoconstrictor activity. This is an option for patients with relative contraindications to triptans due to cardiovascular risk factors.¹⁰

Continue to: Second-line therapies

Intranasal dihydroergotamine has a favorable adverse event profile and greater evidence for efficacy compared with ergotamine. Compared with triptans, intranasal dihydroergotamine has a high level of efficacy but causes more adverse effects.¹⁴ Severe nausea is common, and dihydroergotamine often is used in combination with an antiemetic drug. Dihydroergotamine should not be used within 24 hours of taking a triptan, and it is contraindicated for patients who have hypertension or ischemic heart disease or who are pregnant or breastfeeding. There is also the potential for adverse drug interactions.¹⁵

A meta-analysis found that triptans at standard doses provided pain relief within 2 hours in 42% to 76% of patients, and sustained freedom from pain for 2 hours in 18% to 50% of patients.

Antiemetics may be helpful for migraine associated with severe nausea or vomiting. The dopamine antagonists metoclopramide, prochlorperazine, and chlorpromazine have demonstrated benefit in randomized ­placebo-controlled trials.¹¹ Ondansetron has not been studied extensively, but sometimes is used in clinical practice. Nonoral routes of administration may be useful in patients having trouble swallowing medications or in those experiencing significant nausea or vomiting early during migraine attacks.

Due to the high potential for abuse, opioids should not be used routinely for the treatment of migraine.¹² There is no high-quality evidence supporting the efficacy of barbiturates (ie, butalbital-containing compounds) for acute migraine treatment.¹¹ Moreover, use of these agents may increase the likelihood of progression from episodic to chronic migraine.¹⁶

Gepants for acute migraine treatment

Neuropeptide CGRP is released from trigeminal nerves and is a potent dilator of cerebral and dural vessels, playing a key role in regulating blood flow to the brain. Other roles of CGRP include the release of inflammatory agents from mast cells and the transmission of painful stimuli from intracranial vessels.¹⁷ The CGRP receptor or ligand can be targeted by small-molecule receptor antagonists for acute and preventive migraine treatment (and by monoclonal antibodies solely for prevention, discussed later). It has been theorized that gepants bind to CGRP receptors, resulting in decreased blood flow to the brain, inhibition of neurogenic inflammation, and reduced pain signaling.¹⁷ Unlike triptans and ergotamine derivatives, these novel treatments do not constrict blood vessels and may have a unique role in patients with contraindications to triptans.

The 3 gepants approved for acute treatment—ubrogepant (Ubrelvy),¹⁸ rimegepant (Nurtec),¹⁹ and zavegepant (Zavzpret)²⁰—were compared with placebo in clinical trials and were shown to increase the number of patients who were completely pain free at 2 hours, were free of the most bothersome associated symptom (photophobia, phonophobia, or nausea) at 2 hours, and remained pain free at 24 hours (TABLE 4^18-24).

Continue to: Ubrogrepant

Ubrogepant, in 2 Phase 3 trials (ACHIEVE I and ACHIEVE II) demonstrated effectiveness compared with placebo.^21,22 The most common adverse effects reported were nausea and somnolence at very low rates. Pain-relief rates at 2 hours post dose (> 60% of participants) were higher than pain-free rates, and a significantly higher percentage (> 40%) of ubrogepant-treated participants reported ability to function normally on the Functional Disability Scale.²⁵

Rimegepant was also superior to placebo (59% vs 43%) in pain relief at 2 hours post dose and other secondary endpoints.²³ Rimegepant also has potential drug interactions and dose adjustments (TABLE 4^18-24).

Zavegepant, approved in March 2023, is administered once daily as a 10-mg nasal spray. In its Phase 3 trial, zavegepant was significantly superior to placebo at 2 hours post dose in freedom from pain (24% v 15%), and in freedom from the most bothersome symptom (40% v 31%).²⁴ Dosage modifications are not needed with mild-to-moderate renal or hepatic disease.²⁰

Worth noting. The safety of using ubrogepant to treat more than 8 migraine episodes in a 30-day period has not been established. The safety of using more than 18 doses of zavegepant in a 30-day period also has not been established. With ubrogepant and rimegepant, there are dosing modifications for concomitant use with specific drugs (CYP3A4 inhibitors and inducers) due to potential interactions and in patients with hepatic or renal impairment.^18,19

There are no trials comparing efficacy of CGRP antagonists to triptans. Recognizing that these newer medications would be costly, the AHS position statement released in 2019 recommends that gepants be considered for those with contraindications to triptans or for whom at least 2 oral triptans have failed (as determined by a validated patient outcome questionnaire).¹⁰ Step therapy with documentation of previous trials and therapy failures is often required by insurance companies prior to gepant coverage.

Continue to: Preventive therapies

Preventive therapies

Preventive migraine therapies are used to reduce duration, frequency, and severity of attacks, the need for acute treatment, and overall headache disability.²⁶ Medications typically are chosen based on efficacy, adverse effect profile, and patient comorbidities. Barriers to successful use include poor patient adherence and tolerability, the need for slow dose titration, and long-term use (minimum of 2 months) at maximum tolerated or minimum effective doses. Medications with established efficacy (Level A^a) based on the 2012 guidelines from the American Academy of Neurology (AAN) and the AHS are given in TABLE 5.^27-29

Drugs having received the strongest level of evidence for migraine prevention are metoprolol, propranolol, timolol, topiramate, valproate sodium, divalproex sodium, and onabotulinumtoxinA (Botox), and frovatriptan for menstrual migraine prevention. Because these guidelines were last updated in 2012, they did not cover gepants (which will be discussed shortly). The AHS released a position statement in 2019 supporting the use of anti-CGRP monoclonal antibodies (mAbs) in those who cannot tolerate or have had an inadequate response to a 6-week trial of at least 2 AAN/AHA Level A or B^b treatments.¹⁰ No head-to-head trials exist between non-CGRP preventive therapies and the CGRP antagonists.

