Week 12 of the 2015-2016 U.S. flu season saw two states in the “high” range of the influenza-like illness (ILI) activity scale, the Centers for Disease Control and Prevention reported.

New Jersey was at level 10 on the CDC’s 1-10 scale for the week ending Jan. 2, 2016, and South Carolina was at level 9. The next-most-active state, Texas, was at level 7, putting it in the “moderate” range along with Maryland, which was at level 6, the CDC said.

States in the “low” range were Arizona, Oklahoma, Pennsylvania, and Virginia at level 5 and California, Colorado, and Georgia at level 4. Altogether, there were 24 states at level 2 or higher, according to data from the CDC’s Outpatient Influenza-like Illness Surveillance Network.

Puerto Rico also moved up to level 10 for the week ending Jan. 2 and, in a case of geographic concentration, New York City was at level 6 even though New York State was still at level 1.

The proportion of outpatient visits for ILI nationally was 2.8% at the end of week 12, which is above the national baseline of 2.1%. For comparison, at this point in the 2014-2015 flu season, the proportion of visits for ILI was about 6%, and in 2013-2014 it was around 4.5%.

There were two flu-related pediatric deaths reported during the week, bringing the total to six for the 2015-2016 season. One death was associated with an influenza A (H3) virus and the other was associated with

an influenza A (H1N1)pdm09 virus. Looking again at previous years, there had been single weeks with at least six pediatric deaths by week 12 in each of the last three seasons, the CDC report showed.

[email protected]

Week 12 of the 2015-2016 U.S. flu season saw two states in the “high” range of the influenza-like illness (ILI) activity scale, the Centers for Disease Control and Prevention reported.

New Jersey was at level 10 on the CDC’s 1-10 scale for the week ending Jan. 2, 2016, and South Carolina was at level 9. The next-most-active state, Texas, was at level 7, putting it in the “moderate” range along with Maryland, which was at level 6, the CDC said.

States in the “low” range were Arizona, Oklahoma, Pennsylvania, and Virginia at level 5 and California, Colorado, and Georgia at level 4. Altogether, there were 24 states at level 2 or higher, according to data from the CDC’s Outpatient Influenza-like Illness Surveillance Network.

Puerto Rico also moved up to level 10 for the week ending Jan. 2 and, in a case of geographic concentration, New York City was at level 6 even though New York State was still at level 1.

The proportion of outpatient visits for ILI nationally was 2.8% at the end of week 12, which is above the national baseline of 2.1%. For comparison, at this point in the 2014-2015 flu season, the proportion of visits for ILI was about 6%, and in 2013-2014 it was around 4.5%.

There were two flu-related pediatric deaths reported during the week, bringing the total to six for the 2015-2016 season. One death was associated with an influenza A (H3) virus and the other was associated with

an influenza A (H1N1)pdm09 virus. Looking again at previous years, there had been single weeks with at least six pediatric deaths by week 12 in each of the last three seasons, the CDC report showed.

[email protected]

Week 12 of the 2015-2016 U.S. flu season saw two states in the “high” range of the influenza-like illness (ILI) activity scale, the Centers for Disease Control and Prevention reported.

New Jersey was at level 10 on the CDC’s 1-10 scale for the week ending Jan. 2, 2016, and South Carolina was at level 9. The next-most-active state, Texas, was at level 7, putting it in the “moderate” range along with Maryland, which was at level 6, the CDC said.

States in the “low” range were Arizona, Oklahoma, Pennsylvania, and Virginia at level 5 and California, Colorado, and Georgia at level 4. Altogether, there were 24 states at level 2 or higher, according to data from the CDC’s Outpatient Influenza-like Illness Surveillance Network.

Puerto Rico also moved up to level 10 for the week ending Jan. 2 and, in a case of geographic concentration, New York City was at level 6 even though New York State was still at level 1.

The proportion of outpatient visits for ILI nationally was 2.8% at the end of week 12, which is above the national baseline of 2.1%. For comparison, at this point in the 2014-2015 flu season, the proportion of visits for ILI was about 6%, and in 2013-2014 it was around 4.5%.

There were two flu-related pediatric deaths reported during the week, bringing the total to six for the 2015-2016 season. One death was associated with an influenza A (H3) virus and the other was associated with

an influenza A (H1N1)pdm09 virus. Looking again at previous years, there had been single weeks with at least six pediatric deaths by week 12 in each of the last three seasons, the CDC report showed.

[email protected]

The use of proton pump inhibitors increased the risk of chronic kidney disease by 20%-50%, said the authors of two large population-based cohort analyses published online Jan. 11 in JAMA Internal Medicine.

These are the first such studies to link PPI use to chronic kidney disease (CKD), and the association held up after controlling for multiple potential confounders, said Dr. Benjamin Lazarus of Johns Hopkins University, Baltimore, and his associates. “Further research is required to investigate whether PPI use itself causes kidney damage and, if so, the underlying mechanisms of this association,” they wrote.

Proton pump inhibitors have been linked to other adverse health effects but remain among the most frequently prescribed medications in the United States. To further explore the risk of PPI use, the researchers analyzed data for 10,482 adults from the Atherosclerosis Risk in Communities (ARIC) study who were followed for a median of 13.9 years, and a replication cohort of 248,751 patients from a large rural health care system who were followed for a median of 6.2 years.

©decade3d/thinkstockphotos.com

Incident CKD was defined based on hospital discharge diagnosis codes, reports of end-stage renal disease from the United States Renal Data System Registry, or a glomerular filtration rate of less than 60 mL/min per 1.73 m² that persisted at follow-up visits (JAMA Intern Med. 2016 Jan 11. doi: 0.1001/jamainternmed.2015.7193).

In the ARIC study, there were 56 cases of CKD among 322 self-reported baseline PPI users, for an incidence of 14.2 cases per 1,000 person-years – significantly higher than the rate of 10.7 cases per 1,000 person-years among self-reported baseline nonusers. The 10-year estimated absolute risk of CKD among baseline users was 11.8% – 3.3% higher than the expected risk had they not used PPIs. Furthermore, PPI users were at significantly higher risk of CKD after demographic, socioeconomic, and clinical variables were accounted for (hazard ratio, 1.50; 95% confidence interval, 1.1-2.0), after modeling varying use of PPIs over time (adjusted HR, 1.3; 95% CI, 1.2-1.5), after directly comparing PPI users with H₂ receptor antagonist users (adjusted HR, 1.4; 95% CI, 1.01-1.9), and after comparing baseline PPI users with propensity score–matched nonusers (HR, 1.8; 95% CI, 1.1-2.7).

In the replication cohort, there were 1,921 new cases of CKD among 16,900 patients with an outpatient PPI prescription (incidence of 20.1 cases per 1,000 person-years). The incidence of CKD among the other patients was lower: 18.3 cases per 1,000 person-years. The use of PPIs was significantly associated with incident CKD in all analyses, and the 10-year absolute risk of CKD among baseline PPI users was 15.6% – 1.7% higher than the expected risk had they not used PPIs.

These observational analyses cannot show causality, but a causal relationship between PPIs and CKD “could have a considerable public health impact, give the widespread extent of use,” the researchers emphasized. “More than 15 million Americans used prescription PPIs in 2013, costing more than $10 billion. Study findings suggest that up to 70% of these prescriptions are without indication and that 25% of long-term PPI users could discontinue therapy without developing symptoms. Indeed, there are already calls for the reduction of unnecessary use of PPIs (BMJ. 2008;336:2-3).”

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute, both of which are part of the National Institutes of Health. The researchers had no disclosures.

See below for "Views on the News," a pro/con discussion on PPIs.

Available evidence suggests that proton pump inhibitor use is associated with an increased risk of both acute and chronic kidney disease, hypomagnesemia, Clostridium difficile infection, and osteoporotic fractures. Caution in prescribing PPIs should be used in patients at high risk for any of these conditions. Given the association with kidney disease and low magnesium levels, serum creatinine and magnesium levels probably should be monitored in patients using PPIs, especially those using high doses.

Given the evidence that PPI use is linked with a number of adverse outcomes, we recommend that patients and clinicians discuss the potential benefits and risks of PPI treatment, as well as potential alternative regimens such as histamine H₂ receptor antagonists or lifestyle changes, before PPIs are prescribed. In patients with symptomatic gastrointestinal reflux, ulcer disease, and severe dyspepsia, the benefits of PPI use likely outweigh its potential harms. For less serious symptoms, however, and for prevention of bleeding in low-risk patients, potential harms may outweigh the benefits. A large number of patients are taking PPIs for no clear reason – often remote symptoms of dyspepsia or heartburn that have since resolved. In these patients, PPIs should be stopped to determine if symptomatic treatment is needed.

Dr. Adam J. Schoenfeld and Dr. Deborah Grady are with the University of California, San Francisco. They had no disclosures. These comments were taken from their editorial (JAMA Intern Med. 2016 Jan 11. doi: 10.1001/jamainternmed.2015.7927).

Pro: When used as indicated, PPIs are good medicine

The bottom line is that PPIs should be used continually for the three specific conditions for which they are known to be beneficial – hypersecretory states, gastroesophageal reflux disease (in all its manifestations), and NSAID/aspirin prophylaxis. As with all drugs, treatment always should be at the lowest effective dose. Although it is quite appropriate to limit chronic PPI use to these groups, given the potential association (no causality identified) with various putative side effects including renal disease, in my opinion, the risks of denying PPIs when indicated are higher than the low risks of renal or other possible side effects.

Dr. David C. Metz is associate chief for clinical affairs, GI division; codirector, esophagology and swallowing program; director, acid-peptic program; codirector, neuroendocrine tumor center; and professor of medicine at the Hospital of the University of Pennsylvania, Philadelphia.

The use of proton pump inhibitors increased the risk of chronic kidney disease by 20%-50%, said the authors of two large population-based cohort analyses published online Jan. 11 in JAMA Internal Medicine.

These are the first such studies to link PPI use to chronic kidney disease (CKD), and the association held up after controlling for multiple potential confounders, said Dr. Benjamin Lazarus of Johns Hopkins University, Baltimore, and his associates. “Further research is required to investigate whether PPI use itself causes kidney damage and, if so, the underlying mechanisms of this association,” they wrote.

Proton pump inhibitors have been linked to other adverse health effects but remain among the most frequently prescribed medications in the United States. To further explore the risk of PPI use, the researchers analyzed data for 10,482 adults from the Atherosclerosis Risk in Communities (ARIC) study who were followed for a median of 13.9 years, and a replication cohort of 248,751 patients from a large rural health care system who were followed for a median of 6.2 years.

©decade3d/thinkstockphotos.com

Incident CKD was defined based on hospital discharge diagnosis codes, reports of end-stage renal disease from the United States Renal Data System Registry, or a glomerular filtration rate of less than 60 mL/min per 1.73 m² that persisted at follow-up visits (JAMA Intern Med. 2016 Jan 11. doi: 0.1001/jamainternmed.2015.7193).

In the ARIC study, there were 56 cases of CKD among 322 self-reported baseline PPI users, for an incidence of 14.2 cases per 1,000 person-years – significantly higher than the rate of 10.7 cases per 1,000 person-years among self-reported baseline nonusers. The 10-year estimated absolute risk of CKD among baseline users was 11.8% – 3.3% higher than the expected risk had they not used PPIs. Furthermore, PPI users were at significantly higher risk of CKD after demographic, socioeconomic, and clinical variables were accounted for (hazard ratio, 1.50; 95% confidence interval, 1.1-2.0), after modeling varying use of PPIs over time (adjusted HR, 1.3; 95% CI, 1.2-1.5), after directly comparing PPI users with H₂ receptor antagonist users (adjusted HR, 1.4; 95% CI, 1.01-1.9), and after comparing baseline PPI users with propensity score–matched nonusers (HR, 1.8; 95% CI, 1.1-2.7).

In the replication cohort, there were 1,921 new cases of CKD among 16,900 patients with an outpatient PPI prescription (incidence of 20.1 cases per 1,000 person-years). The incidence of CKD among the other patients was lower: 18.3 cases per 1,000 person-years. The use of PPIs was significantly associated with incident CKD in all analyses, and the 10-year absolute risk of CKD among baseline PPI users was 15.6% – 1.7% higher than the expected risk had they not used PPIs.

These observational analyses cannot show causality, but a causal relationship between PPIs and CKD “could have a considerable public health impact, give the widespread extent of use,” the researchers emphasized. “More than 15 million Americans used prescription PPIs in 2013, costing more than $10 billion. Study findings suggest that up to 70% of these prescriptions are without indication and that 25% of long-term PPI users could discontinue therapy without developing symptoms. Indeed, there are already calls for the reduction of unnecessary use of PPIs (BMJ. 2008;336:2-3).”

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute, both of which are part of the National Institutes of Health. The researchers had no disclosures.

See below for "Views on the News," a pro/con discussion on PPIs.

Available evidence suggests that proton pump inhibitor use is associated with an increased risk of both acute and chronic kidney disease, hypomagnesemia, Clostridium difficile infection, and osteoporotic fractures. Caution in prescribing PPIs should be used in patients at high risk for any of these conditions. Given the association with kidney disease and low magnesium levels, serum creatinine and magnesium levels probably should be monitored in patients using PPIs, especially those using high doses.

Given the evidence that PPI use is linked with a number of adverse outcomes, we recommend that patients and clinicians discuss the potential benefits and risks of PPI treatment, as well as potential alternative regimens such as histamine H₂ receptor antagonists or lifestyle changes, before PPIs are prescribed. In patients with symptomatic gastrointestinal reflux, ulcer disease, and severe dyspepsia, the benefits of PPI use likely outweigh its potential harms. For less serious symptoms, however, and for prevention of bleeding in low-risk patients, potential harms may outweigh the benefits. A large number of patients are taking PPIs for no clear reason – often remote symptoms of dyspepsia or heartburn that have since resolved. In these patients, PPIs should be stopped to determine if symptomatic treatment is needed.

Dr. Adam J. Schoenfeld and Dr. Deborah Grady are with the University of California, San Francisco. They had no disclosures. These comments were taken from their editorial (JAMA Intern Med. 2016 Jan 11. doi: 10.1001/jamainternmed.2015.7927).

Pro: When used as indicated, PPIs are good medicine

The bottom line is that PPIs should be used continually for the three specific conditions for which they are known to be beneficial – hypersecretory states, gastroesophageal reflux disease (in all its manifestations), and NSAID/aspirin prophylaxis. As with all drugs, treatment always should be at the lowest effective dose. Although it is quite appropriate to limit chronic PPI use to these groups, given the potential association (no causality identified) with various putative side effects including renal disease, in my opinion, the risks of denying PPIs when indicated are higher than the low risks of renal or other possible side effects.

Dr. David C. Metz is associate chief for clinical affairs, GI division; codirector, esophagology and swallowing program; director, acid-peptic program; codirector, neuroendocrine tumor center; and professor of medicine at the Hospital of the University of Pennsylvania, Philadelphia.

The use of proton pump inhibitors increased the risk of chronic kidney disease by 20%-50%, said the authors of two large population-based cohort analyses published online Jan. 11 in JAMA Internal Medicine.

These are the first such studies to link PPI use to chronic kidney disease (CKD), and the association held up after controlling for multiple potential confounders, said Dr. Benjamin Lazarus of Johns Hopkins University, Baltimore, and his associates. “Further research is required to investigate whether PPI use itself causes kidney damage and, if so, the underlying mechanisms of this association,” they wrote.

Proton pump inhibitors have been linked to other adverse health effects but remain among the most frequently prescribed medications in the United States. To further explore the risk of PPI use, the researchers analyzed data for 10,482 adults from the Atherosclerosis Risk in Communities (ARIC) study who were followed for a median of 13.9 years, and a replication cohort of 248,751 patients from a large rural health care system who were followed for a median of 6.2 years.

©decade3d/thinkstockphotos.com

Incident CKD was defined based on hospital discharge diagnosis codes, reports of end-stage renal disease from the United States Renal Data System Registry, or a glomerular filtration rate of less than 60 mL/min per 1.73 m² that persisted at follow-up visits (JAMA Intern Med. 2016 Jan 11. doi: 0.1001/jamainternmed.2015.7193).

In the ARIC study, there were 56 cases of CKD among 322 self-reported baseline PPI users, for an incidence of 14.2 cases per 1,000 person-years – significantly higher than the rate of 10.7 cases per 1,000 person-years among self-reported baseline nonusers. The 10-year estimated absolute risk of CKD among baseline users was 11.8% – 3.3% higher than the expected risk had they not used PPIs. Furthermore, PPI users were at significantly higher risk of CKD after demographic, socioeconomic, and clinical variables were accounted for (hazard ratio, 1.50; 95% confidence interval, 1.1-2.0), after modeling varying use of PPIs over time (adjusted HR, 1.3; 95% CI, 1.2-1.5), after directly comparing PPI users with H₂ receptor antagonist users (adjusted HR, 1.4; 95% CI, 1.01-1.9), and after comparing baseline PPI users with propensity score–matched nonusers (HR, 1.8; 95% CI, 1.1-2.7).

In the replication cohort, there were 1,921 new cases of CKD among 16,900 patients with an outpatient PPI prescription (incidence of 20.1 cases per 1,000 person-years). The incidence of CKD among the other patients was lower: 18.3 cases per 1,000 person-years. The use of PPIs was significantly associated with incident CKD in all analyses, and the 10-year absolute risk of CKD among baseline PPI users was 15.6% – 1.7% higher than the expected risk had they not used PPIs.

These observational analyses cannot show causality, but a causal relationship between PPIs and CKD “could have a considerable public health impact, give the widespread extent of use,” the researchers emphasized. “More than 15 million Americans used prescription PPIs in 2013, costing more than $10 billion. Study findings suggest that up to 70% of these prescriptions are without indication and that 25% of long-term PPI users could discontinue therapy without developing symptoms. Indeed, there are already calls for the reduction of unnecessary use of PPIs (BMJ. 2008;336:2-3).”

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute, both of which are part of the National Institutes of Health. The researchers had no disclosures.

See below for "Views on the News," a pro/con discussion on PPIs.

Available evidence suggests that proton pump inhibitor use is associated with an increased risk of both acute and chronic kidney disease, hypomagnesemia, Clostridium difficile infection, and osteoporotic fractures. Caution in prescribing PPIs should be used in patients at high risk for any of these conditions. Given the association with kidney disease and low magnesium levels, serum creatinine and magnesium levels probably should be monitored in patients using PPIs, especially those using high doses.

Given the evidence that PPI use is linked with a number of adverse outcomes, we recommend that patients and clinicians discuss the potential benefits and risks of PPI treatment, as well as potential alternative regimens such as histamine H₂ receptor antagonists or lifestyle changes, before PPIs are prescribed. In patients with symptomatic gastrointestinal reflux, ulcer disease, and severe dyspepsia, the benefits of PPI use likely outweigh its potential harms. For less serious symptoms, however, and for prevention of bleeding in low-risk patients, potential harms may outweigh the benefits. A large number of patients are taking PPIs for no clear reason – often remote symptoms of dyspepsia or heartburn that have since resolved. In these patients, PPIs should be stopped to determine if symptomatic treatment is needed.

Dr. Adam J. Schoenfeld and Dr. Deborah Grady are with the University of California, San Francisco. They had no disclosures. These comments were taken from their editorial (JAMA Intern Med. 2016 Jan 11. doi: 10.1001/jamainternmed.2015.7927).

Pro: When used as indicated, PPIs are good medicine

The bottom line is that PPIs should be used continually for the three specific conditions for which they are known to be beneficial – hypersecretory states, gastroesophageal reflux disease (in all its manifestations), and NSAID/aspirin prophylaxis. As with all drugs, treatment always should be at the lowest effective dose. Although it is quite appropriate to limit chronic PPI use to these groups, given the potential association (no causality identified) with various putative side effects including renal disease, in my opinion, the risks of denying PPIs when indicated are higher than the low risks of renal or other possible side effects.