CGRP-targeted prevention

Four anti-CGRP mAbs and 2 gepants have been approved for migraine prevention in the United States. Differences between products include targets (ligand vs receptor), antibody IgG subtype, bioavailability, route of administration, and frequency of administration.²⁸ As noted in the Phase 3 studies (TABLE 6^19,30-47), these therapies are highly efficacious, safe, and tolerable.

Gepants. Rimegepant, discussed earlier for migraine treatment, is one of the CGRP receptor antagonists approved for prevention. The other is atogepant (Qulipta), approved only for prevention. Ubrogepant is not approved for prevention.

Anti-CGRP mAb is the only medication class specifically created for migraine prevention.^10,26 As already noted, several efficacious non-CGRP treatment options are available for migraine prevention. However, higher doses of those agents, if needed, can lead to intolerable adverse effects for some patients, thereby limiting overall efficacy. ­Anti-CGRP mAbs, a targeted, highly efficacious treatment option, offer efficacy comparable to non-CGRP agents with a more favorable adverse effect profile for those who cannot tolerate or achieve only minimal efficacy with traditional preventive therapies.¹⁰

Continue to: The targeted anti-CGRP approach...

The targeted anti-CGRP approach, which can be used by patients with liver or kidney disease, results in decreased toxicity and minimal drug interactions. Long half-lives allow for monthly or quarterly injections, possibly resulting in increased compliance.²⁸ Dose titration is not needed, allowing for more rapid symptom management. The large molecular size of a mAb limits its transfer across the blood-brain barrier, making central nervous system adverse effects unlikely.²⁸ Despite the compelling mAb pharmacologic properties, their use may be limited by a lack of long-term safety data and the need for parenteral administration. Although ­immunogenicity—the development of neutralizing antibodies—can limit long-term tolerability or efficacy of mAbs generally,^26,28 anti-CGRP mAbs were engineered to minimally activate the immune system and have not been associated with immune suppression, opportunistic infections, malignancies, or decreased efficacy.²⁸

Unlike triptans and ergotamine derivatives, gepants do not constrict blood vessels and may have a unique role in patients with contraindications to triptans.

A pooled meta-analysis including 4 trials (3166 patients) found that CGRP mAbs compared with placebo significantly improved patient response rates, defined as at least a 50% and 75% reduction in monthly ­headache/migraine days from baseline to Weeks 9 to 12.⁴⁸ Another meta-analysis including 8 trials (2292 patients) found a significant reduction from baseline in monthly migraine days and monthly acute migraine medication consumption among patients taking CGRP mAbs compared with those taking placebo.⁴⁹ Open-label extension studies have shown progressive and cumulative benefits in individuals who respond to anti-CGRP mAbs. Therefore, several treatment cycles may be necessary to determine overall efficacy of therapy.^10,28

Cost initially can be a barrier. Insurance companies often require step therapy before agreeing to cover mAb therapy, which aligns with the 2019 AHS position statement.¹⁰Due to differences in insurance coverage, out-of-pocket expenses can vary greatly. However, options are available through online manufacturer assistance to reduce cost, making it comparable to other migraine treatments. Safety and efficacy studies of anti-CGRP mAbs use in pregnant individuals are limited. At this time, they should not be prescribed for those who are pregnant, planning to become pregnant, or breastfeeding. Counsel nonpregnant patients on appropriate contraception while using a mAb due to possible teratogenicity and negative pregnancy outcomes.^28,50

When combination treatment may be appropriate

Monotherapy is the usual approach to preventing migraine due to advantages of efficacy, simplified regimens, lower cost, and reduced adverse effects.⁵¹ However, if a patient does not benefit from monotherapy even after trying dose titrations as tolerated or switching therapies, trying complementary combination therapy is appropriate. Despite a shortage of clinical trials supporting the use of 2 or more preventive medications with different mechanisms of action, this strategy is used clinically.¹⁰ Consider combination therapy in those with refractory disease, partial responses, or intolerance to recommended doses.⁵² Articles reporting on case study reviews have rationalized the combined use of onabotulinumtoxinA and anti-CGRP mAbs, noting better migraine control.^51,53 The 2019 AHS position statement recommends adding a mAb to an existing preventive treatment regimen with no other changes until mAb effectiveness is determined, as the risk for drug interactions on dual therapy is low.¹⁰ Safety and efficacy also have been demonstrated with the combination of preventive anti-CGRP mAbs and acute treatment with gepants as needed.⁵⁴

Monoclonal antibodies are highly efficacious options for those who cannot tolerate or achieve only minimal efficacy with traditional preventive therapies.

Overall, gepants and mAbs are as effective as traditional acute and preventive treatments for migraine, and they cause fewer adverse effects and often allow a more simplified regimen. Gepants and mAbs are viable options in the primary care setting. Due to limited long-term data and high cost, however, they routinely are used for refractory migraine rather than as first-line agents. These therapies are especially favorable options for patients when traditional migraine therapies yield inadequate efficacy, cause intolerable adverse effects, are contraindicated, or introduce the risk for medication interactions.

CORRESPONDENCE
Emily Peterson, PharmD, BCACP, 3640 Middlebury Road, Iowa City, IA 52242; [email protected]

Migraine is a headache disorder that often causes unilateral pain, photophobia, phonophobia, nausea, and vomiting. More than 70% of office visits for migraine are made to primary care physicians.¹ Recent data suggest migraine may be caused primarily by neuronal dysfunction and only secondarily by vasodilation.² Although there are numerous classes of drugs used for migraine prevention and treatment, their success has been limited by inadequate efficacy, tolerability, and patient adherence.³ The discovery of pro-inflammatory markers such as calcitonin gene-related peptide (CGRP) has led to the development of new medications to prevent and treat migraine.⁴

IMAGE: © SCOTT BODELL

Pathophysiology, Dx and triggers, indications for pharmacotherapy

Pathophysiology. A migraine is thought to be caused by cortical spreading depression (CSD), a depolarization of glial and neuronal cell membranes.⁵This results in increased cortical excitability, central trigeminal-thalamic sensitization, and defective descending pain modulatory activity.⁶The activation of the trigeminal sensory pathways, primarily the ophthalmic branch, sends nociceptive signals to second-order neurons mediated by the release of neurotransmitters, such as CGRPs.⁵ This activation explains in part the primary location for a migraine, which is around the eye and the neighboring cranial regions. The pain perceived by the patient is caused by these second-order neurons.

It has been theorized that gepants bind to calcitonin gene-related peptide receptors, resulting in decreased blood flow to the brain, inhibition of neurogenic inflammation, and reduced pain signaling.

Dx and triggers. In 2018, the International Headache Society revised its guidelines for the diagnosis of migraine.⁷ According to the 3rd edition of The International Classification of Headache Disorders (ICHD-3), the diagnosis of migraine is made when a patient has at least 5 headache attacks that last 4 to 72 hours and have at least 2 of the following characteristics: (1) unilateral location, (2) pulsating quality, (3) moderate-to-severe pain intensity, and (4) aggravated by or causing avoidance of routine physical activity.⁷ The headache attacks also should have (1) associated nausea or vomiting or (2) photophobia and phonophobia.⁷ The presence of atypical signs or symptoms as indicated by the SNNOOP10 mnemonic raises concerns for secondary headaches and the need for further investigation into the cause of the headache (TABLE 1).⁸ It is not possible to detect every secondary headache with standard neuroimaging, but the SNNOOP10 red flags can help determine when imaging may be indicated.⁸ Potential triggers for migraine can be found in TABLE 2.⁹

Indications for pharmacotherapy. All patients receiving a diagnosis of migraine should be offered acute pharmacologic treatment. Consider preventive therapy anytime there are ≥ 4 headache days per month, debilitating attacks despite acute therapy, overuse of acute medication (> 2 d/wk), difficulty tolerating acute medication, patient preference, or presence of certain migraine subtypes.^7,10

Acute treatments

Abortive therapies for migraine include analgesics such as nonsteroidal anti-­inflammatory drugs (NSAIDs) and acetaminophen, and ergot alkaloids, triptans, or small-molecule CGRP receptor antagonists (gepants). Prompt administration increases the chance of success with acute therapy. Medications with the highest levels of efficacy based on the 2015 guidelines from the American Headache Society (AHS) are given in TABLE 3.¹¹ Lasmiditan (Reyvow) is not included in the 2015 guidelines, as it was approved after publication of the guidelines.

Non-CGRP first-line therapies

NSAIDs and acetaminophen. NSAIDs such as aspirin, diclofenac, ibuprofen, and naproxen have a high level of evidence to support their use as first-line treatments for mild-to-moderate migraine attacks. Trials consistently demonstrate their superiority to placebo in headache relief and complete pain relief at 2 hours. There is no recommendation for selecting one NSAID over another; however, consider their frequency of dosing and ­adverse effect profiles. The number needed to treat for complete pain relief at 2 hours ranges from 7 to 10 for most NSAIDs.^11,12 In some placebo-controlled studies, acetaminophen was less effective than NSAIDs, but was safer because it did not cause gastric irritation or antiplatelet effects.¹²

Triptans inhibit 5-HT_1B/1D receptors. Consider formulation, route of administration, cost, and pharmacokinetics when selecting a triptan. Patients who do not respond well to one triptan may respond favorably to another. A meta-analysis of the effectiveness of the 7 available agents found that triptans at standard doses provided pain relief within 2 hours in 42% to 76% of patients, and sustained freedom from pain for 2 hours in 18% to 50% of patients.¹³ Lasmiditan is a selective serotonin receptor (5-HT_1F) agonist that lacks vasoconstrictor activity. This is an option for patients with relative contraindications to triptans due to cardiovascular risk factors.¹⁰

Continue to: Second-line therapies

Intranasal dihydroergotamine has a favorable adverse event profile and greater evidence for efficacy compared with ergotamine. Compared with triptans, intranasal dihydroergotamine has a high level of efficacy but causes more adverse effects.¹⁴ Severe nausea is common, and dihydroergotamine often is used in combination with an antiemetic drug. Dihydroergotamine should not be used within 24 hours of taking a triptan, and it is contraindicated for patients who have hypertension or ischemic heart disease or who are pregnant or breastfeeding. There is also the potential for adverse drug interactions.¹⁵

A meta-analysis found that triptans at standard doses provided pain relief within 2 hours in 42% to 76% of patients, and sustained freedom from pain for 2 hours in 18% to 50% of patients.

Antiemetics may be helpful for migraine associated with severe nausea or vomiting. The dopamine antagonists metoclopramide, prochlorperazine, and chlorpromazine have demonstrated benefit in randomized ­placebo-controlled trials.¹¹ Ondansetron has not been studied extensively, but sometimes is used in clinical practice. Nonoral routes of administration may be useful in patients having trouble swallowing medications or in those experiencing significant nausea or vomiting early during migraine attacks.

Due to the high potential for abuse, opioids should not be used routinely for the treatment of migraine.¹² There is no high-quality evidence supporting the efficacy of barbiturates (ie, butalbital-containing compounds) for acute migraine treatment.¹¹ Moreover, use of these agents may increase the likelihood of progression from episodic to chronic migraine.¹⁶

Gepants for acute migraine treatment

Neuropeptide CGRP is released from trigeminal nerves and is a potent dilator of cerebral and dural vessels, playing a key role in regulating blood flow to the brain. Other roles of CGRP include the release of inflammatory agents from mast cells and the transmission of painful stimuli from intracranial vessels.¹⁷ The CGRP receptor or ligand can be targeted by small-molecule receptor antagonists for acute and preventive migraine treatment (and by monoclonal antibodies solely for prevention, discussed later). It has been theorized that gepants bind to CGRP receptors, resulting in decreased blood flow to the brain, inhibition of neurogenic inflammation, and reduced pain signaling.¹⁷ Unlike triptans and ergotamine derivatives, these novel treatments do not constrict blood vessels and may have a unique role in patients with contraindications to triptans.

The 3 gepants approved for acute treatment—ubrogepant (Ubrelvy),¹⁸ rimegepant (Nurtec),¹⁹ and zavegepant (Zavzpret)²⁰—were compared with placebo in clinical trials and were shown to increase the number of patients who were completely pain free at 2 hours, were free of the most bothersome associated symptom (photophobia, phonophobia, or nausea) at 2 hours, and remained pain free at 24 hours (TABLE 4^18-24).