Dr. David C. Metz is associate chief for clinical affairs, GI division; codirector, esophagology and swallowing program; director, acid-peptic program; codirector, neuroendocrine tumor center; and professor of medicine at the Hospital of the University of Pennsylvania, Philadelphia.

The use of proton pump inhibitors increased the risk of chronic kidney disease by 20%-50%, said the authors of two large population-based cohort analyses published online Jan. 11 in JAMA Internal Medicine.

These are the first such studies to link PPI use to chronic kidney disease (CKD), and the association held up after controlling for multiple potential confounders, said Dr. Benjamin Lazarus of Johns Hopkins University, Baltimore, and his associates. “Further research is required to investigate whether PPI use itself causes kidney damage and, if so, the underlying mechanisms of this association,” they wrote.

Proton pump inhibitors have been linked to other adverse health effects but remain among the most frequently prescribed medications in the United States. To further explore the risk of PPI use, the researchers analyzed data for 10,482 adults from the Atherosclerosis Risk in Communities (ARIC) study who were followed for a median of 13.9 years, and a replication cohort of 248,751 patients from a large rural health care system who were followed for a median of 6.2 years.

©decade3d/thinkstockphotos.com

Incident CKD was defined based on hospital discharge diagnosis codes, reports of end-stage renal disease from the United States Renal Data System Registry, or a glomerular filtration rate of less than 60 mL/min per 1.73 m² that persisted at follow-up visits (JAMA Intern Med. 2016 Jan 11. doi: 0.1001/jamainternmed.2015.7193).

In the ARIC study, there were 56 cases of CKD among 322 self-reported baseline PPI users, for an incidence of 14.2 cases per 1,000 person-years – significantly higher than the rate of 10.7 cases per 1,000 person-years among self-reported baseline nonusers. The 10-year estimated absolute risk of CKD among baseline users was 11.8% – 3.3% higher than the expected risk had they not used PPIs. Furthermore, PPI users were at significantly higher risk of CKD after demographic, socioeconomic, and clinical variables were accounted for (hazard ratio, 1.50; 95% confidence interval, 1.1-2.0), after modeling varying use of PPIs over time (adjusted HR, 1.3; 95% CI, 1.2-1.5), after directly comparing PPI users with H₂ receptor antagonist users (adjusted HR, 1.4; 95% CI, 1.01-1.9), and after comparing baseline PPI users with propensity score–matched nonusers (HR, 1.8; 95% CI, 1.1-2.7).

In the replication cohort, there were 1,921 new cases of CKD among 16,900 patients with an outpatient PPI prescription (incidence of 20.1 cases per 1,000 person-years). The incidence of CKD among the other patients was lower: 18.3 cases per 1,000 person-years. The use of PPIs was significantly associated with incident CKD in all analyses, and the 10-year absolute risk of CKD among baseline PPI users was 15.6% – 1.7% higher than the expected risk had they not used PPIs.

These observational analyses cannot show causality, but a causal relationship between PPIs and CKD “could have a considerable public health impact, give the widespread extent of use,” the researchers emphasized. “More than 15 million Americans used prescription PPIs in 2013, costing more than $10 billion. Study findings suggest that up to 70% of these prescriptions are without indication and that 25% of long-term PPI users could discontinue therapy without developing symptoms. Indeed, there are already calls for the reduction of unnecessary use of PPIs (BMJ. 2008;336:2-3).”

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute, both of which are part of the National Institutes of Health. The researchers had no disclosures.

The use of proton pump inhibitors increased the risk of chronic kidney disease by 20%-50%, said the authors of two large population-based cohort analyses published online Jan. 11 in JAMA Internal Medicine.

These are the first such studies to link PPI use to chronic kidney disease (CKD), and the association held up after controlling for multiple potential confounders, said Dr. Benjamin Lazarus of Johns Hopkins University, Baltimore, and his associates. “Further research is required to investigate whether PPI use itself causes kidney damage and, if so, the underlying mechanisms of this association,” they wrote.

Proton pump inhibitors have been linked to other adverse health effects but remain among the most frequently prescribed medications in the United States. To further explore the risk of PPI use, the researchers analyzed data for 10,482 adults from the Atherosclerosis Risk in Communities (ARIC) study who were followed for a median of 13.9 years, and a replication cohort of 248,751 patients from a large rural health care system who were followed for a median of 6.2 years.

©decade3d/thinkstockphotos.com

Incident CKD was defined based on hospital discharge diagnosis codes, reports of end-stage renal disease from the United States Renal Data System Registry, or a glomerular filtration rate of less than 60 mL/min per 1.73 m² that persisted at follow-up visits (JAMA Intern Med. 2016 Jan 11. doi: 0.1001/jamainternmed.2015.7193).

In the ARIC study, there were 56 cases of CKD among 322 self-reported baseline PPI users, for an incidence of 14.2 cases per 1,000 person-years – significantly higher than the rate of 10.7 cases per 1,000 person-years among self-reported baseline nonusers. The 10-year estimated absolute risk of CKD among baseline users was 11.8% – 3.3% higher than the expected risk had they not used PPIs. Furthermore, PPI users were at significantly higher risk of CKD after demographic, socioeconomic, and clinical variables were accounted for (hazard ratio, 1.50; 95% confidence interval, 1.1-2.0), after modeling varying use of PPIs over time (adjusted HR, 1.3; 95% CI, 1.2-1.5), after directly comparing PPI users with H₂ receptor antagonist users (adjusted HR, 1.4; 95% CI, 1.01-1.9), and after comparing baseline PPI users with propensity score–matched nonusers (HR, 1.8; 95% CI, 1.1-2.7).

In the replication cohort, there were 1,921 new cases of CKD among 16,900 patients with an outpatient PPI prescription (incidence of 20.1 cases per 1,000 person-years). The incidence of CKD among the other patients was lower: 18.3 cases per 1,000 person-years. The use of PPIs was significantly associated with incident CKD in all analyses, and the 10-year absolute risk of CKD among baseline PPI users was 15.6% – 1.7% higher than the expected risk had they not used PPIs.

These observational analyses cannot show causality, but a causal relationship between PPIs and CKD “could have a considerable public health impact, give the widespread extent of use,” the researchers emphasized. “More than 15 million Americans used prescription PPIs in 2013, costing more than $10 billion. Study findings suggest that up to 70% of these prescriptions are without indication and that 25% of long-term PPI users could discontinue therapy without developing symptoms. Indeed, there are already calls for the reduction of unnecessary use of PPIs (BMJ. 2008;336:2-3).”

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute, both of which are part of the National Institutes of Health. The researchers had no disclosures.

The use of proton pump inhibitors increased the risk of chronic kidney disease by 20%-50%, said the authors of two large population-based cohort analyses published online Jan. 11 in JAMA Internal Medicine.

These are the first such studies to link PPI use to chronic kidney disease (CKD), and the association held up after controlling for multiple potential confounders, said Dr. Benjamin Lazarus of Johns Hopkins University, Baltimore, and his associates. “Further research is required to investigate whether PPI use itself causes kidney damage and, if so, the underlying mechanisms of this association,” they wrote.

Proton pump inhibitors have been linked to other adverse health effects but remain among the most frequently prescribed medications in the United States. To further explore the risk of PPI use, the researchers analyzed data for 10,482 adults from the Atherosclerosis Risk in Communities (ARIC) study who were followed for a median of 13.9 years, and a replication cohort of 248,751 patients from a large rural health care system who were followed for a median of 6.2 years.

©decade3d/thinkstockphotos.com

Incident CKD was defined based on hospital discharge diagnosis codes, reports of end-stage renal disease from the United States Renal Data System Registry, or a glomerular filtration rate of less than 60 mL/min per 1.73 m² that persisted at follow-up visits (JAMA Intern Med. 2016 Jan 11. doi: 0.1001/jamainternmed.2015.7193).

In the ARIC study, there were 56 cases of CKD among 322 self-reported baseline PPI users, for an incidence of 14.2 cases per 1,000 person-years – significantly higher than the rate of 10.7 cases per 1,000 person-years among self-reported baseline nonusers. The 10-year estimated absolute risk of CKD among baseline users was 11.8% – 3.3% higher than the expected risk had they not used PPIs. Furthermore, PPI users were at significantly higher risk of CKD after demographic, socioeconomic, and clinical variables were accounted for (hazard ratio, 1.50; 95% confidence interval, 1.1-2.0), after modeling varying use of PPIs over time (adjusted HR, 1.3; 95% CI, 1.2-1.5), after directly comparing PPI users with H₂ receptor antagonist users (adjusted HR, 1.4; 95% CI, 1.01-1.9), and after comparing baseline PPI users with propensity score–matched nonusers (HR, 1.8; 95% CI, 1.1-2.7).

In the replication cohort, there were 1,921 new cases of CKD among 16,900 patients with an outpatient PPI prescription (incidence of 20.1 cases per 1,000 person-years). The incidence of CKD among the other patients was lower: 18.3 cases per 1,000 person-years. The use of PPIs was significantly associated with incident CKD in all analyses, and the 10-year absolute risk of CKD among baseline PPI users was 15.6% – 1.7% higher than the expected risk had they not used PPIs.

These observational analyses cannot show causality, but a causal relationship between PPIs and CKD “could have a considerable public health impact, give the widespread extent of use,” the researchers emphasized. “More than 15 million Americans used prescription PPIs in 2013, costing more than $10 billion. Study findings suggest that up to 70% of these prescriptions are without indication and that 25% of long-term PPI users could discontinue therapy without developing symptoms. Indeed, there are already calls for the reduction of unnecessary use of PPIs (BMJ. 2008;336:2-3).”

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute, both of which are part of the National Institutes of Health. The researchers had no disclosures.

The U.S. Department of Health and Human Services and the U.S. Department of Agriculture have released the eighth iteration of the Dietary Guidelines for Americans, a set of recommendations for healthy eating habits Americans should adopt to prevent development of hypertension, heart disease, and type 2 diabetes, among other conditions.

The new guidelines, effective through 2020, highlight the importance of eating a wide variety of fruits, vegetables, grains, and dairy products, while staying away from processed foods heavy in saturated fats, sugar, and cholesterol as much as possible. The difference between this and earlier editions of the guidelines, the health agencies say, is to promote the importance of a wider variety of foods Americans should be consuming, rather than focusing on just a few isolated foods that should be integrated into an otherwise inadequate diet.

Courtesy of National Cancer Institute

“Protecting the health of the American public includes empowering them with the tools they need to make healthy choices in their daily lives,” Secretary of Health and Human Services Sylvia M. Burwell said in a statement. “By focusing on small shifts in what we eat and drink, eating healthy becomes more manageable. The Dietary Guidelines provide science-based recommendations on food and nutrition so people can make decisions that may help keep their weight under control, and prevent chronic conditions, like Type 2 diabetes, hypertension, and heart disease.”

The American Medical Association voiced their support of the new guidelines, saying that they are “extremely pleased that the new recommendations call for significantly reducing the amount of added sugars and sugar sweetened beverages from the American diet.” Similarly, the American College of Cardiology issued a statement saying that the existence of “a source of clear science-based information about diet” is more important than ever for Americans in the face of increasingly omnipresent and often confusing information available; the college also lauded the recommendations to limit the intake of added sugars, saturated and trans fats, and sodium. The American Heart Association released a new Authoritative Review of data on the topic of nutritional balance as it related to chronic diseases.

While the recommendations may seem common sense and geared more towards patients and laymen, they are of equal importance to health care providers. Dr. Carolyn Lopez – a Chicago-area family physician and adjunct professor of medicine at Northwestern University – called the guidelines an important resource for physicians, with several elements that will be of particular benefit to physicians and clinicians looking to improve the quality of care given to their patients.

“People [should] understand that while individual food choices are important, the pattern of eating is paramount,” Dr. Lopez explained in an interview. “It’s not impossible to bring vegetables into breakfast – veggie omelettes are great – but it’s hard to imagine bringing a vegetable into the whole grain cereals with skim milk breakfast.”

As a family practitioner, however, Dr. Lopez stressed the difficulty of any doctor having a significant enough amount of time with each patient to really go in-depth into what needs to be done to enact meaningful nutritional and lifestyle changes. “These guidelines can only be effective if the whole team is talking to patients,” she explained. “On its own, it would be extraordinarily difficult [or] impossible to accomplish.

Dr. Nazrat Mirza, a pediatrician who is medical director of the IDEAL Pediatric Weight Management Clinic at Children’s National Health System, Washington, said in an interview that the guidelines are “significant in that they are leading us even closer to healthier dietary living – and from my pediatric perspective, healthier children who will grow into healthier adults. We must keep in mind that these guidelines are not prescriptive – but generalized to relatively healthy people. In particular, the recommendation to reduce sugar intake with specification of an upper limit of 10% of calories from added sugar factored into the suggested daily nutritional intake is an excellent update. Added sugar consumption is linked to diabetes, so any reduction in recommended intake will steer people away from potentially developing diabetes.”

She continued, “In my clinic and day-to-day counseling of patients, being able to point to helpful resources such as these guidelines is crucial. These guidelines will continue to serve as yet another way to reach parents and affect the daily dietary habits they practice at home. I was happy to see resources such as MyPlate.gov referenced in the guidelines; that is a tool I use regularly. When educating families on what a healthy plate looks like, I’m able to point directly to the MyPlate.gov posters hanging in the clinic. Comprehensive resources such as these guidelines, [which] give parents actual examples of foods, and deliver the information in a clear, concise, implementable way, are the best methods to reach parents and kids.” 

“As a medical provider, such guidelines provide us with tools and reinforcement to say ‘this is policy,’ when approaching schools about the food and drink options they offer children on a daily basis – because the schools are going to have to follow these guidelines. If these guidelines can enforce public policy for the kids to eat healthy, ... and we can implement changes according to the guidelines, that would help greatly in the prevention of chronic disorders such as obesity, hypertension and diabetes – which is a step in the right direction,” said Dr. Mirza, also of George Washington University, Washington.

“Most physicians are so rushed nowadays by the health care system that they typically do not have adequate time to discuss these very important issues,” Dr. Rodbard said in an interview. “It takes time and perseverance to educate the patient and provide individualized care, assessing their current diet, assessing their willingness or potential for changing their diet or increasing their physical activity.”

On that last point. Dr. Rodbard criticized the new guidelines for not emphasizing the importance of exercise enough. “More clarity and emphasis on physical activity should have been provided,” she said, adding that “people need continual, gentle reminders with repetition and long-term follow-up.” Dr. Rodbard summed up the guidelines as “marginally adequate” but “a step in the right direction.”

An endocrinologist who practices in Winter Park, Fla., Dr. Victor L. Roberts – a Fellow of the ACP and ACE – agreed that time with the patients is critical in order for these guidelines to have any effect, calling the guidelines “just the GPS, not the destination.”

Preaching an ABC strategy – accountability, behavior, and calories, the latter of which he stressed is the most important part of any dietary strategy – Dr. Roberts explained that clinicians and physicians should leave the more specific dietary advice to nutritional experts and focus on telling their patients to watch calories, watch the amount of food they’re eating of any given type, and to exercise more.

“These guidelines crystallize and summarize what we’ve already known, and what we should have been practicing and advocating, for decades,” Dr. Roberts said in an interview, adding that “the difficulty is putting these recommendations into practice and having patients and doctors accept responsibility.”

Ultimately, the three doctors who treat adult patients concurred that the new guidelines are imperfect, and likely won’t result in any automatic widespread change. Dr. Rodbard admitted that she does not anticipate the guidelines affecting the way she treats her patients very much, if at all, while Dr. Lopez said that she’s “not sure it’s going to have a major effect.” Furthermore, the sheer volume of data and information available often leads to patients simply not knowing what to believe, which Dr. Roberts described as a “glazed over” effect of being told so many different things from so many different sources, patients just tune everything out.

Ultimately, while it’s important for health care providers to give advice and recommendations as necessary, these should be done on an individual basis. And, if a patient requires extensive dietary and nutritional intervention, that should be left in the hands of specialist who can accurately determine what the patient is capable of, what their goals should be, and how to tailor a plan specifically for them.

“I don’t know many clinicians, even in my own specialty, who know much about what specifically to eat,” said Dr. Roberts. “That should come from nutritional medicine people, not us.”

Dr. Lopez, Dr. Rodbard, and Dr. Roberts did not report any relevant financial disclosures.

[email protected]

*This article was updated 1/12/2016.

The U.S. Department of Health and Human Services and the U.S. Department of Agriculture have released the eighth iteration of the Dietary Guidelines for Americans, a set of recommendations for healthy eating habits Americans should adopt to prevent development of hypertension, heart disease, and type 2 diabetes, among other conditions.

The new guidelines, effective through 2020, highlight the importance of eating a wide variety of fruits, vegetables, grains, and dairy products, while staying away from processed foods heavy in saturated fats, sugar, and cholesterol as much as possible. The difference between this and earlier editions of the guidelines, the health agencies say, is to promote the importance of a wider variety of foods Americans should be consuming, rather than focusing on just a few isolated foods that should be integrated into an otherwise inadequate diet.

Courtesy of National Cancer Institute

“Protecting the health of the American public includes empowering them with the tools they need to make healthy choices in their daily lives,” Secretary of Health and Human Services Sylvia M. Burwell said in a statement. “By focusing on small shifts in what we eat and drink, eating healthy becomes more manageable. The Dietary Guidelines provide science-based recommendations on food and nutrition so people can make decisions that may help keep their weight under control, and prevent chronic conditions, like Type 2 diabetes, hypertension, and heart disease.”

The American Medical Association voiced their support of the new guidelines, saying that they are “extremely pleased that the new recommendations call for significantly reducing the amount of added sugars and sugar sweetened beverages from the American diet.” Similarly, the American College of Cardiology issued a statement saying that the existence of “a source of clear science-based information about diet” is more important than ever for Americans in the face of increasingly omnipresent and often confusing information available; the college also lauded the recommendations to limit the intake of added sugars, saturated and trans fats, and sodium. The American Heart Association released a new Authoritative Review of data on the topic of nutritional balance as it related to chronic diseases.

While the recommendations may seem common sense and geared more towards patients and laymen, they are of equal importance to health care providers. Dr. Carolyn Lopez – a Chicago-area family physician and adjunct professor of medicine at Northwestern University – called the guidelines an important resource for physicians, with several elements that will be of particular benefit to physicians and clinicians looking to improve the quality of care given to their patients.

“People [should] understand that while individual food choices are important, the pattern of eating is paramount,” Dr. Lopez explained in an interview. “It’s not impossible to bring vegetables into breakfast – veggie omelettes are great – but it’s hard to imagine bringing a vegetable into the whole grain cereals with skim milk breakfast.”

As a family practitioner, however, Dr. Lopez stressed the difficulty of any doctor having a significant enough amount of time with each patient to really go in-depth into what needs to be done to enact meaningful nutritional and lifestyle changes. “These guidelines can only be effective if the whole team is talking to patients,” she explained. “On its own, it would be extraordinarily difficult [or] impossible to accomplish.

Dr. Nazrat Mirza, a pediatrician who is medical director of the IDEAL Pediatric Weight Management Clinic at Children’s National Health System, Washington, said in an interview that the guidelines are “significant in that they are leading us even closer to healthier dietary living – and from my pediatric perspective, healthier children who will grow into healthier adults. We must keep in mind that these guidelines are not prescriptive – but generalized to relatively healthy people. In particular, the recommendation to reduce sugar intake with specification of an upper limit of 10% of calories from added sugar factored into the suggested daily nutritional intake is an excellent update. Added sugar consumption is linked to diabetes, so any reduction in recommended intake will steer people away from potentially developing diabetes.”

She continued, “In my clinic and day-to-day counseling of patients, being able to point to helpful resources such as these guidelines is crucial. These guidelines will continue to serve as yet another way to reach parents and affect the daily dietary habits they practice at home. I was happy to see resources such as MyPlate.gov referenced in the guidelines; that is a tool I use regularly. When educating families on what a healthy plate looks like, I’m able to point directly to the MyPlate.gov posters hanging in the clinic. Comprehensive resources such as these guidelines, [which] give parents actual examples of foods, and deliver the information in a clear, concise, implementable way, are the best methods to reach parents and kids.” 