Continue to: Ubrogrepant

Ubrogepant, in 2 Phase 3 trials (ACHIEVE I and ACHIEVE II) demonstrated effectiveness compared with placebo.^21,22 The most common adverse effects reported were nausea and somnolence at very low rates. Pain-relief rates at 2 hours post dose (> 60% of participants) were higher than pain-free rates, and a significantly higher percentage (> 40%) of ubrogepant-treated participants reported ability to function normally on the Functional Disability Scale.²⁵

Rimegepant was also superior to placebo (59% vs 43%) in pain relief at 2 hours post dose and other secondary endpoints.²³ Rimegepant also has potential drug interactions and dose adjustments (TABLE 4^18-24).

Zavegepant, approved in March 2023, is administered once daily as a 10-mg nasal spray. In its Phase 3 trial, zavegepant was significantly superior to placebo at 2 hours post dose in freedom from pain (24% v 15%), and in freedom from the most bothersome symptom (40% v 31%).²⁴ Dosage modifications are not needed with mild-to-moderate renal or hepatic disease.²⁰

Worth noting. The safety of using ubrogepant to treat more than 8 migraine episodes in a 30-day period has not been established. The safety of using more than 18 doses of zavegepant in a 30-day period also has not been established. With ubrogepant and rimegepant, there are dosing modifications for concomitant use with specific drugs (CYP3A4 inhibitors and inducers) due to potential interactions and in patients with hepatic or renal impairment.^18,19

There are no trials comparing efficacy of CGRP antagonists to triptans. Recognizing that these newer medications would be costly, the AHS position statement released in 2019 recommends that gepants be considered for those with contraindications to triptans or for whom at least 2 oral triptans have failed (as determined by a validated patient outcome questionnaire).¹⁰ Step therapy with documentation of previous trials and therapy failures is often required by insurance companies prior to gepant coverage.

Continue to: Preventive therapies

Preventive therapies

Preventive migraine therapies are used to reduce duration, frequency, and severity of attacks, the need for acute treatment, and overall headache disability.²⁶ Medications typically are chosen based on efficacy, adverse effect profile, and patient comorbidities. Barriers to successful use include poor patient adherence and tolerability, the need for slow dose titration, and long-term use (minimum of 2 months) at maximum tolerated or minimum effective doses. Medications with established efficacy (Level A^a) based on the 2012 guidelines from the American Academy of Neurology (AAN) and the AHS are given in TABLE 5.^27-29

Drugs having received the strongest level of evidence for migraine prevention are metoprolol, propranolol, timolol, topiramate, valproate sodium, divalproex sodium, and onabotulinumtoxinA (Botox), and frovatriptan for menstrual migraine prevention. Because these guidelines were last updated in 2012, they did not cover gepants (which will be discussed shortly). The AHS released a position statement in 2019 supporting the use of anti-CGRP monoclonal antibodies (mAbs) in those who cannot tolerate or have had an inadequate response to a 6-week trial of at least 2 AAN/AHA Level A or B^b treatments.¹⁰ No head-to-head trials exist between non-CGRP preventive therapies and the CGRP antagonists.

CGRP-targeted prevention

Four anti-CGRP mAbs and 2 gepants have been approved for migraine prevention in the United States. Differences between products include targets (ligand vs receptor), antibody IgG subtype, bioavailability, route of administration, and frequency of administration.²⁸ As noted in the Phase 3 studies (TABLE 6^19,30-47), these therapies are highly efficacious, safe, and tolerable.

Gepants. Rimegepant, discussed earlier for migraine treatment, is one of the CGRP receptor antagonists approved for prevention. The other is atogepant (Qulipta), approved only for prevention. Ubrogepant is not approved for prevention.

Anti-CGRP mAb is the only medication class specifically created for migraine prevention.^10,26 As already noted, several efficacious non-CGRP treatment options are available for migraine prevention. However, higher doses of those agents, if needed, can lead to intolerable adverse effects for some patients, thereby limiting overall efficacy. ­Anti-CGRP mAbs, a targeted, highly efficacious treatment option, offer efficacy comparable to non-CGRP agents with a more favorable adverse effect profile for those who cannot tolerate or achieve only minimal efficacy with traditional preventive therapies.¹⁰

Continue to: The targeted anti-CGRP approach...

The targeted anti-CGRP approach, which can be used by patients with liver or kidney disease, results in decreased toxicity and minimal drug interactions. Long half-lives allow for monthly or quarterly injections, possibly resulting in increased compliance.²⁸ Dose titration is not needed, allowing for more rapid symptom management. The large molecular size of a mAb limits its transfer across the blood-brain barrier, making central nervous system adverse effects unlikely.²⁸ Despite the compelling mAb pharmacologic properties, their use may be limited by a lack of long-term safety data and the need for parenteral administration. Although ­immunogenicity—the development of neutralizing antibodies—can limit long-term tolerability or efficacy of mAbs generally,^26,28 anti-CGRP mAbs were engineered to minimally activate the immune system and have not been associated with immune suppression, opportunistic infections, malignancies, or decreased efficacy.²⁸

Unlike triptans and ergotamine derivatives, gepants do not constrict blood vessels and may have a unique role in patients with contraindications to triptans.

A pooled meta-analysis including 4 trials (3166 patients) found that CGRP mAbs compared with placebo significantly improved patient response rates, defined as at least a 50% and 75% reduction in monthly ­headache/migraine days from baseline to Weeks 9 to 12.⁴⁸ Another meta-analysis including 8 trials (2292 patients) found a significant reduction from baseline in monthly migraine days and monthly acute migraine medication consumption among patients taking CGRP mAbs compared with those taking placebo.⁴⁹ Open-label extension studies have shown progressive and cumulative benefits in individuals who respond to anti-CGRP mAbs. Therefore, several treatment cycles may be necessary to determine overall efficacy of therapy.^10,28

Cost initially can be a barrier. Insurance companies often require step therapy before agreeing to cover mAb therapy, which aligns with the 2019 AHS position statement.¹⁰Due to differences in insurance coverage, out-of-pocket expenses can vary greatly. However, options are available through online manufacturer assistance to reduce cost, making it comparable to other migraine treatments. Safety and efficacy studies of anti-CGRP mAbs use in pregnant individuals are limited. At this time, they should not be prescribed for those who are pregnant, planning to become pregnant, or breastfeeding. Counsel nonpregnant patients on appropriate contraception while using a mAb due to possible teratogenicity and negative pregnancy outcomes.^28,50

When combination treatment may be appropriate

Monotherapy is the usual approach to preventing migraine due to advantages of efficacy, simplified regimens, lower cost, and reduced adverse effects.⁵¹ However, if a patient does not benefit from monotherapy even after trying dose titrations as tolerated or switching therapies, trying complementary combination therapy is appropriate. Despite a shortage of clinical trials supporting the use of 2 or more preventive medications with different mechanisms of action, this strategy is used clinically.¹⁰ Consider combination therapy in those with refractory disease, partial responses, or intolerance to recommended doses.⁵² Articles reporting on case study reviews have rationalized the combined use of onabotulinumtoxinA and anti-CGRP mAbs, noting better migraine control.^51,53 The 2019 AHS position statement recommends adding a mAb to an existing preventive treatment regimen with no other changes until mAb effectiveness is determined, as the risk for drug interactions on dual therapy is low.¹⁰ Safety and efficacy also have been demonstrated with the combination of preventive anti-CGRP mAbs and acute treatment with gepants as needed.⁵⁴

Monoclonal antibodies are highly efficacious options for those who cannot tolerate or achieve only minimal efficacy with traditional preventive therapies.

Overall, gepants and mAbs are as effective as traditional acute and preventive treatments for migraine, and they cause fewer adverse effects and often allow a more simplified regimen. Gepants and mAbs are viable options in the primary care setting. Due to limited long-term data and high cost, however, they routinely are used for refractory migraine rather than as first-line agents. These therapies are especially favorable options for patients when traditional migraine therapies yield inadequate efficacy, cause intolerable adverse effects, are contraindicated, or introduce the risk for medication interactions.

CORRESPONDENCE
Emily Peterson, PharmD, BCACP, 3640 Middlebury Road, Iowa City, IA 52242; [email protected]

Migraine is a headache disorder that often causes unilateral pain, photophobia, phonophobia, nausea, and vomiting. More than 70% of office visits for migraine are made to primary care physicians.¹ Recent data suggest migraine may be caused primarily by neuronal dysfunction and only secondarily by vasodilation.² Although there are numerous classes of drugs used for migraine prevention and treatment, their success has been limited by inadequate efficacy, tolerability, and patient adherence.³ The discovery of pro-inflammatory markers such as calcitonin gene-related peptide (CGRP) has led to the development of new medications to prevent and treat migraine.⁴

IMAGE: © SCOTT BODELL

Pathophysiology, Dx and triggers, indications for pharmacotherapy

Pathophysiology. A migraine is thought to be caused by cortical spreading depression (CSD), a depolarization of glial and neuronal cell membranes.⁵This results in increased cortical excitability, central trigeminal-thalamic sensitization, and defective descending pain modulatory activity.⁶The activation of the trigeminal sensory pathways, primarily the ophthalmic branch, sends nociceptive signals to second-order neurons mediated by the release of neurotransmitters, such as CGRPs.⁵ This activation explains in part the primary location for a migraine, which is around the eye and the neighboring cranial regions. The pain perceived by the patient is caused by these second-order neurons.

It has been theorized that gepants bind to calcitonin gene-related peptide receptors, resulting in decreased blood flow to the brain, inhibition of neurogenic inflammation, and reduced pain signaling.

Dx and triggers. In 2018, the International Headache Society revised its guidelines for the diagnosis of migraine.⁷ According to the 3rd edition of The International Classification of Headache Disorders (ICHD-3), the diagnosis of migraine is made when a patient has at least 5 headache attacks that last 4 to 72 hours and have at least 2 of the following characteristics: (1) unilateral location, (2) pulsating quality, (3) moderate-to-severe pain intensity, and (4) aggravated by or causing avoidance of routine physical activity.⁷ The headache attacks also should have (1) associated nausea or vomiting or (2) photophobia and phonophobia.⁷ The presence of atypical signs or symptoms as indicated by the SNNOOP10 mnemonic raises concerns for secondary headaches and the need for further investigation into the cause of the headache (TABLE 1).⁸ It is not possible to detect every secondary headache with standard neuroimaging, but the SNNOOP10 red flags can help determine when imaging may be indicated.⁸ Potential triggers for migraine can be found in TABLE 2.⁹

Indications for pharmacotherapy. All patients receiving a diagnosis of migraine should be offered acute pharmacologic treatment. Consider preventive therapy anytime there are ≥ 4 headache days per month, debilitating attacks despite acute therapy, overuse of acute medication (> 2 d/wk), difficulty tolerating acute medication, patient preference, or presence of certain migraine subtypes.^7,10

Acute treatments

Abortive therapies for migraine include analgesics such as nonsteroidal anti-­inflammatory drugs (NSAIDs) and acetaminophen, and ergot alkaloids, triptans, or small-molecule CGRP receptor antagonists (gepants). Prompt administration increases the chance of success with acute therapy. Medications with the highest levels of efficacy based on the 2015 guidelines from the American Headache Society (AHS) are given in TABLE 3.¹¹ Lasmiditan (Reyvow) is not included in the 2015 guidelines, as it was approved after publication of the guidelines.