“As a medical provider, such guidelines provide us with tools and reinforcement to say ‘this is policy,’ when approaching schools about the food and drink options they offer children on a daily basis – because the schools are going to have to follow these guidelines. If these guidelines can enforce public policy for the kids to eat healthy, ... and we can implement changes according to the guidelines, that would help greatly in the prevention of chronic disorders such as obesity, hypertension and diabetes – which is a step in the right direction,” said Dr. Mirza, also of George Washington University, Washington.

“Most physicians are so rushed nowadays by the health care system that they typically do not have adequate time to discuss these very important issues,” Dr. Rodbard said in an interview. “It takes time and perseverance to educate the patient and provide individualized care, assessing their current diet, assessing their willingness or potential for changing their diet or increasing their physical activity.”

On that last point. Dr. Rodbard criticized the new guidelines for not emphasizing the importance of exercise enough. “More clarity and emphasis on physical activity should have been provided,” she said, adding that “people need continual, gentle reminders with repetition and long-term follow-up.” Dr. Rodbard summed up the guidelines as “marginally adequate” but “a step in the right direction.”

An endocrinologist who practices in Winter Park, Fla., Dr. Victor L. Roberts – a Fellow of the ACP and ACE – agreed that time with the patients is critical in order for these guidelines to have any effect, calling the guidelines “just the GPS, not the destination.”

Preaching an ABC strategy – accountability, behavior, and calories, the latter of which he stressed is the most important part of any dietary strategy – Dr. Roberts explained that clinicians and physicians should leave the more specific dietary advice to nutritional experts and focus on telling their patients to watch calories, watch the amount of food they’re eating of any given type, and to exercise more.

“These guidelines crystallize and summarize what we’ve already known, and what we should have been practicing and advocating, for decades,” Dr. Roberts said in an interview, adding that “the difficulty is putting these recommendations into practice and having patients and doctors accept responsibility.”

Ultimately, the three doctors who treat adult patients concurred that the new guidelines are imperfect, and likely won’t result in any automatic widespread change. Dr. Rodbard admitted that she does not anticipate the guidelines affecting the way she treats her patients very much, if at all, while Dr. Lopez said that she’s “not sure it’s going to have a major effect.” Furthermore, the sheer volume of data and information available often leads to patients simply not knowing what to believe, which Dr. Roberts described as a “glazed over” effect of being told so many different things from so many different sources, patients just tune everything out.

Ultimately, while it’s important for health care providers to give advice and recommendations as necessary, these should be done on an individual basis. And, if a patient requires extensive dietary and nutritional intervention, that should be left in the hands of specialist who can accurately determine what the patient is capable of, what their goals should be, and how to tailor a plan specifically for them.

“I don’t know many clinicians, even in my own specialty, who know much about what specifically to eat,” said Dr. Roberts. “That should come from nutritional medicine people, not us.”

Dr. Lopez, Dr. Rodbard, and Dr. Roberts did not report any relevant financial disclosures.

[email protected]

*This article was updated 1/12/2016.

The U.S. Department of Health and Human Services and the U.S. Department of Agriculture have released the eighth iteration of the Dietary Guidelines for Americans, a set of recommendations for healthy eating habits Americans should adopt to prevent development of hypertension, heart disease, and type 2 diabetes, among other conditions.

The new guidelines, effective through 2020, highlight the importance of eating a wide variety of fruits, vegetables, grains, and dairy products, while staying away from processed foods heavy in saturated fats, sugar, and cholesterol as much as possible. The difference between this and earlier editions of the guidelines, the health agencies say, is to promote the importance of a wider variety of foods Americans should be consuming, rather than focusing on just a few isolated foods that should be integrated into an otherwise inadequate diet.

Courtesy of National Cancer Institute

“Protecting the health of the American public includes empowering them with the tools they need to make healthy choices in their daily lives,” Secretary of Health and Human Services Sylvia M. Burwell said in a statement. “By focusing on small shifts in what we eat and drink, eating healthy becomes more manageable. The Dietary Guidelines provide science-based recommendations on food and nutrition so people can make decisions that may help keep their weight under control, and prevent chronic conditions, like Type 2 diabetes, hypertension, and heart disease.”

The American Medical Association voiced their support of the new guidelines, saying that they are “extremely pleased that the new recommendations call for significantly reducing the amount of added sugars and sugar sweetened beverages from the American diet.” Similarly, the American College of Cardiology issued a statement saying that the existence of “a source of clear science-based information about diet” is more important than ever for Americans in the face of increasingly omnipresent and often confusing information available; the college also lauded the recommendations to limit the intake of added sugars, saturated and trans fats, and sodium. The American Heart Association released a new Authoritative Review of data on the topic of nutritional balance as it related to chronic diseases.

While the recommendations may seem common sense and geared more towards patients and laymen, they are of equal importance to health care providers. Dr. Carolyn Lopez – a Chicago-area family physician and adjunct professor of medicine at Northwestern University – called the guidelines an important resource for physicians, with several elements that will be of particular benefit to physicians and clinicians looking to improve the quality of care given to their patients.

“People [should] understand that while individual food choices are important, the pattern of eating is paramount,” Dr. Lopez explained in an interview. “It’s not impossible to bring vegetables into breakfast – veggie omelettes are great – but it’s hard to imagine bringing a vegetable into the whole grain cereals with skim milk breakfast.”

As a family practitioner, however, Dr. Lopez stressed the difficulty of any doctor having a significant enough amount of time with each patient to really go in-depth into what needs to be done to enact meaningful nutritional and lifestyle changes. “These guidelines can only be effective if the whole team is talking to patients,” she explained. “On its own, it would be extraordinarily difficult [or] impossible to accomplish.

Dr. Nazrat Mirza, a pediatrician who is medical director of the IDEAL Pediatric Weight Management Clinic at Children’s National Health System, Washington, said in an interview that the guidelines are “significant in that they are leading us even closer to healthier dietary living – and from my pediatric perspective, healthier children who will grow into healthier adults. We must keep in mind that these guidelines are not prescriptive – but generalized to relatively healthy people. In particular, the recommendation to reduce sugar intake with specification of an upper limit of 10% of calories from added sugar factored into the suggested daily nutritional intake is an excellent update. Added sugar consumption is linked to diabetes, so any reduction in recommended intake will steer people away from potentially developing diabetes.”

She continued, “In my clinic and day-to-day counseling of patients, being able to point to helpful resources such as these guidelines is crucial. These guidelines will continue to serve as yet another way to reach parents and affect the daily dietary habits they practice at home. I was happy to see resources such as MyPlate.gov referenced in the guidelines; that is a tool I use regularly. When educating families on what a healthy plate looks like, I’m able to point directly to the MyPlate.gov posters hanging in the clinic. Comprehensive resources such as these guidelines, [which] give parents actual examples of foods, and deliver the information in a clear, concise, implementable way, are the best methods to reach parents and kids.” 

“As a medical provider, such guidelines provide us with tools and reinforcement to say ‘this is policy,’ when approaching schools about the food and drink options they offer children on a daily basis – because the schools are going to have to follow these guidelines. If these guidelines can enforce public policy for the kids to eat healthy, ... and we can implement changes according to the guidelines, that would help greatly in the prevention of chronic disorders such as obesity, hypertension and diabetes – which is a step in the right direction,” said Dr. Mirza, also of George Washington University, Washington.

“Most physicians are so rushed nowadays by the health care system that they typically do not have adequate time to discuss these very important issues,” Dr. Rodbard said in an interview. “It takes time and perseverance to educate the patient and provide individualized care, assessing their current diet, assessing their willingness or potential for changing their diet or increasing their physical activity.”

On that last point. Dr. Rodbard criticized the new guidelines for not emphasizing the importance of exercise enough. “More clarity and emphasis on physical activity should have been provided,” she said, adding that “people need continual, gentle reminders with repetition and long-term follow-up.” Dr. Rodbard summed up the guidelines as “marginally adequate” but “a step in the right direction.”

An endocrinologist who practices in Winter Park, Fla., Dr. Victor L. Roberts – a Fellow of the ACP and ACE – agreed that time with the patients is critical in order for these guidelines to have any effect, calling the guidelines “just the GPS, not the destination.”

Preaching an ABC strategy – accountability, behavior, and calories, the latter of which he stressed is the most important part of any dietary strategy – Dr. Roberts explained that clinicians and physicians should leave the more specific dietary advice to nutritional experts and focus on telling their patients to watch calories, watch the amount of food they’re eating of any given type, and to exercise more.

“These guidelines crystallize and summarize what we’ve already known, and what we should have been practicing and advocating, for decades,” Dr. Roberts said in an interview, adding that “the difficulty is putting these recommendations into practice and having patients and doctors accept responsibility.”

Ultimately, the three doctors who treat adult patients concurred that the new guidelines are imperfect, and likely won’t result in any automatic widespread change. Dr. Rodbard admitted that she does not anticipate the guidelines affecting the way she treats her patients very much, if at all, while Dr. Lopez said that she’s “not sure it’s going to have a major effect.” Furthermore, the sheer volume of data and information available often leads to patients simply not knowing what to believe, which Dr. Roberts described as a “glazed over” effect of being told so many different things from so many different sources, patients just tune everything out.

Ultimately, while it’s important for health care providers to give advice and recommendations as necessary, these should be done on an individual basis. And, if a patient requires extensive dietary and nutritional intervention, that should be left in the hands of specialist who can accurately determine what the patient is capable of, what their goals should be, and how to tailor a plan specifically for them.

“I don’t know many clinicians, even in my own specialty, who know much about what specifically to eat,” said Dr. Roberts. “That should come from nutritional medicine people, not us.”

Dr. Lopez, Dr. Rodbard, and Dr. Roberts did not report any relevant financial disclosures.

[email protected]

*This article was updated 1/12/2016.

From the Cincinnati Children’s Hospital Medical Center, Cincinnati, OH.

Abstract

• Objective: To review the management of migraine in adolescent patients.
• Methods: Literature review in the context of 2 clinical cases.
• Results: Migraine is common in adolescents and can affect school and social functioning. Management options include lifestyle modifications and acute and preventative therapies. First-line medications for migraine in the adolescent population are over-the-counter medications, including ibuprofen, acetaminophen, and naproxen. Studies of efficacy of triptans in the treatment of pediatric migraine have been limited and results conflicting, largely due to high placebo response rates. Several classes of medications are commonly used for migraine prevention, including antidepressants and antiepileptics. Currently, topiramate is the only medication approved for prevention of migraine in patients 12 years and older. Biobehavioral treatments such as relaxation training, biofeedback, and cognitive behavioral therapy have been evaluated in randomized controlled trials and found to be efficacious.
• Conclusion: Approach to management of migraine in adolescents should be multifactorial with attention to an aggressive acute treatment regimen, preventive medications when indicated, and biobehavioral management.

Case Study 1

Initial Presentation

A 13-year-old left-handed boy with allergic rhinitis has been referred by his pediatrician for evaluation of headaches.

History

The headaches have been occurring since he was 7 years old. He describes a bilateral frontal and periorbital pain, which is either aching or throbbing in nature. There is associated photophobia and phonophobia, and the pain worsens with activity. When he was younger the headaches were frequently associated with emesis. He occasionally gets tenderness of his face during the headaches, mostly in the areas adjacent to his nose and above his eyes and occasionally associated rhinorrhea.

Initially the headaches were mild and occurring infrequently, but for the past 6 months they have been more severe and occurring 1 to 3 times per week, sometimes on consecutive days. They typically begin in the afternoon but at times occur soon after waking in the morning. If they do occur in the morning, they worsen after getting out of bed. He denies any type of warning symptoms indicating the headache will occur, and has no associated focal neurologic symptoms associated with the headaches. His mother tries to minimize medication intake so will typically wait to see if the headache is severe before giving him medication, typically 2 chewable children’s ibuprofen, which helps some of the time; however, his headache often does not completely abate unless he naps. He has also been taking loratadine daily due to concerns that his headaches may be secondary to chronic sinusitis.

He is a good student and enjoys school, but notes stress surrounding tests. He reports missing 4 days of school in the past 3 months as well as coming late twice. He thinks that there were 9 additional days in which he was unable to function at his full ability at school and at least 5 times he was unable to concentrate on his homework. He plays soccer 4 to 5 times per week. He says twice he had to skip soccer practice to due to headache and at least 3 other times he needed to take breaks during soccer due to headache. He is unsure how much he drinks on an average day but he drinks mostly with meals. He does not drink caffeine. He gets into bed at 10 pm and sometimes does not fall asleep until after 11 pm, often due to worry about tests. He often plays with his tablet when trying to fall asleep. He wakes up at 6 am for school. He typically eats 3 meals per day but occasionally misses breakfast if he is rushed in the morning.

Physical Examination

On examination, the patient is a well-developed, well-nourished male in no apparent distress. His weight was 50.9 kg (68th percentile), height 163.7 cm (65th percentile), BMI 19.9 (69th percentile), blood pressure 118/62 mm Hg, and heart rate 79 bpm. His general physical examination, including skin, HEENT, extremities, lung, cardiac, and abdominal examination was normal, with lungs clear to auscultation, heart with a regular rate and rhythm, and abdomen soft and tender without organomegaly.

On neurologic examination he was alert and attentive with normal mental status. Speech was fluent. Skull, spine, and meninges were normocephalic and atraumatic with a supple neck. Cranial nerves II through XII were normal with a normal fundoscopic examination including sharp disk, no papilledema, and normal fundus bilaterally. Motor examination was normal for tone and bulk with full strength throughout. Sensory examination was normal for light touch, temperature, vibration, and joint position sense. Finger-nose-finger fine finger movement and heel-knee-shin were normal. Deep tendon reflexes were symmetric and 2+ throughout with toes downgoing. Station and gait were normal including toe walking, heel walking, tandem walking, running, skipping, one-legged standing, Fog gate procedure, and there was no Romberg’s sign.

He had a normal comprehensive headache examination. There was no tenderness at typical migraine trigger points (nuchal line and mandibular process) and no tenderness at supraorbital notch. Neck was supple with normal rotation and normal bilateral trapezius muscle tightness. No bruits or palpitations were heard over carotid or jugular veins. There was a negative Muller sign with no pain on neck bending with pressure, and no signs of allergy or sinus symptoms.

• What is the initial evaluation of a teen with recurrent headaches?

The overwhelming majority of children and adolescents presenting to medical attention with recurrent headaches will have a primary headache disorder, most commonly migraine [1].However, ruling out a secondary cause is typically of concern, both for providers and parents, and the decision regarding whether to image is often a daunting one. In a review of 6 large studies in which imaging was done in pediatric patients who were examined by a neurologist, only 14 patients were found to have CNS lesions requiring intervention, and all of these patients had abnormalities on physical exam [2]. An American Academy of Neurology (AAN) practice parameter published in 2002 recommended considering neuroimaging only in patients with abnormal neurologic examination, co-existing seizures, concerning associated neurologic features, or recent onset of severe headache or change in headache type [2].There are additional factors which may prompt one to consider imaging as well including atypical auras or very short (< 5 minutes) or protracted ( > 60 minutes) auras, trigeminal autonomic cephalalgia, brief headaches precipitated by cough, frequent early morning headaches or which wake the patient from sleep, headaches with primarily occipital location, headaches in a patient less than 6 years old or in a child who cannot describe the headaches well, or migrainous headaches in a child without any family history of migraine or migraine equivalents. However, recent studies continue to show that the imaging yield in patients with headaches is low and further studies are needed to elucidate which patients truly require imaging [3].

Given this, a thorough history, family history, physical exam, and detailed neurologic exam including fundoscopy are imperative. In addition to the general neurologic exam, a focused headache exam should be performed, including Mueller’s maneuver, auscultation for cranial bruits, evaluation of the temporomandibular joint, palpation of possible trigger points, and maneuvers to assess for cervical spine disease [4].

Classification of Symptoms         

Once establishing the likelihood of a primary headache disorder, the International Classification of Headache Disorders, 3rd edition, beta version (ICHD IIIβ) [5]should be used to classify the headache diagnosis. Note that while this classification system was established for adults, most criteria are similar for children and adolescents, and the typical differences are noted in the comments of the ICHD IIIβ [5].Migraine is the most common type of primary headache brought to medical attention [1]. Migraine without aura is described as a recurrent headache disorder (at least 5 lifetime attacks) with attacks lasting 4 to 72 hours, typically unilateral, throbbing in nature, moderate to severe in intensity, aggravated by routine physical activity, and associated with nausea and/or photophobia and phonophobia. In young children, migraine is more frequently bilateral, the gastrointestinal symptoms often more pronounced than photophobia and phonophobia, and migraines may be shorter, lasting at least 2 hours without treatment [5].As patients reach adolescence, migraine features typically start to evolve into patterns described in adults. Differentiating migraine from other primary headaches, such as tension-type, can be challenging, especially in children in whom migraines are more likely to be shorter and bilateral. Tension-type headaches are bilateral or diffuse, pressing or tightening pain that is non-pulsatile lasting at least 30 minutes. The pain is described as mild to moderate in intensity and not aggravated by activity [5].They may be associated with photophobia or phonophobia (not both) and they may not be associated with nausea or vomiting [5].

• Is any further workup indicated?

The patient has recurrent headaches which have been present for 5 years. While they have increased in frequency, there has not been any change in their quality. His headache description and history have no “red flag” features, and a thorough examination is normal. Therefore, neuroimaging and further workup would not be indicated in this case.

• What is the diagnosis?

The patient’s headaches are throbbing in nature, exacerbated by activity, associated with nausea, photophobia, and phonophobia, and are moderate to severe. Using the ICHD IIIβ, he meets criteria for migraine without aura. While his headaches are frequent, he is having less than 15 headache days per month, so this is episodic migraine. Note that he complains of forehead and periorbital pain and occasional rhinorrhea with his headaches, leading him to have been placed on loratadine for treatment of presumed allergic sinusitis. Children meeting criteria for migraine are very frequently misdiagnosed as having sinusitis [6]due to the overlap in location of migraine pain and proximity to the frontal and maxillary sinuses, as well as the presence of autonomic features frequently present in migraine, reportedly present in 70% of pediatric migraine patients [7].The negative headache examination, including Muller’s maneuver, points against sinus disease as well.

• What is the approach to management of the adolescent with migraine?

Approach to management of migraine in adolescents should be multifactorial, with attention to an aggressive acute treatment regimen, preventive medications when indicated, and biobehavioral management.

Acute Treatment

General Approach

In counseling patients with migraine, and in particular adolescents, it should be stressed that achieving a normal level of functioning as soon as possible is the goal of therapy. Common missteps in treatment include failure to take acute medication early into the headache, incorrect dosing, incompletely treating the headache, and avoidance of participating in daily activities when headaches occur.

Adolescent patients may frequently wait to take an acute medication, typically due participation in another activity, not having medication with them, or discomfort with taking medication in front of peers or at school. Additionally, patients who have headaches beginning in early childhood, with pronounced gastrointestinal (GI) features, may be aware that their headaches resolve after vomiting, and therefore get used to not treating with medications. When these patients reach adolescence, when GI symptoms tend to become less pronounced, they will need to be educated that taking medication early is imperative. Acute medications are typically more effective when taken earlier in the course of a migraine, and the importance of pausing to take medication at the onset of the headache should be stressed to all patients and parents. With that in mind, however, care should be taken to counsel patients regarding the potential for development of medication overuse headache. When headaches are frequent, a more detailed and intricate plan may need to be devised so that adolescents and parents know which headaches to treat with medication.

Given that first-line medications for treatment of migraines are over-the-counter, underdosing occurs commonly, as dosing listed on packaging is typically age-based, not weight-based. At initial visits, young adolescent patients will frequently report that a particular medication is not effective, but this is often because they are still receiving low/less optimal dosing. Clinicians should remember to follow weights and recommend dosing changes at the initial visit and follow-up visits as well.

Treatment goals, ie, complete resolution of pain and migrainous features with ability to return to normal functioning, should be made clear to patients and families at the onset of treatment. Patients frequently fall into a pattern of continuing to treat with a medication that may lessen but not completely ablate the pain of a headache, and then sleep and avoid activity. Upon awakening, the headache may be gone, however, given incomplete initial treatment, the headache may be more likely to recur within 24 hours. At that point, the headache may be more difficult to treat and therefore cause further decrease in functioning. If this cycle perpetuates, disability can become extremely burdensome in adolescents, significantly affecting school and social functioning. Therefore, a detailed plan for initial steps in management as well as steps to take should initial therapy fail to fully break the headache should be given to every patient.

Of note, given that dehydration is now recognized as a common trigger for migraine [8,9], it is generally our recommendation to drink 16 to 32 oz (depending on weight) of a hydrating fluid together with whichever acute medication is chosen, as rehydration likely assists in breaking migraines as well [8].

Medications

Over-the-Counter Agents

The first-line medications for migraine in the pediatric and adolescent populations are over-the counter medications, including ibuprofen, acetaminophen, and naproxen sodium. Ibuprofen has been well studied in pediatrics and was found to be safe and effective in 2 studies [10,11]at doses of 7.5–10 mg/kg. Again, care should be taken to ensure timely administration of ibuprofen at onset of headache, or aura if present, with appropriate weight-based dosing. Naproxen sodium has not been studied in pediatrics for treatment of migraine. However in practice, it is often used in similar doses of 10 mg/kg, with good efficacy. Although ibuprofen and naproxen sodium are both nonsteroidal anti-inflammatory medications (NSAIDs), anecdotally many patients report successful treatment with one NSAID when another has failed. Aspirin has shown efficacy in adults for treatment of acute migraine [12].It is likely effective in the pediatric population as well, but it is generally avoided due to long-standing concerns for precipitation of Reye syndrome in children. In adolescents over 16 years old, however, it is a reasonable option if there are no contraindications.

In one study, acetaminophen was compared to ibuprofen and placebo for treatment of migraine in children and adolescents and found to be effective more frequently than placebo but not as frequently as ibuprofen [10],likely due to its only minimal anti-inflammatory effects. It is a reasonable option for children and adolescents, particularly in those who have contraindications to NSAIDs.

While these over-the-counter medications are generally safe and well tolerated, clinicians should not overlook the potential for toxicity as well as medication overuse headache, and patients should be counseled to avoid use of any of these medications for more than 2 to 3 headache days per week.

Triptans

Studies of efficacy of triptans in treatment of pediatric migraine have been limited and results conflicting, largely due to high placebo response rates. However, some have shown efficacy over placebo, and in the past few years have received FDA approval for use in the pediatric and adolescent populations. Clinicians should remember that these medications are vasoconstrictors, so they should not be used in patients with vascular disease or in patients with migraine with brainstem aura or hemiplegic migraine. Additionally, due to the risk of serotonin syndrome, they should not be used in patients on monoamine oxidase inhibitors. It is also important to educate patients to limit use of these medications to 4 to 6 times per month to avoid precipitation of medication overuse headache.

Almotriptan was approved by the FDA in 2009 for use in patients 12 years and older, based on a large randomized controlled trial comparing doses of 6.25, 12.5, and 25 mg with placebo in patients ages 12 to 17 years old. All doses resulted in statistically significant pain relief as compared to placebo, and interestingly, the 12.5-mg dose seemed to be the most effective [13].

Rizatriptan received FDA approval in 2012 for use in patients 6 years and older. In 2 randomized controlled trials in patients 6 to 17 years old, rizatriptan (5 mg for patients < 40 kg, 10 mg for patients ≥ 40 kg) was more effective than placebo in providing pain freedom at 2 hours [14,15].One earlier trial found efficacy only on some measures (weekend treatment, decrease in nausea and functional disability) but no statistically significant difference than placebo in terms of overall efficacy in achieving pain freedom at 2 hours [16].However, this trial had a higher placebo response rate than typically seen in adult triptan trials. In a recent long-term open-label study in patients 12 to 17 years old, rizatriptan was found to be generally safe and well-tolerated with consistent efficacy of 46% to 51% pain freedom at 2 hours over time [17].

A combination pill consisting of sumatriptan and naproxen (Treximet) received FDA approval in May 2015 for patients 12 years and older. This was based on a randomized controlled parallel-group trial in patients 12 to 17 years old using the sumatriptan/naproxen combination in various dose combinations: 10/60 mg, 30/180 mg, or 85/500 [18].All doses were found to be equally effective in providing pain relief at 2 hours as compared to placebo, with a higher chance of sustained pain relief at 24 hours in the group receiving the 85/500 dose. In this trial, and in a long-term open-label safety trial [19],all doses were generally well tolerated with minimal adverse reactions.

Most recently, in June 2015, zolmitriptan nasal spray was approved for patients 12 years of age and older. In the large “Double-Diamond” study, which used a novel design to attempt to minimize placebo effect, zolmitriptan nasal spray (5 mg) was found to have a significantly higher headache response rate at 1 hour than placebo, and was significantly superior to placebo with regard to multiple secondary end-points [20].Additionally, a long-term open-label trial in patients 12 to 17 years old using oral zolmitriptan (2.5 mg or 5 mg) found it to be generally effective and well tolerated [21].

No other triptans have been approved for children or adolescents, however, most are widely used in clinical practice. There is good evidence for the efficacy and tolerability of sumatriptan nasal spray [22–26]in adolescents, and it is approved for use in adolescents with migraine in Europe. Although oral sumatriptan was the first triptan available clinically in the United States and is very widely used, there is surprisingly little published evidence for its use in the pediatric and adolescent populations. In fact, 2 randomized controlled trials in adolescents failed to show efficacy of oral sumatriptan as compared to placebo [27,28].Despite this, given its availability it is a reasonable choice for adolescent patients and is often one of the first tried. There has been 1 randomized controlled trial in adolescents for eletriptan without significant differences in efficacy at 2 hours as compared to placebo, although similar to other trials the placebo rate was high and there were some differences seen in secondary outcomes measures [29].Similarly, one randomized controlled trial of naratriptan 12.5-mg tablets failed to show efficacy as compared to placebo in pain relief [30].At present time, for frovatriptan there has only been a study looking at the pharmacokinetics and safety in adolescents, which found that it was generally well tolerated and recommended adolescent dosing similar to adult dosing [31].

In choosing a triptan, clinicians should keep in mind availability of alternate forms of administration, absence or presence of significant emesis, and the age of the patient. For patients who are unable to swallow pills or who have significant emesis associated with their migraines, nasal sprays and oral dissolving forms (melts) are good options. The nasal sprays (zolmitriptan and sumatriptan) additionally have the benefit of a quicker onset (~15 minutes) in general than the oral formulations. The downside to these nasal formulations is bad taste, which is frequently reported by patients. Patients should be counseled in proper administration of these nasal sprays (ie, avoiding inhalation, which causes the medication to enter the mouth) to minimize the bad taste and maximize absorption through the nasal mucosa. Other alternatives are the oral dissolving forms (rizatriptan and zolmitriptan). Given the FDA approval, the rizatriptan melt tablets are often the first-line triptan for children under age 12, but zolmitriptan melts are an option as well.

Preventive Treatment

General Approach

The decision to place an adolescent on a daily preventive medication should be based on a combination of headache frequency, severity, ease of breaking headaches, and overall disability as established by a disability scale (such as the PedMIDAS). Any patient with headaches occurring one or more days per week, those whose headaches are not easily treated or tend to be prolonged, and those with a PedMIDAS score of 30 or more should be considered candidate for a daily preventive. It is particularly important to consider starting a preventive early in adolescent patients given the possibility of impacting overall disease progression at a young age. While the natural history of headaches that start in the young is still being investigated, a known risk factor for transformation of episodic to chronic migraine is frequent headaches [32].It is therefore imperative to attempt to intervene early to improve quality of life in the present and also to prevent a downward cycle into chronicity, potential medication overuse, and worsening disability.

At present, there are several classes of medications that are commonly used for migraine prevention, including antidepressants, antiepileptics, antihistamines, and antihypertensives. Patients should be educated regarding the medication’s typical use, the specific way in which it is used in migraine, potential side effects, and overall expectations of efficacy. Most preventives need to be titrated up slowly to maximize tolerability, and patients need to understand that it may take time before they start to see results. In general, we recommend titrating up over the course of 4 to 12 weeks (depending on medication and dose goal), and then a substantial trial of 4 to 6 weeks on a full dose of medication before determining efficacy. If a medication shows a trend towards improvement but the patient has not met treatment goals, medication can be titrated up further at that point as tolerated. Patients and families should also understand that these medications are not intended as a “cure” for migraine but rather as a tool for improvement, which should be used in conjunction with the rest of a detailed plan. Generally, if a patient is well controlled for 4 to 6 months (ie, 3 or less headaches/month that are easily broken with medications, and a PedMIDAS < 30), attempts should be made to wean off of medication.

Medications

First-line Therapies

Currently, topiramate is the only medication approved for prevention of migraine in patients 12 years and older (approved in March 2014). Three randomized double-blind placebo-controlled trials in children and adolescents have found topiramate to be superior to placebo in multiple endpoints [33–35].Doses in these trials were 2–3 mg/kg/day, 100 mg/day, and 50 or 100 mg/day, respectively. Notably, the 50 mg/day dose was not found to be superior to placebo. Multiple retrospective, open-label, and drug comparison trials have shown effectiveness and tolerability as well [36–42].We typically use a goal dose of 2 mg/kg/day, which is reached after titrating over 8 to 12 weeks, which minimizes side effects (most commonly paresthesias, memory/language dysfunction, appetite suppression, and drowsiness), but higher doses can be used if needed.

Amitriptyline has consistently shown efficacy in adult migraine trials and is therefore one of the most commonly used medications worldwide for prevention of migraine in children and adolescents. Surprisingly, there have been no published randomized controlled trials using amitriptyline in the pediatric population, although a trial comparing amitriptyline, topiramate, and placebo is currently underway (Childhood and Adolescent Migraine Prevention Study) [43].In 2 retrospective pediatric studies improvement with amitriptyline was reported in 84.2% and 89% of patients, respectively [44,45].We typically use a goal dose of 1 mg/kg/day, also with an 8- to 12-week titration. The most common side effects with amitriptyline are somnolence, dry mouth, and weight gain, but it is generally well tolerated in children and adolescents. There is also a risk of worsening depression and suicidal thoughts, so it is recommended to use caution if considering prescribing to a patient with underlying depression. It is typically administered in once daily dosing a few hours before bed to minimize morning drowsiness. There is also a concern for precipitation of arrhythmias, and while there are no guidelines recommending screening ECGs, this should be considered in patients with a family history of heart disease. Of note, many practitioners use nortriptyline in place of amitriptyline as it can be less sedating. It should be noted, however, that evidence for its efficacy is lacking. Additionally, it may carry a higher risk of arrhythmia [44].

Second-line Therapies

The second-line therapies typically considered are other antiepileptics, valproic acid, levetiracetam, and zonisamide, for which there is some evidence, although mostly in the form of open-label or retrospective studies [46–51]. Of note, despite the many promising retrospective and open-label studies for valproic acid [46–48], one randomized double-blind placebo control trial comparing various doses of extended release divalproex sodium with placebo in adolescent patients failed to show a statistically significant treatment difference between any dose and placebo [52].It is, however, frequently prescribed and anecdotally quite efficacious. Given concerns about potential for teratogenicity, and possible effects on ovarian function, as well as potential for weight gain and hair loss, it should be used with caution in adolescent females.

Antihypertensives (beta blockers and calcium channel blockers) have long been used for prevention of migraine in both the adult and pediatric population, but evidence for their use in the pediatric population is conflicting. An early double-blind crossover study of propranolol in patients 7 to 16 years old showed significant efficacy as compared with placebo [53].However, in 2 subsequent studies it failed to show efficacy as compared with placebo and self-hypnosis, respectively [54,55].Given the conflicting evidence and the potential for hypotension, depression, and exercise-induced asthma, use of propranolol has fallen out of favor by experts for use in pediatric and adolescent migraine prevention. Flunarizine, a nonselective calcium channel blocker, has demonstrated effectiveness in pediatric migraine prevention [56,57],and is actually approved in Europe for this indication, but it is not available in the United States.

Cyproheptadine is an antihistamine with antiserotonergic properties which is used frequently for migraine prevention in young children who are unable to swallow tablets, although evidence is limited to 1 retrospective study [45].However, given the propensity for weight gain with this medication, it is generally not recommended for use in adolescents.

In recent years, there has been a growing interest in nutraceuticals given their general tolerability and minimal side effects, as well as a comfort in using a more “natural” approach, particularly in pediatrics. Evidence is limited but some of the frequently used substances may be beneficial. Butterbur (petasites hybridus) has strong evidence in adults and is recommended by the AAN for migraine prevention in adults [58].There is one small pediatric RCT showing efficacy for butterbur as compared to music therapy [59],as well as one promising open-label trial [60]. Typical dosing ranges from 50–150 mg daily. However, butterbur contains pyrrolizidine alkaloids, which are hepatotoxic, and due to the concerns for inadequate monitoring of removal of these substances in the manufacturing of commercial butterbur, it has been generally avoided in the pediatric population. Coenzyme Q10 (CoQ10) is considered possibly effective for adult migraine prevention by the AAN [58].Pediatric evidence is limited to an open-label study showing improvement with supplementation of CoQ10 in deficient patients [61],and a subsequent double-blind placebo-controlled add-on study, which showed improvement in both the CoQ10 and placebo groups but faster improvement in the CoQ10 group [62].Typical pediatric dosing is 1–2 mg/kg/day. Magnesium is considered by the AAN to be a good option for migraine prevention in adults [58].One randomized controlled trial in children however had equivocal results [63],while one small prospective open-label study had positive results [64]. Magnesium supplementation may be more effective in patients who have low ionized magnesium levels, but this is difficult to measure reliably in the clinical setting. Doses of 9 mg/kg/day can be used with the most common side effects reported being gastrointestinal upset and diarrhea, generally dose dependent. Riboflavin is also considered by the AAN to be probably effective for prevention in adults [58],but again the evidence in children is limited to one positive retrospective study [65]and 2 equivocal randomized controlled trials [66,67],one of which had an unusually high placebo rate [66]. Appropriate dosing is also something of debate, as riboflavin is minimally absorbed and has a short half-life, so while studies were done using 200–400 mg daily, smaller more frequent dosing may be needed.

A potential approach to treatment with vitamins is to check for deficiencies, but currently only the study mentioned above in which CoQ10 levels were checked showed improvement with normalizing of low levels [61,62].Further research into this topic is needed to elucidate whether checking and repleting levels of specific vitamins would be beneficial in prevention of migraines in certain patients.

Healthy Habits

The importance of maintaining healthy lifestyle habits and modifying potentially detrimental ones should be stressed to patients and families, and counseling regarding these issues should be provided at every visit, as repetition is often key to patients understanding their importance. Skipping meals is a commonly reported migraine trigger [68,69].This is not an uncommon occurrence even in the most well-meaning of families; adolescents often report not feeling hungry in the morning, and in the rush to get to school will often skip breakfast. Many patients report not liking school lunches leading them to go most of the day without food. Adolescent girls may skip meals due to weight concerns. Patients need to be reminded that well-balanced meals throughout the day is imperative, and they often may need specific counseling on how to achieve this practically. Of note, unless a specific migraine trigger has been identified in a given patient, we do not generally recommend restricting any specific food lists.

Maintaining good sleep hygiene and a consistent sleep schedule is also often difficult for adolescent patients, with after-school activities, homework, and screen use (eg, television, electronic devices) often contributing to late bedtimes with then forced early morning waking for school. However, improvement in sleep hygiene has been shown to be effective in improving migraines in children and adolescents [70],and realistic plans for improvement in sleep should be discussed with patients.

Dehydration is also a common migraine trigger [8,9],so the importance of staying well hydrated should be stressed as well. Again, specific recommendations for how this can be achieved are often needed, especially given adolescents’ busy schedules. Additionally, many schools do not allow water bottles to be carried, and often a school note is needed so patients may be allowed to carry a water bottle at school and also be provided extra bathroom breaks as needed.

Also important is stressing maintenance of daily functioning throughout migraine treatment. By the time adolescents seek medical care, they may already be in a cycle of missing school due to headaches, and some may even be receiving home-schooling. The goals of staying in school and learning to function with headaches should be stressed, often with the help of coping skills, which will be discussed below, as it has been shown that functional disability generally improves before pain [71].

Behavioral Treatments

Psychological treatments are an important aspect of migraine management. Biobehavioral treatments such as relaxation training, biofeedback, and multimodal cognitive behavioral therapy (CBT) have been evaluated in randomized controlled trials and reviewed in meta-analyses in pediatric migraine populations and found to be efficacious [72–75].These treatments have been shown to reduce pain intensity and disability for children and adolescents with headaches and therapeutic gains appear to be maintained [72].

Relaxation training typically includes instruction in techniques such as diaphragmatic breathing, progressive muscle relaxation, and guided imagery. Relaxation training is most effective with children 7 years of age or older [76].Biofeedback is often used in conjunction with relaxation training to provide audio or visual feedback about normally unconscious physiological body responses associated with increased relaxation. Effective biofeedback parameters used with children and adolescents with migraine headache include electromyographic (EMG) activity and peripheral skin temperature [77].Biofeedback techniques can help children and adolescents become more aware of physical responses, better control these responses and generalize physical responses outside of therapy sessions to better cope with pain [76].CBT involves instruction in skills such as biofeedback-assisted relaxation training, activity pacing, distraction, and cognitive strategies for coping with pain. CBT was shown to be effective in a recent study comparing adolescent patients with chronic migraine receiving amitriptyline and CBT with patients receiving amitriptyline and standard headache education [78]. Patients who received CBT plus amitriptyline had greater reductions in days with headache and migraine-related disability compared with patients who received headache education plus amitriptyline [78].Hypnosis and acceptance and commitment therapy (ACT) are also psychological treatments used with children and adolescents with migraine headaches. ACT prioritizes the outcome of improved functioning above headache reduction and has broadly demonstrated efficacy for chronic pain [79]. Both treatments have shown promising benefit but there has been less evidence supporting the use of these therapies in pediatric headache than other well-established behavioral treatments.

The presence of comorbid psychiatric issues such as anxiety, depression, or ADHD can make the treatment of patients with migraine headaches more complex. A recent study found that approximately 30% of a sample of children and adolescents with chronic daily headache had a lifetime psychiatric diagnoses and having a lifetime psychiatric diagnosis was associated with poorer headache-related disability and quality of life [80].As a result, more intensive behavioral treatment for children and adolescents with a psychiatric comorbidity may be needed to focus on emotional and behavioral issues.

Pediatric psychologists can assess pain-related disability and coping difficulties and treat children and adolescents with migraine headaches. Children are often referred to a psychologist or other mental health professional if headaches are severe or impairing functioning. Unfortunately, access to this therapy is sometimes limited, but when available, should be offered to any migraine patients with significant disability requiring prevention, and specifically to patients with chronic migraine.

• How should the patient be treated?

Acute Treatment

The patient reports only minimal response to ibuprofen. However, he is only taking 200 mg and does not take it until well after the headache has started. He should be instructed to take ibuprofen 600 mg (~10 mg/kg) as soon as the headache starts, along with 32 oz of a sports drink, and told that he should repeat this dose in 4 hours if his headache has not completely resolved with the first dose. As his headaches are occurring less than 3 times per week on average, he can do this with every headache. He should be given a note for school allowing him to receive the medication at school, and noting the importance of allowing him to get the medication as soon as he reports a headache. Given that some of his headaches occur on consecutive days, we suspect some may be continuations of a prior headache, so again the importance of obtaining complete pain relief from his acute medication should be stressed. If at his next follow-up visit he reports not always having complete relief with ibuprofen, we would consider trying naproxen instead, and/or adding a triptan, most likely sumatriptan 100 mg given its availability. He would need to understand that he may only use the triptan for 4 to 6 headache days/month. Depending on his response to sumatriptan, it could be used alone or in combination with his NSAID. He also may be instructed to use an NSAID alone for more mild headaches and his NSAID together with sumatriptan for more severe headaches.