Non-CGRP first-line therapies

NSAIDs and acetaminophen. NSAIDs such as aspirin, diclofenac, ibuprofen, and naproxen have a high level of evidence to support their use as first-line treatments for mild-to-moderate migraine attacks. Trials consistently demonstrate their superiority to placebo in headache relief and complete pain relief at 2 hours. There is no recommendation for selecting one NSAID over another; however, consider their frequency of dosing and ­adverse effect profiles. The number needed to treat for complete pain relief at 2 hours ranges from 7 to 10 for most NSAIDs.^11,12 In some placebo-controlled studies, acetaminophen was less effective than NSAIDs, but was safer because it did not cause gastric irritation or antiplatelet effects.¹²

Triptans inhibit 5-HT_1B/1D receptors. Consider formulation, route of administration, cost, and pharmacokinetics when selecting a triptan. Patients who do not respond well to one triptan may respond favorably to another. A meta-analysis of the effectiveness of the 7 available agents found that triptans at standard doses provided pain relief within 2 hours in 42% to 76% of patients, and sustained freedom from pain for 2 hours in 18% to 50% of patients.¹³ Lasmiditan is a selective serotonin receptor (5-HT_1F) agonist that lacks vasoconstrictor activity. This is an option for patients with relative contraindications to triptans due to cardiovascular risk factors.¹⁰

Continue to: Second-line therapies

Intranasal dihydroergotamine has a favorable adverse event profile and greater evidence for efficacy compared with ergotamine. Compared with triptans, intranasal dihydroergotamine has a high level of efficacy but causes more adverse effects.¹⁴ Severe nausea is common, and dihydroergotamine often is used in combination with an antiemetic drug. Dihydroergotamine should not be used within 24 hours of taking a triptan, and it is contraindicated for patients who have hypertension or ischemic heart disease or who are pregnant or breastfeeding. There is also the potential for adverse drug interactions.¹⁵

A meta-analysis found that triptans at standard doses provided pain relief within 2 hours in 42% to 76% of patients, and sustained freedom from pain for 2 hours in 18% to 50% of patients.

Antiemetics may be helpful for migraine associated with severe nausea or vomiting. The dopamine antagonists metoclopramide, prochlorperazine, and chlorpromazine have demonstrated benefit in randomized ­placebo-controlled trials.¹¹ Ondansetron has not been studied extensively, but sometimes is used in clinical practice. Nonoral routes of administration may be useful in patients having trouble swallowing medications or in those experiencing significant nausea or vomiting early during migraine attacks.

Due to the high potential for abuse, opioids should not be used routinely for the treatment of migraine.¹² There is no high-quality evidence supporting the efficacy of barbiturates (ie, butalbital-containing compounds) for acute migraine treatment.¹¹ Moreover, use of these agents may increase the likelihood of progression from episodic to chronic migraine.¹⁶

Gepants for acute migraine treatment

Neuropeptide CGRP is released from trigeminal nerves and is a potent dilator of cerebral and dural vessels, playing a key role in regulating blood flow to the brain. Other roles of CGRP include the release of inflammatory agents from mast cells and the transmission of painful stimuli from intracranial vessels.¹⁷ The CGRP receptor or ligand can be targeted by small-molecule receptor antagonists for acute and preventive migraine treatment (and by monoclonal antibodies solely for prevention, discussed later). It has been theorized that gepants bind to CGRP receptors, resulting in decreased blood flow to the brain, inhibition of neurogenic inflammation, and reduced pain signaling.¹⁷ Unlike triptans and ergotamine derivatives, these novel treatments do not constrict blood vessels and may have a unique role in patients with contraindications to triptans.

The 3 gepants approved for acute treatment—ubrogepant (Ubrelvy),¹⁸ rimegepant (Nurtec),¹⁹ and zavegepant (Zavzpret)²⁰—were compared with placebo in clinical trials and were shown to increase the number of patients who were completely pain free at 2 hours, were free of the most bothersome associated symptom (photophobia, phonophobia, or nausea) at 2 hours, and remained pain free at 24 hours (TABLE 4^18-24).

Continue to: Ubrogrepant

Ubrogepant, in 2 Phase 3 trials (ACHIEVE I and ACHIEVE II) demonstrated effectiveness compared with placebo.^21,22 The most common adverse effects reported were nausea and somnolence at very low rates. Pain-relief rates at 2 hours post dose (> 60% of participants) were higher than pain-free rates, and a significantly higher percentage (> 40%) of ubrogepant-treated participants reported ability to function normally on the Functional Disability Scale.²⁵

Rimegepant was also superior to placebo (59% vs 43%) in pain relief at 2 hours post dose and other secondary endpoints.²³ Rimegepant also has potential drug interactions and dose adjustments (TABLE 4^18-24).

Zavegepant, approved in March 2023, is administered once daily as a 10-mg nasal spray. In its Phase 3 trial, zavegepant was significantly superior to placebo at 2 hours post dose in freedom from pain (24% v 15%), and in freedom from the most bothersome symptom (40% v 31%).²⁴ Dosage modifications are not needed with mild-to-moderate renal or hepatic disease.²⁰

Worth noting. The safety of using ubrogepant to treat more than 8 migraine episodes in a 30-day period has not been established. The safety of using more than 18 doses of zavegepant in a 30-day period also has not been established. With ubrogepant and rimegepant, there are dosing modifications for concomitant use with specific drugs (CYP3A4 inhibitors and inducers) due to potential interactions and in patients with hepatic or renal impairment.^18,19

There are no trials comparing efficacy of CGRP antagonists to triptans. Recognizing that these newer medications would be costly, the AHS position statement released in 2019 recommends that gepants be considered for those with contraindications to triptans or for whom at least 2 oral triptans have failed (as determined by a validated patient outcome questionnaire).¹⁰ Step therapy with documentation of previous trials and therapy failures is often required by insurance companies prior to gepant coverage.

Continue to: Preventive therapies

Preventive therapies

Preventive migraine therapies are used to reduce duration, frequency, and severity of attacks, the need for acute treatment, and overall headache disability.²⁶ Medications typically are chosen based on efficacy, adverse effect profile, and patient comorbidities. Barriers to successful use include poor patient adherence and tolerability, the need for slow dose titration, and long-term use (minimum of 2 months) at maximum tolerated or minimum effective doses. Medications with established efficacy (Level A^a) based on the 2012 guidelines from the American Academy of Neurology (AAN) and the AHS are given in TABLE 5.^27-29

Drugs having received the strongest level of evidence for migraine prevention are metoprolol, propranolol, timolol, topiramate, valproate sodium, divalproex sodium, and onabotulinumtoxinA (Botox), and frovatriptan for menstrual migraine prevention. Because these guidelines were last updated in 2012, they did not cover gepants (which will be discussed shortly). The AHS released a position statement in 2019 supporting the use of anti-CGRP monoclonal antibodies (mAbs) in those who cannot tolerate or have had an inadequate response to a 6-week trial of at least 2 AAN/AHA Level A or B^b treatments.¹⁰ No head-to-head trials exist between non-CGRP preventive therapies and the CGRP antagonists.