Preventive Treatment

PedMIDAS score is a 25, indicating mild disability, however his migraines are frequent, occurring 1–3 times per week and clearly having a significant impact on his functioning. We would therefore recommend starting a prophylactic medication. He notes difficulty remembering to take medications as well as difficulty falling asleep, so amitriptyline would be a good choice for him. For his weight of 50.9 kg, we would start with at 12.5 mg at night and increase by 12.5 mg every 2 weeks to a dose of 50 mg (~1mg/kg/day). He and Mom should be counseled that it will likely take at least a few weeks on his goal dose before they start to see results. He should be counseled also to report to Mom immediately if he has any depressive or suicidal thoughts. Topiramate is another option, especially as it is FDA-approved for migraine prevention in children older than 12 years, although twice daily dosing may be a factor in maintaining compliance. Careful discussion with the patient and family in regards to the potential risks and benefits is important prior to starting any preventative medication.

Biobehavioral Management

The patient should be drinking 8–10 cups of non-caffeinated fluid per day and additional cups on days he plays soccer. He should be given a school note to this effect so he may carry a water bottle at school. He eats well, but the importance of not skipping breakfast should be stressed, and ideas for fitting this in should be given. The importance of a consistent bedtime routine should be stressed, with good sleep hygiene to assist with easier sleep onset. It should be made clear that he should not be using screens within an hour prior to bed. He already exercises frequently and should be commended for being active. Given his report of frequent headaches which are impairing school attendance, functioning at school, and participation in soccer activities, screening for potential co-morbid psychiatric issues and making a referral for further treatment with a pediatric pain psychologist focused on coping with chronic pain is appropriate.

Case Study 2

Initial Presentation and History

A 16-year-old right-handed girl who has been having headaches since she was 10 years old presents for evaluation. She reports unilateral mostly right-sided headaches, which are throbbing and associated with photophobia, phonophobia, osmophobia, nausea, and occasionally vomiting. She has no premonitory or aura symptoms. Her headaches typically occur once a week but she has noted that they tend to be more frequent around the time of her menses and that often these headaches do not fully respond to naproxen, which typically works to break her migraines during other times in the month. Upon further review, she believes these headaches typically start on the day or two prior to her menses, and that this happens almost every month. She often misses school due to these headaches. Her mother would like to know whether the patient should see a gynecologist to potentially be placed on birth control to control her headaches.

Physical Examination

On examination, weight was 61.5 kg (75.8 percentile), height 157.1 cm (18.4 percentile), BMI 24.91 (84 percentile), blood pressure 112/55 mm Hg, and heart rate 90 bpm. Her general physical and neurologic exam results were normal. She had tightness over the left trapezius muscles, otherwise the remainder of headache examination was unremarkable.

• What is the probable diagnosis?

According to the ICHD-IIIβ, the patient meets criteria for episodic migraine without aura. Based on the history, she likely also has menstrually related migraine without aura [5].Officially, however, 3 months of prospective documentation is needed to make this diagnosis. Menstrually related migraine is included in the appendix of the ICHD-IIIβ, meaning there is ongoing debate about how it should be classified. According to the current appendix criteria, headaches should meet criteria for migraine without aura and also have documented and prospectively recorded evidence over at least 3 consecutive cycles with headaches confirmed on day 1+/– 2 (ie, 2 days prior to onset of menstruation or within the first 3 days of menstruation) in at least 2 out of 3 menstrual cycles, with migraines occurring during other times of the month as well [5]. This is distinguished from pure menstrual migraine without aura, in which migraines occur only during days 1+/–2 of menstruation but not during other times of the month [5].While we therefore cannot say that the patient meets ICHD IIIβ criteria for menstrually related migraine due to the lack of prospective documentation, her history suggests this.

Menstrually Related Migraine

An association of migraine with menses is well described in adults, occurring in up to 60% of adult female migraine patients [81].In adults, it has been observed that the migraines associated with the menstrual cycle tend to be more severe [82],associated with more nausea and vomiting [82],longer and less responsive to acute medications [83],and associated with more work-related disability [83]. Recently, analysis of data from the American Migraine Prevalence and Prevention (AMPP) Study found that women with pure menstrual migraine and menstrually associated migraine have on average higher MIDAS scores than those with non-menstrual migraine [81].

Only one study has explored menstrually related migraines in adolescents [84].It was a clinic-based study that found a similar prevalence—50% of adolescent patients who had reached menarch noted an association of migraine with their menses. Overall worse disability was not demonstrated in this study, but individual menstrual attacks were not compared with nonmenstrual attacks [84].No other studies have addressed this population, but it is clear that the pattern of menstrually related migraine exists in adolescents and it is important to recognize this pattern as these patients may require additional focused care in addition to standard migraine management.

• What are treatment options?

In adults, options for more specific management of pure menstrual migraine and menstrually related migraine include intermittent prophylaxis with NSAIDs or triptans or use of hormonal contraceptives. There are no studies addressing any of these treatments in adolescents, so at this point management decisions must be based on evidence extrapolated from adult studies as well as attention to specific concerns in adolescent patients.

Generally, intermittent prophylaxis (using a medication a few days prior to and during the first few days of menses) with various medications has shown efficacy in adult studies. This approach may be more appropriate for patients with pure menstrual migraine, as there is less likelihood of precipitating medication overuse in this population. It can be considered in patients with menstrually related migraine as well if typical daily preventives have not been effective. One small open-label trial using naproxen 550 mg daily prior to and during menses (at differing schedules depending on the month) showed slightly decreased frequency and severity of headaches during that time [85].However, triptans are what are most commonly used.

Triptans

Frovatriptan is the longest-acting triptan and the one used most commonly for intermittent prophylaxis. One double-blind randomized controlled crossover study showed improvements in headache frequency, severity, and duration using frovatriptan 2.5 mg BID for 6 days total starting 2 days prior to menses [86].Frovatriptan 2.5 mg daily showed some efficacy as well but was not as effective as 2.5 mg BID [86].One prospective randomized placebo-controlled trial demonstrated more headache-free cycles using frovatriptan 2.5 mg BID for 6 days total starting 2 days prior to menses, as compared to placebo [87].

Naratriptan, also a longer-acting triptan, was studied in 3 prospective double-blind trials at doses of 1 mg BID used for 5 days total starting 2 days prior to menses, and all 3 showed a decrease in headache frequency as compared to placebo [88,89].Of note no efficacy was shown using 2.5 mg daily [88].

Less commonly used for intermittent prophylaxis are the shorter-acting triptans, but they have shown some efficacy as well. In one prospective study using oral sumatriptan 25 mg TID for 5 days each cycle starting 2 to 3 days before onset of menses, there seemed to be at least some improvement with sumatriptan in most cycles treated [90].Zolmitriptan was studied in one prospective double-blind placebo-controlled study using 2.5 mg BID or 2.5 mg TID for 7 days total with each cycle and was found to be associated with a significant reduction in headache frequency as compared with placebo [91].There has been one prospective trial using eletriptan 20 mg TID for 6 days total starting 2 days prior to menses, which also showed improvement in headache activity in 55% of patients [92].

Hormonal Contraceptives

In general for adult patients, hormonal contraceptives are not considered first-line treatment for menstrually related migraine. However, in patients who do not respond to other modes of treatment, or who plan to use hormonal contraception for contraceptive purposes, published expert opinions have recommended considering extended or continuous hormonal regimens [93,94].

Estrogen withdrawal during the luteal phase of the monthly cycle has long been speculated to be of importance in the pathophysiology of menstrually related migraine [93]and the relationship between hormonal contraceptives and migraine is complicated. Headache is a commonly reported side effect of combined hormonal contraceptives [95]; however, this effect seems to occur mostly during the hormone-free week [96]. It has been shown that headache occurs less frequently in women using an extended cycle regimen (84 or 168 days) as compared to those using a traditional monthly cyclic regimen [97,98].Studies addressing the use of combined hormonal contraceptives for women specifically with menstrually related migraine are limited. One small prospective randomized study showed improvement in menstrually related migraine in patients treated with a low dose (20 mcg ethinyl E[2]) oral hormonal contraceptive in both a 21/7 cycle and a 24/4 cycle, with more improvement in the group using a 24/4 cycle [99].Another showed improvement in menstrually related migraine in all study patients treated with a low-dose hormonal contraceptive (20 mcg ethinyl estradiol) on a 21/7 regimen, but with additional 0.9 mg conjugated equine estrogen during the placebo week [100].There has been one randomized placebo-controlled double-blind trial in patients with menstrually related migraine using an extended 168 hormonal regimen along with frovatriptan vs. placebo for 5 days during the hormone-free interval. Overall daily headache scores were decreased from pre-study cycles, and the increase in headaches during the hormone-free interval was lower in the frovatriptan group [101].A recent study showed that contraceptive-induced amenorrhea can be beneficial for decreasing migraine frequency in patients with menstrual migraine [102].There have been no studies addressing the use of hormonal contraceptives for migraine management in adolescents.

In adolescents, the decision regarding use of hormonal contraceptives is more complicated. There is less of a chance that adolescent patients, especially younger ones, would be planning to use hormones for contraception so their use may be solely for the purpose of migraine management. However, hormonal contraceptives are commonly used in adolescents for management of other menstrual-related disorders, such as menorrhagia, dysmenorrhea, and endometriosis, and extended cycle and continuous regimens have become more popular with adolescent providers in general [103].The general concern with using hormonal contraceptives in adolescents is that they have potential for longer-term use than adult patients, and the effects of using hormonal contraceptives long term are unknown. The major concerns are for potential interference with expected increase in bone mineral density in adolescents, effects on fertility, and risk for cancer and cardiovascular disease [103].Additionally, specifically in migraine patients, is the concern for increased stroke risk. The increased risk for ischemic stroke in patients with migraine, although more specifically with migraine with aura, is well known [104–106]and migraine has recently been shown to be a risk factor for ischemic stroke in adolescents as well [107]. In adults, the use of hormonal contraceptives in patients with migraine with aura is known to increase the risk of ischemic stroke [106],and this has not been studied in adolescents. Given the various unknowns in the use of hormonal contraceptives in patients with menstrually related migraines, we would not recommend this as first-line treatment. However, similarly to adults, in patients who do not respond to other methods of migraine management, or who seek to use hormonal contraceptives for contraception or for other menstrually related disorders, extended or continuous cycle hormonal contraceptives may be a reasonable option, at the lowest possible estrogen dose. However, migraine with aura should be screened for, and its presence should prompt reconsideration of combined hormonal contraceptive use.

• How should this patient be managed?

The patient is having frequent and disabling migraines, so starting a preventive medication would be appropriate. She has migraines throughout the month in addition to during her menses, so a daily prophylactic would be more appropriate than intermittent prophylaxis surrounding her menstrual cycle only. At this point, our recommendation would be to start a daily preventive with either amitriptyline or topiramate. Given that naproxen is not breaking some of her migraines, she should be given a prescription for a triptan. Sumatriptan 100 mg would be an appropriate first choice, and she can be instructed to use it along with her naproxen at the onset of her menstrual migraines. She can use it for other migraines as well but she should be instructed not to use it more than 4 to 6 times per month. She should keep a diary for the next 3 months noting most importantly headache days as well as days of menstruation, so that a more definitive pattern can be confirmed and an official diagnosis based on ICHD-IIIβ criteria can be made. If her migraines do not improve with daily preventives, at that point discussion regarding potential for intermittent prophylaxis or trial of extended cycle hormonal contraception may be considered, although with caution and discussion of risks and benefits.

Corresponding author: Hope O’Brien, MD, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave., MLC 2015 Cincinnati, OH 45229.

Financial disclosures: None.

From the Cincinnati Children’s Hospital Medical Center, Cincinnati, OH.

Abstract

• Objective: To review the management of migraine in adolescent patients.
• Methods: Literature review in the context of 2 clinical cases.
• Results: Migraine is common in adolescents and can affect school and social functioning. Management options include lifestyle modifications and acute and preventative therapies. First-line medications for migraine in the adolescent population are over-the-counter medications, including ibuprofen, acetaminophen, and naproxen. Studies of efficacy of triptans in the treatment of pediatric migraine have been limited and results conflicting, largely due to high placebo response rates. Several classes of medications are commonly used for migraine prevention, including antidepressants and antiepileptics. Currently, topiramate is the only medication approved for prevention of migraine in patients 12 years and older. Biobehavioral treatments such as relaxation training, biofeedback, and cognitive behavioral therapy have been evaluated in randomized controlled trials and found to be efficacious.
• Conclusion: Approach to management of migraine in adolescents should be multifactorial with attention to an aggressive acute treatment regimen, preventive medications when indicated, and biobehavioral management.

Case Study 1

Initial Presentation

A 13-year-old left-handed boy with allergic rhinitis has been referred by his pediatrician for evaluation of headaches.

History

The headaches have been occurring since he was 7 years old. He describes a bilateral frontal and periorbital pain, which is either aching or throbbing in nature. There is associated photophobia and phonophobia, and the pain worsens with activity. When he was younger the headaches were frequently associated with emesis. He occasionally gets tenderness of his face during the headaches, mostly in the areas adjacent to his nose and above his eyes and occasionally associated rhinorrhea.

Initially the headaches were mild and occurring infrequently, but for the past 6 months they have been more severe and occurring 1 to 3 times per week, sometimes on consecutive days. They typically begin in the afternoon but at times occur soon after waking in the morning. If they do occur in the morning, they worsen after getting out of bed. He denies any type of warning symptoms indicating the headache will occur, and has no associated focal neurologic symptoms associated with the headaches. His mother tries to minimize medication intake so will typically wait to see if the headache is severe before giving him medication, typically 2 chewable children’s ibuprofen, which helps some of the time; however, his headache often does not completely abate unless he naps. He has also been taking loratadine daily due to concerns that his headaches may be secondary to chronic sinusitis.

He is a good student and enjoys school, but notes stress surrounding tests. He reports missing 4 days of school in the past 3 months as well as coming late twice. He thinks that there were 9 additional days in which he was unable to function at his full ability at school and at least 5 times he was unable to concentrate on his homework. He plays soccer 4 to 5 times per week. He says twice he had to skip soccer practice to due to headache and at least 3 other times he needed to take breaks during soccer due to headache. He is unsure how much he drinks on an average day but he drinks mostly with meals. He does not drink caffeine. He gets into bed at 10 pm and sometimes does not fall asleep until after 11 pm, often due to worry about tests. He often plays with his tablet when trying to fall asleep. He wakes up at 6 am for school. He typically eats 3 meals per day but occasionally misses breakfast if he is rushed in the morning.

Physical Examination

On examination, the patient is a well-developed, well-nourished male in no apparent distress. His weight was 50.9 kg (68th percentile), height 163.7 cm (65th percentile), BMI 19.9 (69th percentile), blood pressure 118/62 mm Hg, and heart rate 79 bpm. His general physical examination, including skin, HEENT, extremities, lung, cardiac, and abdominal examination was normal, with lungs clear to auscultation, heart with a regular rate and rhythm, and abdomen soft and tender without organomegaly.

On neurologic examination he was alert and attentive with normal mental status. Speech was fluent. Skull, spine, and meninges were normocephalic and atraumatic with a supple neck. Cranial nerves II through XII were normal with a normal fundoscopic examination including sharp disk, no papilledema, and normal fundus bilaterally. Motor examination was normal for tone and bulk with full strength throughout. Sensory examination was normal for light touch, temperature, vibration, and joint position sense. Finger-nose-finger fine finger movement and heel-knee-shin were normal. Deep tendon reflexes were symmetric and 2+ throughout with toes downgoing. Station and gait were normal including toe walking, heel walking, tandem walking, running, skipping, one-legged standing, Fog gate procedure, and there was no Romberg’s sign.

He had a normal comprehensive headache examination. There was no tenderness at typical migraine trigger points (nuchal line and mandibular process) and no tenderness at supraorbital notch. Neck was supple with normal rotation and normal bilateral trapezius muscle tightness. No bruits or palpitations were heard over carotid or jugular veins. There was a negative Muller sign with no pain on neck bending with pressure, and no signs of allergy or sinus symptoms.

• What is the initial evaluation of a teen with recurrent headaches?

The overwhelming majority of children and adolescents presenting to medical attention with recurrent headaches will have a primary headache disorder, most commonly migraine [1].However, ruling out a secondary cause is typically of concern, both for providers and parents, and the decision regarding whether to image is often a daunting one. In a review of 6 large studies in which imaging was done in pediatric patients who were examined by a neurologist, only 14 patients were found to have CNS lesions requiring intervention, and all of these patients had abnormalities on physical exam [2]. An American Academy of Neurology (AAN) practice parameter published in 2002 recommended considering neuroimaging only in patients with abnormal neurologic examination, co-existing seizures, concerning associated neurologic features, or recent onset of severe headache or change in headache type [2].There are additional factors which may prompt one to consider imaging as well including atypical auras or very short (< 5 minutes) or protracted ( > 60 minutes) auras, trigeminal autonomic cephalalgia, brief headaches precipitated by cough, frequent early morning headaches or which wake the patient from sleep, headaches with primarily occipital location, headaches in a patient less than 6 years old or in a child who cannot describe the headaches well, or migrainous headaches in a child without any family history of migraine or migraine equivalents. However, recent studies continue to show that the imaging yield in patients with headaches is low and further studies are needed to elucidate which patients truly require imaging [3].

Given this, a thorough history, family history, physical exam, and detailed neurologic exam including fundoscopy are imperative. In addition to the general neurologic exam, a focused headache exam should be performed, including Mueller’s maneuver, auscultation for cranial bruits, evaluation of the temporomandibular joint, palpation of possible trigger points, and maneuvers to assess for cervical spine disease [4].

Classification of Symptoms         

Once establishing the likelihood of a primary headache disorder, the International Classification of Headache Disorders, 3rd edition, beta version (ICHD IIIβ) [5]should be used to classify the headache diagnosis. Note that while this classification system was established for adults, most criteria are similar for children and adolescents, and the typical differences are noted in the comments of the ICHD IIIβ [5].Migraine is the most common type of primary headache brought to medical attention [1]. Migraine without aura is described as a recurrent headache disorder (at least 5 lifetime attacks) with attacks lasting 4 to 72 hours, typically unilateral, throbbing in nature, moderate to severe in intensity, aggravated by routine physical activity, and associated with nausea and/or photophobia and phonophobia. In young children, migraine is more frequently bilateral, the gastrointestinal symptoms often more pronounced than photophobia and phonophobia, and migraines may be shorter, lasting at least 2 hours without treatment [5].As patients reach adolescence, migraine features typically start to evolve into patterns described in adults. Differentiating migraine from other primary headaches, such as tension-type, can be challenging, especially in children in whom migraines are more likely to be shorter and bilateral. Tension-type headaches are bilateral or diffuse, pressing or tightening pain that is non-pulsatile lasting at least 30 minutes. The pain is described as mild to moderate in intensity and not aggravated by activity [5].They may be associated with photophobia or phonophobia (not both) and they may not be associated with nausea or vomiting [5].

• Is any further workup indicated?

The patient has recurrent headaches which have been present for 5 years. While they have increased in frequency, there has not been any change in their quality. His headache description and history have no “red flag” features, and a thorough examination is normal. Therefore, neuroimaging and further workup would not be indicated in this case.

• What is the diagnosis?

The patient’s headaches are throbbing in nature, exacerbated by activity, associated with nausea, photophobia, and phonophobia, and are moderate to severe. Using the ICHD IIIβ, he meets criteria for migraine without aura. While his headaches are frequent, he is having less than 15 headache days per month, so this is episodic migraine. Note that he complains of forehead and periorbital pain and occasional rhinorrhea with his headaches, leading him to have been placed on loratadine for treatment of presumed allergic sinusitis. Children meeting criteria for migraine are very frequently misdiagnosed as having sinusitis [6]due to the overlap in location of migraine pain and proximity to the frontal and maxillary sinuses, as well as the presence of autonomic features frequently present in migraine, reportedly present in 70% of pediatric migraine patients [7].The negative headache examination, including Muller’s maneuver, points against sinus disease as well.