CGRP-targeted prevention

Four anti-CGRP mAbs and 2 gepants have been approved for migraine prevention in the United States. Differences between products include targets (ligand vs receptor), antibody IgG subtype, bioavailability, route of administration, and frequency of administration.²⁸ As noted in the Phase 3 studies (TABLE 6^19,30-47), these therapies are highly efficacious, safe, and tolerable.

Gepants. Rimegepant, discussed earlier for migraine treatment, is one of the CGRP receptor antagonists approved for prevention. The other is atogepant (Qulipta), approved only for prevention. Ubrogepant is not approved for prevention.

Anti-CGRP mAb is the only medication class specifically created for migraine prevention.^10,26 As already noted, several efficacious non-CGRP treatment options are available for migraine prevention. However, higher doses of those agents, if needed, can lead to intolerable adverse effects for some patients, thereby limiting overall efficacy. ­Anti-CGRP mAbs, a targeted, highly efficacious treatment option, offer efficacy comparable to non-CGRP agents with a more favorable adverse effect profile for those who cannot tolerate or achieve only minimal efficacy with traditional preventive therapies.¹⁰

Continue to: The targeted anti-CGRP approach...

The targeted anti-CGRP approach, which can be used by patients with liver or kidney disease, results in decreased toxicity and minimal drug interactions. Long half-lives allow for monthly or quarterly injections, possibly resulting in increased compliance.²⁸ Dose titration is not needed, allowing for more rapid symptom management. The large molecular size of a mAb limits its transfer across the blood-brain barrier, making central nervous system adverse effects unlikely.²⁸ Despite the compelling mAb pharmacologic properties, their use may be limited by a lack of long-term safety data and the need for parenteral administration. Although ­immunogenicity—the development of neutralizing antibodies—can limit long-term tolerability or efficacy of mAbs generally,^26,28 anti-CGRP mAbs were engineered to minimally activate the immune system and have not been associated with immune suppression, opportunistic infections, malignancies, or decreased efficacy.²⁸

Unlike triptans and ergotamine derivatives, gepants do not constrict blood vessels and may have a unique role in patients with contraindications to triptans.

A pooled meta-analysis including 4 trials (3166 patients) found that CGRP mAbs compared with placebo significantly improved patient response rates, defined as at least a 50% and 75% reduction in monthly ­headache/migraine days from baseline to Weeks 9 to 12.⁴⁸ Another meta-analysis including 8 trials (2292 patients) found a significant reduction from baseline in monthly migraine days and monthly acute migraine medication consumption among patients taking CGRP mAbs compared with those taking placebo.⁴⁹ Open-label extension studies have shown progressive and cumulative benefits in individuals who respond to anti-CGRP mAbs. Therefore, several treatment cycles may be necessary to determine overall efficacy of therapy.^10,28

Cost initially can be a barrier. Insurance companies often require step therapy before agreeing to cover mAb therapy, which aligns with the 2019 AHS position statement.¹⁰Due to differences in insurance coverage, out-of-pocket expenses can vary greatly. However, options are available through online manufacturer assistance to reduce cost, making it comparable to other migraine treatments. Safety and efficacy studies of anti-CGRP mAbs use in pregnant individuals are limited. At this time, they should not be prescribed for those who are pregnant, planning to become pregnant, or breastfeeding. Counsel nonpregnant patients on appropriate contraception while using a mAb due to possible teratogenicity and negative pregnancy outcomes.^28,50

When combination treatment may be appropriate

Monotherapy is the usual approach to preventing migraine due to advantages of efficacy, simplified regimens, lower cost, and reduced adverse effects.⁵¹ However, if a patient does not benefit from monotherapy even after trying dose titrations as tolerated or switching therapies, trying complementary combination therapy is appropriate. Despite a shortage of clinical trials supporting the use of 2 or more preventive medications with different mechanisms of action, this strategy is used clinically.¹⁰ Consider combination therapy in those with refractory disease, partial responses, or intolerance to recommended doses.⁵² Articles reporting on case study reviews have rationalized the combined use of onabotulinumtoxinA and anti-CGRP mAbs, noting better migraine control.^51,53 The 2019 AHS position statement recommends adding a mAb to an existing preventive treatment regimen with no other changes until mAb effectiveness is determined, as the risk for drug interactions on dual therapy is low.¹⁰ Safety and efficacy also have been demonstrated with the combination of preventive anti-CGRP mAbs and acute treatment with gepants as needed.⁵⁴

Monoclonal antibodies are highly efficacious options for those who cannot tolerate or achieve only minimal efficacy with traditional preventive therapies.

Overall, gepants and mAbs are as effective as traditional acute and preventive treatments for migraine, and they cause fewer adverse effects and often allow a more simplified regimen. Gepants and mAbs are viable options in the primary care setting. Due to limited long-term data and high cost, however, they routinely are used for refractory migraine rather than as first-line agents. These therapies are especially favorable options for patients when traditional migraine therapies yield inadequate efficacy, cause intolerable adverse effects, are contraindicated, or introduce the risk for medication interactions.

CORRESPONDENCE
Emily Peterson, PharmD, BCACP, 3640 Middlebury Road, Iowa City, IA 52242; [email protected]

The U.S. Food and Drug Administration has approved motixafortide (Aphexda, BioLineRx) in combination with filgrastim (G-CSF) to mobilize hematopoietic stem cells for collection and subsequent autologous transplantation in patients with multiple myeloma.

The success of autologous stem cell transplantation (ASCT) depends on adequate mobilization of stem cells during the treatment process. Collection of a sufficient number of stem cells to perform two transplantations is recommended. However, in up to 47% of patients, collecting target numbers of hematopoietic stem cells for ASCT after one apheresis session remains a challenge, BioLineRx explained in a press release today, announcing the approval.

The goal of combining motixafortide with filgrastim is to mobilize stem cells more reliably than filgrastim can alone, with fewer days of apheresis sessions and fewer doses of filgrastim.

“We believe [motixafortide] will play a critical role in addressing unmet needs and introduce a new treatment paradigm for” patients with multiple myeloma, CEO Philip Serlin said in the release.

The drug approval was based on the GENESIS trial, which randomized 122 patients to either motixafortide plus filgrastim or placebo plus filgrastim.

BioLineRx said the trial included patients considered representative of the typical multiple myeloma population undergoing ASCT, with a median age of 63 years and with about 70% of patients in both arms of the trial receiving lenalidomide-containing induction therapy.

Motixafortide plus filgrastim enabled 67.5% of patients to achieve the stem cell collection goal of 6 million or more CD34+ cells/kg within two apheresis sessions, versus 9.5% of patients receiving the placebo plus filgrastim regimen. Additionally, 92.5% of patients reached the stem cell collection goal in up to two apheresis sessions in the motixafortide arm and 21.4% in the placebo arm.

However, “the data are descriptive and were not statistically powered nor prespecified. The information should be cautiously interpreted,” the company said.

Serious adverse reactions occurred in 5.4% of patients in the motixafortide arm, including vomiting, injection-site reaction, hypersensitivity reaction, injection-site cellulitis, hypokalemia, and hypoxia. The most common adverse reactions, occurring in more than 20% of patients, were injection site reactions (pain, erythema, and pruritus), pruritus, flushing, and back pain.

Labeling for the subcutaneous injection is available online.

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

The U.S. Food and Drug Administration has approved motixafortide (Aphexda, BioLineRx) in combination with filgrastim (G-CSF) to mobilize hematopoietic stem cells for collection and subsequent autologous transplantation in patients with multiple myeloma.

The success of autologous stem cell transplantation (ASCT) depends on adequate mobilization of stem cells during the treatment process. Collection of a sufficient number of stem cells to perform two transplantations is recommended. However, in up to 47% of patients, collecting target numbers of hematopoietic stem cells for ASCT after one apheresis session remains a challenge, BioLineRx explained in a press release today, announcing the approval.

The goal of combining motixafortide with filgrastim is to mobilize stem cells more reliably than filgrastim can alone, with fewer days of apheresis sessions and fewer doses of filgrastim.

“We believe [motixafortide] will play a critical role in addressing unmet needs and introduce a new treatment paradigm for” patients with multiple myeloma, CEO Philip Serlin said in the release.

The drug approval was based on the GENESIS trial, which randomized 122 patients to either motixafortide plus filgrastim or placebo plus filgrastim.

BioLineRx said the trial included patients considered representative of the typical multiple myeloma population undergoing ASCT, with a median age of 63 years and with about 70% of patients in both arms of the trial receiving lenalidomide-containing induction therapy.

Motixafortide plus filgrastim enabled 67.5% of patients to achieve the stem cell collection goal of 6 million or more CD34+ cells/kg within two apheresis sessions, versus 9.5% of patients receiving the placebo plus filgrastim regimen. Additionally, 92.5% of patients reached the stem cell collection goal in up to two apheresis sessions in the motixafortide arm and 21.4% in the placebo arm.

However, “the data are descriptive and were not statistically powered nor prespecified. The information should be cautiously interpreted,” the company said.

Serious adverse reactions occurred in 5.4% of patients in the motixafortide arm, including vomiting, injection-site reaction, hypersensitivity reaction, injection-site cellulitis, hypokalemia, and hypoxia. The most common adverse reactions, occurring in more than 20% of patients, were injection site reactions (pain, erythema, and pruritus), pruritus, flushing, and back pain.

Labeling for the subcutaneous injection is available online.

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

The U.S. Food and Drug Administration has approved motixafortide (Aphexda, BioLineRx) in combination with filgrastim (G-CSF) to mobilize hematopoietic stem cells for collection and subsequent autologous transplantation in patients with multiple myeloma.

The success of autologous stem cell transplantation (ASCT) depends on adequate mobilization of stem cells during the treatment process. Collection of a sufficient number of stem cells to perform two transplantations is recommended. However, in up to 47% of patients, collecting target numbers of hematopoietic stem cells for ASCT after one apheresis session remains a challenge, BioLineRx explained in a press release today, announcing the approval.

The goal of combining motixafortide with filgrastim is to mobilize stem cells more reliably than filgrastim can alone, with fewer days of apheresis sessions and fewer doses of filgrastim.

“We believe [motixafortide] will play a critical role in addressing unmet needs and introduce a new treatment paradigm for” patients with multiple myeloma, CEO Philip Serlin said in the release.

The drug approval was based on the GENESIS trial, which randomized 122 patients to either motixafortide plus filgrastim or placebo plus filgrastim.

BioLineRx said the trial included patients considered representative of the typical multiple myeloma population undergoing ASCT, with a median age of 63 years and with about 70% of patients in both arms of the trial receiving lenalidomide-containing induction therapy.

Motixafortide plus filgrastim enabled 67.5% of patients to achieve the stem cell collection goal of 6 million or more CD34+ cells/kg within two apheresis sessions, versus 9.5% of patients receiving the placebo plus filgrastim regimen. Additionally, 92.5% of patients reached the stem cell collection goal in up to two apheresis sessions in the motixafortide arm and 21.4% in the placebo arm.

However, “the data are descriptive and were not statistically powered nor prespecified. The information should be cautiously interpreted,” the company said.

Serious adverse reactions occurred in 5.4% of patients in the motixafortide arm, including vomiting, injection-site reaction, hypersensitivity reaction, injection-site cellulitis, hypokalemia, and hypoxia. The most common adverse reactions, occurring in more than 20% of patients, were injection site reactions (pain, erythema, and pruritus), pruritus, flushing, and back pain.

Labeling for the subcutaneous injection is available online.

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