• What is the approach to management of the adolescent with migraine?

Approach to management of migraine in adolescents should be multifactorial, with attention to an aggressive acute treatment regimen, preventive medications when indicated, and biobehavioral management.

Acute Treatment

General Approach

In counseling patients with migraine, and in particular adolescents, it should be stressed that achieving a normal level of functioning as soon as possible is the goal of therapy. Common missteps in treatment include failure to take acute medication early into the headache, incorrect dosing, incompletely treating the headache, and avoidance of participating in daily activities when headaches occur.

Adolescent patients may frequently wait to take an acute medication, typically due participation in another activity, not having medication with them, or discomfort with taking medication in front of peers or at school. Additionally, patients who have headaches beginning in early childhood, with pronounced gastrointestinal (GI) features, may be aware that their headaches resolve after vomiting, and therefore get used to not treating with medications. When these patients reach adolescence, when GI symptoms tend to become less pronounced, they will need to be educated that taking medication early is imperative. Acute medications are typically more effective when taken earlier in the course of a migraine, and the importance of pausing to take medication at the onset of the headache should be stressed to all patients and parents. With that in mind, however, care should be taken to counsel patients regarding the potential for development of medication overuse headache. When headaches are frequent, a more detailed and intricate plan may need to be devised so that adolescents and parents know which headaches to treat with medication.

Given that first-line medications for treatment of migraines are over-the-counter, underdosing occurs commonly, as dosing listed on packaging is typically age-based, not weight-based. At initial visits, young adolescent patients will frequently report that a particular medication is not effective, but this is often because they are still receiving low/less optimal dosing. Clinicians should remember to follow weights and recommend dosing changes at the initial visit and follow-up visits as well.

Treatment goals, ie, complete resolution of pain and migrainous features with ability to return to normal functioning, should be made clear to patients and families at the onset of treatment. Patients frequently fall into a pattern of continuing to treat with a medication that may lessen but not completely ablate the pain of a headache, and then sleep and avoid activity. Upon awakening, the headache may be gone, however, given incomplete initial treatment, the headache may be more likely to recur within 24 hours. At that point, the headache may be more difficult to treat and therefore cause further decrease in functioning. If this cycle perpetuates, disability can become extremely burdensome in adolescents, significantly affecting school and social functioning. Therefore, a detailed plan for initial steps in management as well as steps to take should initial therapy fail to fully break the headache should be given to every patient.

Of note, given that dehydration is now recognized as a common trigger for migraine [8,9], it is generally our recommendation to drink 16 to 32 oz (depending on weight) of a hydrating fluid together with whichever acute medication is chosen, as rehydration likely assists in breaking migraines as well [8].

Medications

Over-the-Counter Agents

The first-line medications for migraine in the pediatric and adolescent populations are over-the counter medications, including ibuprofen, acetaminophen, and naproxen sodium. Ibuprofen has been well studied in pediatrics and was found to be safe and effective in 2 studies [10,11]at doses of 7.5–10 mg/kg. Again, care should be taken to ensure timely administration of ibuprofen at onset of headache, or aura if present, with appropriate weight-based dosing. Naproxen sodium has not been studied in pediatrics for treatment of migraine. However in practice, it is often used in similar doses of 10 mg/kg, with good efficacy. Although ibuprofen and naproxen sodium are both nonsteroidal anti-inflammatory medications (NSAIDs), anecdotally many patients report successful treatment with one NSAID when another has failed. Aspirin has shown efficacy in adults for treatment of acute migraine [12].It is likely effective in the pediatric population as well, but it is generally avoided due to long-standing concerns for precipitation of Reye syndrome in children. In adolescents over 16 years old, however, it is a reasonable option if there are no contraindications.

In one study, acetaminophen was compared to ibuprofen and placebo for treatment of migraine in children and adolescents and found to be effective more frequently than placebo but not as frequently as ibuprofen [10],likely due to its only minimal anti-inflammatory effects. It is a reasonable option for children and adolescents, particularly in those who have contraindications to NSAIDs.

While these over-the-counter medications are generally safe and well tolerated, clinicians should not overlook the potential for toxicity as well as medication overuse headache, and patients should be counseled to avoid use of any of these medications for more than 2 to 3 headache days per week.

Triptans

Studies of efficacy of triptans in treatment of pediatric migraine have been limited and results conflicting, largely due to high placebo response rates. However, some have shown efficacy over placebo, and in the past few years have received FDA approval for use in the pediatric and adolescent populations. Clinicians should remember that these medications are vasoconstrictors, so they should not be used in patients with vascular disease or in patients with migraine with brainstem aura or hemiplegic migraine. Additionally, due to the risk of serotonin syndrome, they should not be used in patients on monoamine oxidase inhibitors. It is also important to educate patients to limit use of these medications to 4 to 6 times per month to avoid precipitation of medication overuse headache.

Almotriptan was approved by the FDA in 2009 for use in patients 12 years and older, based on a large randomized controlled trial comparing doses of 6.25, 12.5, and 25 mg with placebo in patients ages 12 to 17 years old. All doses resulted in statistically significant pain relief as compared to placebo, and interestingly, the 12.5-mg dose seemed to be the most effective [13].

Rizatriptan received FDA approval in 2012 for use in patients 6 years and older. In 2 randomized controlled trials in patients 6 to 17 years old, rizatriptan (5 mg for patients < 40 kg, 10 mg for patients ≥ 40 kg) was more effective than placebo in providing pain freedom at 2 hours [14,15].One earlier trial found efficacy only on some measures (weekend treatment, decrease in nausea and functional disability) but no statistically significant difference than placebo in terms of overall efficacy in achieving pain freedom at 2 hours [16].However, this trial had a higher placebo response rate than typically seen in adult triptan trials. In a recent long-term open-label study in patients 12 to 17 years old, rizatriptan was found to be generally safe and well-tolerated with consistent efficacy of 46% to 51% pain freedom at 2 hours over time [17].

A combination pill consisting of sumatriptan and naproxen (Treximet) received FDA approval in May 2015 for patients 12 years and older. This was based on a randomized controlled parallel-group trial in patients 12 to 17 years old using the sumatriptan/naproxen combination in various dose combinations: 10/60 mg, 30/180 mg, or 85/500 [18].All doses were found to be equally effective in providing pain relief at 2 hours as compared to placebo, with a higher chance of sustained pain relief at 24 hours in the group receiving the 85/500 dose. In this trial, and in a long-term open-label safety trial [19],all doses were generally well tolerated with minimal adverse reactions.

Most recently, in June 2015, zolmitriptan nasal spray was approved for patients 12 years of age and older. In the large “Double-Diamond” study, which used a novel design to attempt to minimize placebo effect, zolmitriptan nasal spray (5 mg) was found to have a significantly higher headache response rate at 1 hour than placebo, and was significantly superior to placebo with regard to multiple secondary end-points [20].Additionally, a long-term open-label trial in patients 12 to 17 years old using oral zolmitriptan (2.5 mg or 5 mg) found it to be generally effective and well tolerated [21].

No other triptans have been approved for children or adolescents, however, most are widely used in clinical practice. There is good evidence for the efficacy and tolerability of sumatriptan nasal spray [22–26]in adolescents, and it is approved for use in adolescents with migraine in Europe. Although oral sumatriptan was the first triptan available clinically in the United States and is very widely used, there is surprisingly little published evidence for its use in the pediatric and adolescent populations. In fact, 2 randomized controlled trials in adolescents failed to show efficacy of oral sumatriptan as compared to placebo [27,28].Despite this, given its availability it is a reasonable choice for adolescent patients and is often one of the first tried. There has been 1 randomized controlled trial in adolescents for eletriptan without significant differences in efficacy at 2 hours as compared to placebo, although similar to other trials the placebo rate was high and there were some differences seen in secondary outcomes measures [29].Similarly, one randomized controlled trial of naratriptan 12.5-mg tablets failed to show efficacy as compared to placebo in pain relief [30].At present time, for frovatriptan there has only been a study looking at the pharmacokinetics and safety in adolescents, which found that it was generally well tolerated and recommended adolescent dosing similar to adult dosing [31].

In choosing a triptan, clinicians should keep in mind availability of alternate forms of administration, absence or presence of significant emesis, and the age of the patient. For patients who are unable to swallow pills or who have significant emesis associated with their migraines, nasal sprays and oral dissolving forms (melts) are good options. The nasal sprays (zolmitriptan and sumatriptan) additionally have the benefit of a quicker onset (~15 minutes) in general than the oral formulations. The downside to these nasal formulations is bad taste, which is frequently reported by patients. Patients should be counseled in proper administration of these nasal sprays (ie, avoiding inhalation, which causes the medication to enter the mouth) to minimize the bad taste and maximize absorption through the nasal mucosa. Other alternatives are the oral dissolving forms (rizatriptan and zolmitriptan). Given the FDA approval, the rizatriptan melt tablets are often the first-line triptan for children under age 12, but zolmitriptan melts are an option as well.

Preventive Treatment

General Approach

The decision to place an adolescent on a daily preventive medication should be based on a combination of headache frequency, severity, ease of breaking headaches, and overall disability as established by a disability scale (such as the PedMIDAS). Any patient with headaches occurring one or more days per week, those whose headaches are not easily treated or tend to be prolonged, and those with a PedMIDAS score of 30 or more should be considered candidate for a daily preventive. It is particularly important to consider starting a preventive early in adolescent patients given the possibility of impacting overall disease progression at a young age. While the natural history of headaches that start in the young is still being investigated, a known risk factor for transformation of episodic to chronic migraine is frequent headaches [32].It is therefore imperative to attempt to intervene early to improve quality of life in the present and also to prevent a downward cycle into chronicity, potential medication overuse, and worsening disability.

At present, there are several classes of medications that are commonly used for migraine prevention, including antidepressants, antiepileptics, antihistamines, and antihypertensives. Patients should be educated regarding the medication’s typical use, the specific way in which it is used in migraine, potential side effects, and overall expectations of efficacy. Most preventives need to be titrated up slowly to maximize tolerability, and patients need to understand that it may take time before they start to see results. In general, we recommend titrating up over the course of 4 to 12 weeks (depending on medication and dose goal), and then a substantial trial of 4 to 6 weeks on a full dose of medication before determining efficacy. If a medication shows a trend towards improvement but the patient has not met treatment goals, medication can be titrated up further at that point as tolerated. Patients and families should also understand that these medications are not intended as a “cure” for migraine but rather as a tool for improvement, which should be used in conjunction with the rest of a detailed plan. Generally, if a patient is well controlled for 4 to 6 months (ie, 3 or less headaches/month that are easily broken with medications, and a PedMIDAS < 30), attempts should be made to wean off of medication.

Medications

First-line Therapies

Currently, topiramate is the only medication approved for prevention of migraine in patients 12 years and older (approved in March 2014). Three randomized double-blind placebo-controlled trials in children and adolescents have found topiramate to be superior to placebo in multiple endpoints [33–35].Doses in these trials were 2–3 mg/kg/day, 100 mg/day, and 50 or 100 mg/day, respectively. Notably, the 50 mg/day dose was not found to be superior to placebo. Multiple retrospective, open-label, and drug comparison trials have shown effectiveness and tolerability as well [36–42].We typically use a goal dose of 2 mg/kg/day, which is reached after titrating over 8 to 12 weeks, which minimizes side effects (most commonly paresthesias, memory/language dysfunction, appetite suppression, and drowsiness), but higher doses can be used if needed.

Amitriptyline has consistently shown efficacy in adult migraine trials and is therefore one of the most commonly used medications worldwide for prevention of migraine in children and adolescents. Surprisingly, there have been no published randomized controlled trials using amitriptyline in the pediatric population, although a trial comparing amitriptyline, topiramate, and placebo is currently underway (Childhood and Adolescent Migraine Prevention Study) [43].In 2 retrospective pediatric studies improvement with amitriptyline was reported in 84.2% and 89% of patients, respectively [44,45].We typically use a goal dose of 1 mg/kg/day, also with an 8- to 12-week titration. The most common side effects with amitriptyline are somnolence, dry mouth, and weight gain, but it is generally well tolerated in children and adolescents. There is also a risk of worsening depression and suicidal thoughts, so it is recommended to use caution if considering prescribing to a patient with underlying depression. It is typically administered in once daily dosing a few hours before bed to minimize morning drowsiness. There is also a concern for precipitation of arrhythmias, and while there are no guidelines recommending screening ECGs, this should be considered in patients with a family history of heart disease. Of note, many practitioners use nortriptyline in place of amitriptyline as it can be less sedating. It should be noted, however, that evidence for its efficacy is lacking. Additionally, it may carry a higher risk of arrhythmia [44].

Second-line Therapies

The second-line therapies typically considered are other antiepileptics, valproic acid, levetiracetam, and zonisamide, for which there is some evidence, although mostly in the form of open-label or retrospective studies [46–51]. Of note, despite the many promising retrospective and open-label studies for valproic acid [46–48], one randomized double-blind placebo control trial comparing various doses of extended release divalproex sodium with placebo in adolescent patients failed to show a statistically significant treatment difference between any dose and placebo [52].It is, however, frequently prescribed and anecdotally quite efficacious. Given concerns about potential for teratogenicity, and possible effects on ovarian function, as well as potential for weight gain and hair loss, it should be used with caution in adolescent females.

Antihypertensives (beta blockers and calcium channel blockers) have long been used for prevention of migraine in both the adult and pediatric population, but evidence for their use in the pediatric population is conflicting. An early double-blind crossover study of propranolol in patients 7 to 16 years old showed significant efficacy as compared with placebo [53].However, in 2 subsequent studies it failed to show efficacy as compared with placebo and self-hypnosis, respectively [54,55].Given the conflicting evidence and the potential for hypotension, depression, and exercise-induced asthma, use of propranolol has fallen out of favor by experts for use in pediatric and adolescent migraine prevention. Flunarizine, a nonselective calcium channel blocker, has demonstrated effectiveness in pediatric migraine prevention [56,57],and is actually approved in Europe for this indication, but it is not available in the United States.

Cyproheptadine is an antihistamine with antiserotonergic properties which is used frequently for migraine prevention in young children who are unable to swallow tablets, although evidence is limited to 1 retrospective study [45].However, given the propensity for weight gain with this medication, it is generally not recommended for use in adolescents.

In recent years, there has been a growing interest in nutraceuticals given their general tolerability and minimal side effects, as well as a comfort in using a more “natural” approach, particularly in pediatrics. Evidence is limited but some of the frequently used substances may be beneficial. Butterbur (petasites hybridus) has strong evidence in adults and is recommended by the AAN for migraine prevention in adults [58].There is one small pediatric RCT showing efficacy for butterbur as compared to music therapy [59],as well as one promising open-label trial [60]. Typical dosing ranges from 50–150 mg daily. However, butterbur contains pyrrolizidine alkaloids, which are hepatotoxic, and due to the concerns for inadequate monitoring of removal of these substances in the manufacturing of commercial butterbur, it has been generally avoided in the pediatric population. Coenzyme Q10 (CoQ10) is considered possibly effective for adult migraine prevention by the AAN [58].Pediatric evidence is limited to an open-label study showing improvement with supplementation of CoQ10 in deficient patients [61],and a subsequent double-blind placebo-controlled add-on study, which showed improvement in both the CoQ10 and placebo groups but faster improvement in the CoQ10 group [62].Typical pediatric dosing is 1–2 mg/kg/day. Magnesium is considered by the AAN to be a good option for migraine prevention in adults [58].One randomized controlled trial in children however had equivocal results [63],while one small prospective open-label study had positive results [64]. Magnesium supplementation may be more effective in patients who have low ionized magnesium levels, but this is difficult to measure reliably in the clinical setting. Doses of 9 mg/kg/day can be used with the most common side effects reported being gastrointestinal upset and diarrhea, generally dose dependent. Riboflavin is also considered by the AAN to be probably effective for prevention in adults [58],but again the evidence in children is limited to one positive retrospective study [65]and 2 equivocal randomized controlled trials [66,67],one of which had an unusually high placebo rate [66]. Appropriate dosing is also something of debate, as riboflavin is minimally absorbed and has a short half-life, so while studies were done using 200–400 mg daily, smaller more frequent dosing may be needed.

A potential approach to treatment with vitamins is to check for deficiencies, but currently only the study mentioned above in which CoQ10 levels were checked showed improvement with normalizing of low levels [61,62].Further research into this topic is needed to elucidate whether checking and repleting levels of specific vitamins would be beneficial in prevention of migraines in certain patients.

Healthy Habits

The importance of maintaining healthy lifestyle habits and modifying potentially detrimental ones should be stressed to patients and families, and counseling regarding these issues should be provided at every visit, as repetition is often key to patients understanding their importance. Skipping meals is a commonly reported migraine trigger [68,69].This is not an uncommon occurrence even in the most well-meaning of families; adolescents often report not feeling hungry in the morning, and in the rush to get to school will often skip breakfast. Many patients report not liking school lunches leading them to go most of the day without food. Adolescent girls may skip meals due to weight concerns. Patients need to be reminded that well-balanced meals throughout the day is imperative, and they often may need specific counseling on how to achieve this practically. Of note, unless a specific migraine trigger has been identified in a given patient, we do not generally recommend restricting any specific food lists.

Maintaining good sleep hygiene and a consistent sleep schedule is also often difficult for adolescent patients, with after-school activities, homework, and screen use (eg, television, electronic devices) often contributing to late bedtimes with then forced early morning waking for school. However, improvement in sleep hygiene has been shown to be effective in improving migraines in children and adolescents [70],and realistic plans for improvement in sleep should be discussed with patients.

Dehydration is also a common migraine trigger [8,9],so the importance of staying well hydrated should be stressed as well. Again, specific recommendations for how this can be achieved are often needed, especially given adolescents’ busy schedules. Additionally, many schools do not allow water bottles to be carried, and often a school note is needed so patients may be allowed to carry a water bottle at school and also be provided extra bathroom breaks as needed.

Also important is stressing maintenance of daily functioning throughout migraine treatment. By the time adolescents seek medical care, they may already be in a cycle of missing school due to headaches, and some may even be receiving home-schooling. The goals of staying in school and learning to function with headaches should be stressed, often with the help of coping skills, which will be discussed below, as it has been shown that functional disability generally improves before pain [71].

Behavioral Treatments

Psychological treatments are an important aspect of migraine management. Biobehavioral treatments such as relaxation training, biofeedback, and multimodal cognitive behavioral therapy (CBT) have been evaluated in randomized controlled trials and reviewed in meta-analyses in pediatric migraine populations and found to be efficacious [72–75].These treatments have been shown to reduce pain intensity and disability for children and adolescents with headaches and therapeutic gains appear to be maintained [72].

Relaxation training typically includes instruction in techniques such as diaphragmatic breathing, progressive muscle relaxation, and guided imagery. Relaxation training is most effective with children 7 years of age or older [76].Biofeedback is often used in conjunction with relaxation training to provide audio or visual feedback about normally unconscious physiological body responses associated with increased relaxation. Effective biofeedback parameters used with children and adolescents with migraine headache include electromyographic (EMG) activity and peripheral skin temperature [77].Biofeedback techniques can help children and adolescents become more aware of physical responses, better control these responses and generalize physical responses outside of therapy sessions to better cope with pain [76].CBT involves instruction in skills such as biofeedback-assisted relaxation training, activity pacing, distraction, and cognitive strategies for coping with pain. CBT was shown to be effective in a recent study comparing adolescent patients with chronic migraine receiving amitriptyline and CBT with patients receiving amitriptyline and standard headache education [78]. Patients who received CBT plus amitriptyline had greater reductions in days with headache and migraine-related disability compared with patients who received headache education plus amitriptyline [78].Hypnosis and acceptance and commitment therapy (ACT) are also psychological treatments used with children and adolescents with migraine headaches. ACT prioritizes the outcome of improved functioning above headache reduction and has broadly demonstrated efficacy for chronic pain [79]. Both treatments have shown promising benefit but there has been less evidence supporting the use of these therapies in pediatric headache than other well-established behavioral treatments.

The presence of comorbid psychiatric issues such as anxiety, depression, or ADHD can make the treatment of patients with migraine headaches more complex. A recent study found that approximately 30% of a sample of children and adolescents with chronic daily headache had a lifetime psychiatric diagnoses and having a lifetime psychiatric diagnosis was associated with poorer headache-related disability and quality of life [80].As a result, more intensive behavioral treatment for children and adolescents with a psychiatric comorbidity may be needed to focus on emotional and behavioral issues.

Pediatric psychologists can assess pain-related disability and coping difficulties and treat children and adolescents with migraine headaches. Children are often referred to a psychologist or other mental health professional if headaches are severe or impairing functioning. Unfortunately, access to this therapy is sometimes limited, but when available, should be offered to any migraine patients with significant disability requiring prevention, and specifically to patients with chronic migraine.

• How should the patient be treated?

Acute Treatment

The patient reports only minimal response to ibuprofen. However, he is only taking 200 mg and does not take it until well after the headache has started. He should be instructed to take ibuprofen 600 mg (~10 mg/kg) as soon as the headache starts, along with 32 oz of a sports drink, and told that he should repeat this dose in 4 hours if his headache has not completely resolved with the first dose. As his headaches are occurring less than 3 times per week on average, he can do this with every headache. He should be given a note for school allowing him to receive the medication at school, and noting the importance of allowing him to get the medication as soon as he reports a headache. Given that some of his headaches occur on consecutive days, we suspect some may be continuations of a prior headache, so again the importance of obtaining complete pain relief from his acute medication should be stressed. If at his next follow-up visit he reports not always having complete relief with ibuprofen, we would consider trying naproxen instead, and/or adding a triptan, most likely sumatriptan 100 mg given its availability. He would need to understand that he may only use the triptan for 4 to 6 headache days/month. Depending on his response to sumatriptan, it could be used alone or in combination with his NSAID. He also may be instructed to use an NSAID alone for more mild headaches and his NSAID together with sumatriptan for more severe headaches.

Preventive Treatment

PedMIDAS score is a 25, indicating mild disability, however his migraines are frequent, occurring 1–3 times per week and clearly having a significant impact on his functioning. We would therefore recommend starting a prophylactic medication. He notes difficulty remembering to take medications as well as difficulty falling asleep, so amitriptyline would be a good choice for him. For his weight of 50.9 kg, we would start with at 12.5 mg at night and increase by 12.5 mg every 2 weeks to a dose of 50 mg (~1mg/kg/day). He and Mom should be counseled that it will likely take at least a few weeks on his goal dose before they start to see results. He should be counseled also to report to Mom immediately if he has any depressive or suicidal thoughts. Topiramate is another option, especially as it is FDA-approved for migraine prevention in children older than 12 years, although twice daily dosing may be a factor in maintaining compliance. Careful discussion with the patient and family in regards to the potential risks and benefits is important prior to starting any preventative medication.

Biobehavioral Management

The patient should be drinking 8–10 cups of non-caffeinated fluid per day and additional cups on days he plays soccer. He should be given a school note to this effect so he may carry a water bottle at school. He eats well, but the importance of not skipping breakfast should be stressed, and ideas for fitting this in should be given. The importance of a consistent bedtime routine should be stressed, with good sleep hygiene to assist with easier sleep onset. It should be made clear that he should not be using screens within an hour prior to bed. He already exercises frequently and should be commended for being active. Given his report of frequent headaches which are impairing school attendance, functioning at school, and participation in soccer activities, screening for potential co-morbid psychiatric issues and making a referral for further treatment with a pediatric pain psychologist focused on coping with chronic pain is appropriate.

Case Study 2

Initial Presentation and History

A 16-year-old right-handed girl who has been having headaches since she was 10 years old presents for evaluation. She reports unilateral mostly right-sided headaches, which are throbbing and associated with photophobia, phonophobia, osmophobia, nausea, and occasionally vomiting. She has no premonitory or aura symptoms. Her headaches typically occur once a week but she has noted that they tend to be more frequent around the time of her menses and that often these headaches do not fully respond to naproxen, which typically works to break her migraines during other times in the month. Upon further review, she believes these headaches typically start on the day or two prior to her menses, and that this happens almost every month. She often misses school due to these headaches. Her mother would like to know whether the patient should see a gynecologist to potentially be placed on birth control to control her headaches.

Physical Examination

On examination, weight was 61.5 kg (75.8 percentile), height 157.1 cm (18.4 percentile), BMI 24.91 (84 percentile), blood pressure 112/55 mm Hg, and heart rate 90 bpm. Her general physical and neurologic exam results were normal. She had tightness over the left trapezius muscles, otherwise the remainder of headache examination was unremarkable.

• What is the probable diagnosis?

According to the ICHD-IIIβ, the patient meets criteria for episodic migraine without aura. Based on the history, she likely also has menstrually related migraine without aura [5].Officially, however, 3 months of prospective documentation is needed to make this diagnosis. Menstrually related migraine is included in the appendix of the ICHD-IIIβ, meaning there is ongoing debate about how it should be classified. According to the current appendix criteria, headaches should meet criteria for migraine without aura and also have documented and prospectively recorded evidence over at least 3 consecutive cycles with headaches confirmed on day 1+/– 2 (ie, 2 days prior to onset of menstruation or within the first 3 days of menstruation) in at least 2 out of 3 menstrual cycles, with migraines occurring during other times of the month as well [5]. This is distinguished from pure menstrual migraine without aura, in which migraines occur only during days 1+/–2 of menstruation but not during other times of the month [5].While we therefore cannot say that the patient meets ICHD IIIβ criteria for menstrually related migraine due to the lack of prospective documentation, her history suggests this.

Menstrually Related Migraine

An association of migraine with menses is well described in adults, occurring in up to 60% of adult female migraine patients [81].In adults, it has been observed that the migraines associated with the menstrual cycle tend to be more severe [82],associated with more nausea and vomiting [82],longer and less responsive to acute medications [83],and associated with more work-related disability [83]. Recently, analysis of data from the American Migraine Prevalence and Prevention (AMPP) Study found that women with pure menstrual migraine and menstrually associated migraine have on average higher MIDAS scores than those with non-menstrual migraine [81].

Only one study has explored menstrually related migraines in adolescents [84].It was a clinic-based study that found a similar prevalence—50% of adolescent patients who had reached menarch noted an association of migraine with their menses. Overall worse disability was not demonstrated in this study, but individual menstrual attacks were not compared with nonmenstrual attacks [84].No other studies have addressed this population, but it is clear that the pattern of menstrually related migraine exists in adolescents and it is important to recognize this pattern as these patients may require additional focused care in addition to standard migraine management.

• What are treatment options?

In adults, options for more specific management of pure menstrual migraine and menstrually related migraine include intermittent prophylaxis with NSAIDs or triptans or use of hormonal contraceptives. There are no studies addressing any of these treatments in adolescents, so at this point management decisions must be based on evidence extrapolated from adult studies as well as attention to specific concerns in adolescent patients.

Generally, intermittent prophylaxis (using a medication a few days prior to and during the first few days of menses) with various medications has shown efficacy in adult studies. This approach may be more appropriate for patients with pure menstrual migraine, as there is less likelihood of precipitating medication overuse in this population. It can be considered in patients with menstrually related migraine as well if typical daily preventives have not been effective. One small open-label trial using naproxen 550 mg daily prior to and during menses (at differing schedules depending on the month) showed slightly decreased frequency and severity of headaches during that time [85].However, triptans are what are most commonly used.

Triptans

Frovatriptan is the longest-acting triptan and the one used most commonly for intermittent prophylaxis. One double-blind randomized controlled crossover study showed improvements in headache frequency, severity, and duration using frovatriptan 2.5 mg BID for 6 days total starting 2 days prior to menses [86].Frovatriptan 2.5 mg daily showed some efficacy as well but was not as effective as 2.5 mg BID [86].One prospective randomized placebo-controlled trial demonstrated more headache-free cycles using frovatriptan 2.5 mg BID for 6 days total starting 2 days prior to menses, as compared to placebo [87].

Naratriptan, also a longer-acting triptan, was studied in 3 prospective double-blind trials at doses of 1 mg BID used for 5 days total starting 2 days prior to menses, and all 3 showed a decrease in headache frequency as compared to placebo [88,89].Of note no efficacy was shown using 2.5 mg daily [88].

Less commonly used for intermittent prophylaxis are the shorter-acting triptans, but they have shown some efficacy as well. In one prospective study using oral sumatriptan 25 mg TID for 5 days each cycle starting 2 to 3 days before onset of menses, there seemed to be at least some improvement with sumatriptan in most cycles treated [90].Zolmitriptan was studied in one prospective double-blind placebo-controlled study using 2.5 mg BID or 2.5 mg TID for 7 days total with each cycle and was found to be associated with a significant reduction in headache frequency as compared with placebo [91].There has been one prospective trial using eletriptan 20 mg TID for 6 days total starting 2 days prior to menses, which also showed improvement in headache activity in 55% of patients [92].

Hormonal Contraceptives

In general for adult patients, hormonal contraceptives are not considered first-line treatment for menstrually related migraine. However, in patients who do not respond to other modes of treatment, or who plan to use hormonal contraception for contraceptive purposes, published expert opinions have recommended considering extended or continuous hormonal regimens [93,94].

Estrogen withdrawal during the luteal phase of the monthly cycle has long been speculated to be of importance in the pathophysiology of menstrually related migraine [93]and the relationship between hormonal contraceptives and migraine is complicated. Headache is a commonly reported side effect of combined hormonal contraceptives [95]; however, this effect seems to occur mostly during the hormone-free week [96]. It has been shown that headache occurs less frequently in women using an extended cycle regimen (84 or 168 days) as compared to those using a traditional monthly cyclic regimen [97,98].Studies addressing the use of combined hormonal contraceptives for women specifically with menstrually related migraine are limited. One small prospective randomized study showed improvement in menstrually related migraine in patients treated with a low dose (20 mcg ethinyl E[2]) oral hormonal contraceptive in both a 21/7 cycle and a 24/4 cycle, with more improvement in the group using a 24/4 cycle [99].Another showed improvement in menstrually related migraine in all study patients treated with a low-dose hormonal contraceptive (20 mcg ethinyl estradiol) on a 21/7 regimen, but with additional 0.9 mg conjugated equine estrogen during the placebo week [100].There has been one randomized placebo-controlled double-blind trial in patients with menstrually related migraine using an extended 168 hormonal regimen along with frovatriptan vs. placebo for 5 days during the hormone-free interval. Overall daily headache scores were decreased from pre-study cycles, and the increase in headaches during the hormone-free interval was lower in the frovatriptan group [101].A recent study showed that contraceptive-induced amenorrhea can be beneficial for decreasing migraine frequency in patients with menstrual migraine [102].There have been no studies addressing the use of hormonal contraceptives for migraine management in adolescents.

In adolescents, the decision regarding use of hormonal contraceptives is more complicated. There is less of a chance that adolescent patients, especially younger ones, would be planning to use hormones for contraception so their use may be solely for the purpose of migraine management. However, hormonal contraceptives are commonly used in adolescents for management of other menstrual-related disorders, such as menorrhagia, dysmenorrhea, and endometriosis, and extended cycle and continuous regimens have become more popular with adolescent providers in general [103].The general concern with using hormonal contraceptives in adolescents is that they have potential for longer-term use than adult patients, and the effects of using hormonal contraceptives long term are unknown. The major concerns are for potential interference with expected increase in bone mineral density in adolescents, effects on fertility, and risk for cancer and cardiovascular disease [103].Additionally, specifically in migraine patients, is the concern for increased stroke risk. The increased risk for ischemic stroke in patients with migraine, although more specifically with migraine with aura, is well known [104–106]and migraine has recently been shown to be a risk factor for ischemic stroke in adolescents as well [107]. In adults, the use of hormonal contraceptives in patients with migraine with aura is known to increase the risk of ischemic stroke [106],and this has not been studied in adolescents. Given the various unknowns in the use of hormonal contraceptives in patients with menstrually related migraines, we would not recommend this as first-line treatment. However, similarly to adults, in patients who do not respond to other methods of migraine management, or who seek to use hormonal contraceptives for contraception or for other menstrually related disorders, extended or continuous cycle hormonal contraceptives may be a reasonable option, at the lowest possible estrogen dose. However, migraine with aura should be screened for, and its presence should prompt reconsideration of combined hormonal contraceptive use.

• How should this patient be managed?

The patient is having frequent and disabling migraines, so starting a preventive medication would be appropriate. She has migraines throughout the month in addition to during her menses, so a daily prophylactic would be more appropriate than intermittent prophylaxis surrounding her menstrual cycle only. At this point, our recommendation would be to start a daily preventive with either amitriptyline or topiramate. Given that naproxen is not breaking some of her migraines, she should be given a prescription for a triptan. Sumatriptan 100 mg would be an appropriate first choice, and she can be instructed to use it along with her naproxen at the onset of her menstrual migraines. She can use it for other migraines as well but she should be instructed not to use it more than 4 to 6 times per month. She should keep a diary for the next 3 months noting most importantly headache days as well as days of menstruation, so that a more definitive pattern can be confirmed and an official diagnosis based on ICHD-IIIβ criteria can be made. If her migraines do not improve with daily preventives, at that point discussion regarding potential for intermittent prophylaxis or trial of extended cycle hormonal contraception may be considered, although with caution and discussion of risks and benefits.

Corresponding author: Hope O’Brien, MD, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave., MLC 2015 Cincinnati, OH 45229.

Financial disclosures: None.

From the Cincinnati Children’s Hospital Medical Center, Cincinnati, OH.

Abstract

• Objective: To review the management of migraine in adolescent patients.
• Methods: Literature review in the context of 2 clinical cases.
• Results: Migraine is common in adolescents and can affect school and social functioning. Management options include lifestyle modifications and acute and preventative therapies. First-line medications for migraine in the adolescent population are over-the-counter medications, including ibuprofen, acetaminophen, and naproxen. Studies of efficacy of triptans in the treatment of pediatric migraine have been limited and results conflicting, largely due to high placebo response rates. Several classes of medications are commonly used for migraine prevention, including antidepressants and antiepileptics. Currently, topiramate is the only medication approved for prevention of migraine in patients 12 years and older. Biobehavioral treatments such as relaxation training, biofeedback, and cognitive behavioral therapy have been evaluated in randomized controlled trials and found to be efficacious.
• Conclusion: Approach to management of migraine in adolescents should be multifactorial with attention to an aggressive acute treatment regimen, preventive medications when indicated, and biobehavioral management.

Case Study 1

Initial Presentation

A 13-year-old left-handed boy with allergic rhinitis has been referred by his pediatrician for evaluation of headaches.

History

The headaches have been occurring since he was 7 years old. He describes a bilateral frontal and periorbital pain, which is either aching or throbbing in nature. There is associated photophobia and phonophobia, and the pain worsens with activity. When he was younger the headaches were frequently associated with emesis. He occasionally gets tenderness of his face during the headaches, mostly in the areas adjacent to his nose and above his eyes and occasionally associated rhinorrhea.

Initially the headaches were mild and occurring infrequently, but for the past 6 months they have been more severe and occurring 1 to 3 times per week, sometimes on consecutive days. They typically begin in the afternoon but at times occur soon after waking in the morning. If they do occur in the morning, they worsen after getting out of bed. He denies any type of warning symptoms indicating the headache will occur, and has no associated focal neurologic symptoms associated with the headaches. His mother tries to minimize medication intake so will typically wait to see if the headache is severe before giving him medication, typically 2 chewable children’s ibuprofen, which helps some of the time; however, his headache often does not completely abate unless he naps. He has also been taking loratadine daily due to concerns that his headaches may be secondary to chronic sinusitis.

He is a good student and enjoys school, but notes stress surrounding tests. He reports missing 4 days of school in the past 3 months as well as coming late twice. He thinks that there were 9 additional days in which he was unable to function at his full ability at school and at least 5 times he was unable to concentrate on his homework. He plays soccer 4 to 5 times per week. He says twice he had to skip soccer practice to due to headache and at least 3 other times he needed to take breaks during soccer due to headache. He is unsure how much he drinks on an average day but he drinks mostly with meals. He does not drink caffeine. He gets into bed at 10 pm and sometimes does not fall asleep until after 11 pm, often due to worry about tests. He often plays with his tablet when trying to fall asleep. He wakes up at 6 am for school. He typically eats 3 meals per day but occasionally misses breakfast if he is rushed in the morning.

Physical Examination

On examination, the patient is a well-developed, well-nourished male in no apparent distress. His weight was 50.9 kg (68th percentile), height 163.7 cm (65th percentile), BMI 19.9 (69th percentile), blood pressure 118/62 mm Hg, and heart rate 79 bpm. His general physical examination, including skin, HEENT, extremities, lung, cardiac, and abdominal examination was normal, with lungs clear to auscultation, heart with a regular rate and rhythm, and abdomen soft and tender without organomegaly.

On neurologic examination he was alert and attentive with normal mental status. Speech was fluent. Skull, spine, and meninges were normocephalic and atraumatic with a supple neck. Cranial nerves II through XII were normal with a normal fundoscopic examination including sharp disk, no papilledema, and normal fundus bilaterally. Motor examination was normal for tone and bulk with full strength throughout. Sensory examination was normal for light touch, temperature, vibration, and joint position sense. Finger-nose-finger fine finger movement and heel-knee-shin were normal. Deep tendon reflexes were symmetric and 2+ throughout with toes downgoing. Station and gait were normal including toe walking, heel walking, tandem walking, running, skipping, one-legged standing, Fog gate procedure, and there was no Romberg’s sign.

He had a normal comprehensive headache examination. There was no tenderness at typical migraine trigger points (nuchal line and mandibular process) and no tenderness at supraorbital notch. Neck was supple with normal rotation and normal bilateral trapezius muscle tightness. No bruits or palpitations were heard over carotid or jugular veins. There was a negative Muller sign with no pain on neck bending with pressure, and no signs of allergy or sinus symptoms.

• What is the initial evaluation of a teen with recurrent headaches?

The overwhelming majority of children and adolescents presenting to medical attention with recurrent headaches will have a primary headache disorder, most commonly migraine [1].However, ruling out a secondary cause is typically of concern, both for providers and parents, and the decision regarding whether to image is often a daunting one. In a review of 6 large studies in which imaging was done in pediatric patients who were examined by a neurologist, only 14 patients were found to have CNS lesions requiring intervention, and all of these patients had abnormalities on physical exam [2]. An American Academy of Neurology (AAN) practice parameter published in 2002 recommended considering neuroimaging only in patients with abnormal neurologic examination, co-existing seizures, concerning associated neurologic features, or recent onset of severe headache or change in headache type [2].There are additional factors which may prompt one to consider imaging as well including atypical auras or very short (< 5 minutes) or protracted ( > 60 minutes) auras, trigeminal autonomic cephalalgia, brief headaches precipitated by cough, frequent early morning headaches or which wake the patient from sleep, headaches with primarily occipital location, headaches in a patient less than 6 years old or in a child who cannot describe the headaches well, or migrainous headaches in a child without any family history of migraine or migraine equivalents. However, recent studies continue to show that the imaging yield in patients with headaches is low and further studies are needed to elucidate which patients truly require imaging [3].

Given this, a thorough history, family history, physical exam, and detailed neurologic exam including fundoscopy are imperative. In addition to the general neurologic exam, a focused headache exam should be performed, including Mueller’s maneuver, auscultation for cranial bruits, evaluation of the temporomandibular joint, palpation of possible trigger points, and maneuvers to assess for cervical spine disease [4].

Classification of Symptoms         

Once establishing the likelihood of a primary headache disorder, the International Classification of Headache Disorders, 3rd edition, beta version (ICHD IIIβ) [5]should be used to classify the headache diagnosis. Note that while this classification system was established for adults, most criteria are similar for children and adolescents, and the typical differences are noted in the comments of the ICHD IIIβ [5].Migraine is the most common type of primary headache brought to medical attention [1]. Migraine without aura is described as a recurrent headache disorder (at least 5 lifetime attacks) with attacks lasting 4 to 72 hours, typically unilateral, throbbing in nature, moderate to severe in intensity, aggravated by routine physical activity, and associated with nausea and/or photophobia and phonophobia. In young children, migraine is more frequently bilateral, the gastrointestinal symptoms often more pronounced than photophobia and phonophobia, and migraines may be shorter, lasting at least 2 hours without treatment [5].As patients reach adolescence, migraine features typically start to evolve into patterns described in adults. Differentiating migraine from other primary headaches, such as tension-type, can be challenging, especially in children in whom migraines are more likely to be shorter and bilateral. Tension-type headaches are bilateral or diffuse, pressing or tightening pain that is non-pulsatile lasting at least 30 minutes. The pain is described as mild to moderate in intensity and not aggravated by activity [5].They may be associated with photophobia or phonophobia (not both) and they may not be associated with nausea or vomiting [5].

• Is any further workup indicated?

The patient has recurrent headaches which have been present for 5 years. While they have increased in frequency, there has not been any change in their quality. His headache description and history have no “red flag” features, and a thorough examination is normal. Therefore, neuroimaging and further workup would not be indicated in this case.

• What is the diagnosis?

The patient’s headaches are throbbing in nature, exacerbated by activity, associated with nausea, photophobia, and phonophobia, and are moderate to severe. Using the ICHD IIIβ, he meets criteria for migraine without aura. While his headaches are frequent, he is having less than 15 headache days per month, so this is episodic migraine. Note that he complains of forehead and periorbital pain and occasional rhinorrhea with his headaches, leading him to have been placed on loratadine for treatment of presumed allergic sinusitis. Children meeting criteria for migraine are very frequently misdiagnosed as having sinusitis [6]due to the overlap in location of migraine pain and proximity to the frontal and maxillary sinuses, as well as the presence of autonomic features frequently present in migraine, reportedly present in 70% of pediatric migraine patients [7].The negative headache examination, including Muller’s maneuver, points against sinus disease as well.

• What is the approach to management of the adolescent with migraine?

Approach to management of migraine in adolescents should be multifactorial, with attention to an aggressive acute treatment regimen, preventive medications when indicated, and biobehavioral management.

Acute Treatment

General Approach

In counseling patients with migraine, and in particular adolescents, it should be stressed that achieving a normal level of functioning as soon as possible is the goal of therapy. Common missteps in treatment include failure to take acute medication early into the headache, incorrect dosing, incompletely treating the headache, and avoidance of participating in daily activities when headaches occur.

Adolescent patients may frequently wait to take an acute medication, typically due participation in another activity, not having medication with them, or discomfort with taking medication in front of peers or at school. Additionally, patients who have headaches beginning in early childhood, with pronounced gastrointestinal (GI) features, may be aware that their headaches resolve after vomiting, and therefore get used to not treating with medications. When these patients reach adolescence, when GI symptoms tend to become less pronounced, they will need to be educated that taking medication early is imperative. Acute medications are typically more effective when taken earlier in the course of a migraine, and the importance of pausing to take medication at the onset of the headache should be stressed to all patients and parents. With that in mind, however, care should be taken to counsel patients regarding the potential for development of medication overuse headache. When headaches are frequent, a more detailed and intricate plan may need to be devised so that adolescents and parents know which headaches to treat with medication.

Given that first-line medications for treatment of migraines are over-the-counter, underdosing occurs commonly, as dosing listed on packaging is typically age-based, not weight-based. At initial visits, young adolescent patients will frequently report that a particular medication is not effective, but this is often because they are still receiving low/less optimal dosing. Clinicians should remember to follow weights and recommend dosing changes at the initial visit and follow-up visits as well.

Treatment goals, ie, complete resolution of pain and migrainous features with ability to return to normal functioning, should be made clear to patients and families at the onset of treatment. Patients frequently fall into a pattern of continuing to treat with a medication that may lessen but not completely ablate the pain of a headache, and then sleep and avoid activity. Upon awakening, the headache may be gone, however, given incomplete initial treatment, the headache may be more likely to recur within 24 hours. At that point, the headache may be more difficult to treat and therefore cause further decrease in functioning. If this cycle perpetuates, disability can become extremely burdensome in adolescents, significantly affecting school and social functioning. Therefore, a detailed plan for initial steps in management as well as steps to take should initial therapy fail to fully break the headache should be given to every patient.

Of note, given that dehydration is now recognized as a common trigger for migraine [8,9], it is generally our recommendation to drink 16 to 32 oz (depending on weight) of a hydrating fluid together with whichever acute medication is chosen, as rehydration likely assists in breaking migraines as well [8].

Medications

Over-the-Counter Agents

The first-line medications for migraine in the pediatric and adolescent populations are over-the counter medications, including ibuprofen, acetaminophen, and naproxen sodium. Ibuprofen has been well studied in pediatrics and was found to be safe and effective in 2 studies [10,11]at doses of 7.5–10 mg/kg. Again, care should be taken to ensure timely administration of ibuprofen at onset of headache, or aura if present, with appropriate weight-based dosing. Naproxen sodium has not been studied in pediatrics for treatment of migraine. However in practice, it is often used in similar doses of 10 mg/kg, with good efficacy. Although ibuprofen and naproxen sodium are both nonsteroidal anti-inflammatory medications (NSAIDs), anecdotally many patients report successful treatment with one NSAID when another has failed. Aspirin has shown efficacy in adults for treatment of acute migraine [12].It is likely effective in the pediatric population as well, but it is generally avoided due to long-standing concerns for precipitation of Reye syndrome in children. In adolescents over 16 years old, however, it is a reasonable option if there are no contraindications.

In one study, acetaminophen was compared to ibuprofen and placebo for treatment of migraine in children and adolescents and found to be effective more frequently than placebo but not as frequently as ibuprofen [10],likely due to its only minimal anti-inflammatory effects. It is a reasonable option for children and adolescents, particularly in those who have contraindications to NSAIDs.

While these over-the-counter medications are generally safe and well tolerated, clinicians should not overlook the potential for toxicity as well as medication overuse headache, and patients should be counseled to avoid use of any of these medications for more than 2 to 3 headache days per week.

Triptans

Studies of efficacy of triptans in treatment of pediatric migraine have been limited and results conflicting, largely due to high placebo response rates. However, some have shown efficacy over placebo, and in the past few years have received FDA approval for use in the pediatric and adolescent populations. Clinicians should remember that these medications are vasoconstrictors, so they should not be used in patients with vascular disease or in patients with migraine with brainstem aura or hemiplegic migraine. Additionally, due to the risk of serotonin syndrome, they should not be used in patients on monoamine oxidase inhibitors. It is also important to educate patients to limit use of these medications to 4 to 6 times per month to avoid precipitation of medication overuse headache.

Almotriptan was approved by the FDA in 2009 for use in patients 12 years and older, based on a large randomized controlled trial comparing doses of 6.25, 12.5, and 25 mg with placebo in patients ages 12 to 17 years old. All doses resulted in statistically significant pain relief as compared to placebo, and interestingly, the 12.5-mg dose seemed to be the most effective [13].

Rizatriptan received FDA approval in 2012 for use in patients 6 years and older. In 2 randomized controlled trials in patients 6 to 17 years old, rizatriptan (5 mg for patients < 40 kg, 10 mg for patients ≥ 40 kg) was more effective than placebo in providing pain freedom at 2 hours [14,15].One earlier trial found efficacy only on some measures (weekend treatment, decrease in nausea and functional disability) but no statistically significant difference than placebo in terms of overall efficacy in achieving pain freedom at 2 hours [16].However, this trial had a higher placebo response rate than typically seen in adult triptan trials. In a recent long-term open-label study in patients 12 to 17 years old, rizatriptan was found to be generally safe and well-tolerated with consistent efficacy of 46% to 51% pain freedom at 2 hours over time [17].

A combination pill consisting of sumatriptan and naproxen (Treximet) received FDA approval in May 2015 for patients 12 years and older. This was based on a randomized controlled parallel-group trial in patients 12 to 17 years old using the sumatriptan/naproxen combination in various dose combinations: 10/60 mg, 30/180 mg, or 85/500 [18].All doses were found to be equally effective in providing pain relief at 2 hours as compared to placebo, with a higher chance of sustained pain relief at 24 hours in the group receiving the 85/500 dose. In this trial, and in a long-term open-label safety trial [19],all doses were generally well tolerated with minimal adverse reactions.

Most recently, in June 2015, zolmitriptan nasal spray was approved for patients 12 years of age and older. In the large “Double-Diamond” study, which used a novel design to attempt to minimize placebo effect, zolmitriptan nasal spray (5 mg) was found to have a significantly higher headache response rate at 1 hour than placebo, and was significantly superior to placebo with regard to multiple secondary end-points [20].Additionally, a long-term open-label trial in patients 12 to 17 years old using oral zolmitriptan (2.5 mg or 5 mg) found it to be generally effective and well tolerated [21].

No other triptans have been approved for children or adolescents, however, most are widely used in clinical practice. There is good evidence for the efficacy and tolerability of sumatriptan nasal spray [22–26]in adolescents, and it is approved for use in adolescents with migraine in Europe. Although oral sumatriptan was the first triptan available clinically in the United States and is very widely used, there is surprisingly little published evidence for its use in the pediatric and adolescent populations. In fact, 2 randomized controlled trials in adolescents failed to show efficacy of oral sumatriptan as compared to placebo [27,28].Despite this, given its availability it is a reasonable choice for adolescent patients and is often one of the first tried. There has been 1 randomized controlled trial in adolescents for eletriptan without significant differences in efficacy at 2 hours as compared to placebo, although similar to other trials the placebo rate was high and there were some differences seen in secondary outcomes measures [29].Similarly, one randomized controlled trial of naratriptan 12.5-mg tablets failed to show efficacy as compared to placebo in pain relief [30].At present time, for frovatriptan there has only been a study looking at the pharmacokinetics and safety in adolescents, which found that it was generally well tolerated and recommended adolescent dosing similar to adult dosing [31].

In choosing a triptan, clinicians should keep in mind availability of alternate forms of administration, absence or presence of significant emesis, and the age of the patient. For patients who are unable to swallow pills or who have significant emesis associated with their migraines, nasal sprays and oral dissolving forms (melts) are good options. The nasal sprays (zolmitriptan and sumatriptan) additionally have the benefit of a quicker onset (~15 minutes) in general than the oral formulations. The downside to these nasal formulations is bad taste, which is frequently reported by patients. Patients should be counseled in proper administration of these nasal sprays (ie, avoiding inhalation, which causes the medication to enter the mouth) to minimize the bad taste and maximize absorption through the nasal mucosa. Other alternatives are the oral dissolving forms (rizatriptan and zolmitriptan). Given the FDA approval, the rizatriptan melt tablets are often the first-line triptan for children under age 12, but zolmitriptan melts are an option as well.

Preventive Treatment

General Approach

The decision to place an adolescent on a daily preventive medication should be based on a combination of headache frequency, severity, ease of breaking headaches, and overall disability as established by a disability scale (such as the PedMIDAS). Any patient with headaches occurring one or more days per week, those whose headaches are not easily treated or tend to be prolonged, and those with a PedMIDAS score of 30 or more should be considered candidate for a daily preventive. It is particularly important to consider starting a preventive early in adolescent patients given the possibility of impacting overall disease progression at a young age. While the natural history of headaches that start in the young is still being investigated, a known risk factor for transformation of episodic to chronic migraine is frequent headaches [32].It is therefore imperative to attempt to intervene early to improve quality of life in the present and also to prevent a downward cycle into chronicity, potential medication overuse, and worsening disability.

At present, there are several classes of medications that are commonly used for migraine prevention, including antidepressants, antiepileptics, antihistamines, and antihypertensives. Patients should be educated regarding the medication’s typical use, the specific way in which it is used in migraine, potential side effects, and overall expectations of efficacy. Most preventives need to be titrated up slowly to maximize tolerability, and patients need to understand that it may take time before they start to see results. In general, we recommend titrating up over the course of 4 to 12 weeks (depending on medication and dose goal), and then a substantial trial of 4 to 6 weeks on a full dose of medication before determining efficacy. If a medication shows a trend towards improvement but the patient has not met treatment goals, medication can be titrated up further at that point as tolerated. Patients and families should also understand that these medications are not intended as a “cure” for migraine but rather as a tool for improvement, which should be used in conjunction with the rest of a detailed plan. Generally, if a patient is well controlled for 4 to 6 months (ie, 3 or less headaches/month that are easily broken with medications, and a PedMIDAS < 30), attempts should be made to wean off of medication.

Medications

First-line Therapies

Currently, topiramate is the only medication approved for prevention of migraine in patients 12 years and older (approved in March 2014). Three randomized double-blind placebo-controlled trials in children and adolescents have found topiramate to be superior to placebo in multiple endpoints [33–35].Doses in these trials were 2–3 mg/kg/day, 100 mg/day, and 50 or 100 mg/day, respectively. Notably, the 50 mg/day dose was not found to be superior to placebo. Multiple retrospective, open-label, and drug comparison trials have shown effectiveness and tolerability as well [36–42].We typically use a goal dose of 2 mg/kg/day, which is reached after titrating over 8 to 12 weeks, which minimizes side effects (most commonly paresthesias, memory/language dysfunction, appetite suppression, and drowsiness), but higher doses can be used if needed.

Amitriptyline has consistently shown efficacy in adult migraine trials and is therefore one of the most commonly used medications worldwide for prevention of migraine in children and adolescents. Surprisingly, there have been no published randomized controlled trials using amitriptyline in the pediatric population, although a trial comparing amitriptyline, topiramate, and placebo is currently underway (Childhood and Adolescent Migraine Prevention Study) [43].In 2 retrospective pediatric studies improvement with amitriptyline was reported in 84.2% and 89% of patients, respectively [44,45].We typically use a goal dose of 1 mg/kg/day, also with an 8- to 12-week titration. The most common side effects with amitriptyline are somnolence, dry mouth, and weight gain, but it is generally well tolerated in children and adolescents. There is also a risk of worsening depression and suicidal thoughts, so it is recommended to use caution if considering prescribing to a patient with underlying depression. It is typically administered in once daily dosing a few hours before bed to minimize morning drowsiness. There is also a concern for precipitation of arrhythmias, and while there are no guidelines recommending screening ECGs, this should be considered in patients with a family history of heart disease. Of note, many practitioners use nortriptyline in place of amitriptyline as it can be less sedating. It should be noted, however, that evidence for its efficacy is lacking. Additionally, it may carry a higher risk of arrhythmia [44].

Second-line Therapies

The second-line therapies typically considered are other antiepileptics, valproic acid, levetiracetam, and zonisamide, for which there is some evidence, although mostly in the form of open-label or retrospective studies [46–51]. Of note, despite the many promising retrospective and open-label studies for valproic acid [46–48], one randomized double-blind placebo control trial comparing various doses of extended release divalproex sodium with placebo in adolescent patients failed to show a statistically significant treatment difference between any dose and placebo [52].It is, however, frequently prescribed and anecdotally quite efficacious. Given concerns about potential for teratogenicity, and possible effects on ovarian function, as well as potential for weight gain and hair loss, it should be used with caution in adolescent females.

Antihypertensives (beta blockers and calcium channel blockers) have long been used for prevention of migraine in both the adult and pediatric population, but evidence for their use in the pediatric population is conflicting. An early double-blind crossover study of propranolol in patients 7 to 16 years old showed significant efficacy as compared with placebo [53].However, in 2 subsequent studies it failed to show efficacy as compared with placebo and self-hypnosis, respectively [54,55].Given the conflicting evidence and the potential for hypotension, depression, and exercise-induced asthma, use of propranolol has fallen out of favor by experts for use in pediatric and adolescent migraine prevention. Flunarizine, a nonselective calcium channel blocker, has demonstrated effectiveness in pediatric migraine prevention [56,57],and is actually approved in Europe for this indication, but it is not available in the United States.

Cyproheptadine is an antihistamine with antiserotonergic properties which is used frequently for migraine prevention in young children who are unable to swallow tablets, although evidence is limited to 1 retrospective study [45].However, given the propensity for weight gain with this medication, it is generally not recommended for use in adolescents.

In recent years, there has been a growing interest in nutraceuticals given their general tolerability and minimal side effects, as well as a comfort in using a more “natural” approach, particularly in pediatrics. Evidence is limited but some of the frequently used substances may be beneficial. Butterbur (petasites hybridus) has strong evidence in adults and is recommended by the AAN for migraine prevention in adults [58].There is one small pediatric RCT showing efficacy for butterbur as compared to music therapy [59],as well as one promising open-label trial [60]. Typical dosing ranges from 50–150 mg daily. However, butterbur contains pyrrolizidine alkaloids, which are hepatotoxic, and due to the concerns for inadequate monitoring of removal of these substances in the manufacturing of commercial butterbur, it has been generally avoided in the pediatric population. Coenzyme Q10 (CoQ10) is considered possibly effective for adult migraine prevention by the AAN [58].Pediatric evidence is limited to an open-label study showing improvement with supplementation of CoQ10 in deficient patients [61],and a subsequent double-blind placebo-controlled add-on study, which showed improvement in both the CoQ10 and placebo groups but faster improvement in the CoQ10 group [62].Typical pediatric dosing is 1–2 mg/kg/day. Magnesium is considered by the AAN to be a good option for migraine prevention in adults [58].One randomized controlled trial in children however had equivocal results [63],while one small prospective open-label study had positive results [64]. Magnesium supplementation may be more effective in patients who have low ionized magnesium levels, but this is difficult to measure reliably in the clinical setting. Doses of 9 mg/kg/day can be used with the most common side effects reported being gastrointestinal upset and diarrhea, generally dose dependent. Riboflavin is also considered by the AAN to be probably effective for prevention in adults [58],but again the evidence in children is limited to one positive retrospective study [65]and 2 equivocal randomized controlled trials [66,67],one of which had an unusually high placebo rate [66]. Appropriate dosing is also something of debate, as riboflavin is minimally absorbed and has a short half-life, so while studies were done using 200–400 mg daily, smaller more frequent dosing may be needed.

A potential approach to treatment with vitamins is to check for deficiencies, but currently only the study mentioned above in which CoQ10 levels were checked showed improvement with normalizing of low levels [61,62].Further research into this topic is needed to elucidate whether checking and repleting levels of specific vitamins would be beneficial in prevention of migraines in certain patients.

Healthy Habits

The importance of maintaining healthy lifestyle habits and modifying potentially detrimental ones should be stressed to patients and families, and counseling regarding these issues should be provided at every visit, as repetition is often key to patients understanding their importance. Skipping meals is a commonly reported migraine trigger [68,69].This is not an uncommon occurrence even in the most well-meaning of families; adolescents often report not feeling hungry in the morning, and in the rush to get to school will often skip breakfast. Many patients report not liking school lunches leading them to go most of the day without food. Adolescent girls may skip meals due to weight concerns. Patients need to be reminded that well-balanced meals throughout the day is imperative, and they often may need specific counseling on how to achieve this practically. Of note, unless a specific migraine trigger has been identified in a given patient, we do not generally recommend restricting any specific food lists.

Maintaining good sleep hygiene and a consistent sleep schedule is also often difficult for adolescent patients, with after-school activities, homework, and screen use (eg, television, electronic devices) often contributing to late bedtimes with then forced early morning waking for school. However, improvement in sleep hygiene has been shown to be effective in improving migraines in children and adolescents [70],and realistic plans for improvement in sleep should be discussed with patients.

Dehydration is also a common migraine trigger [8,9],so the importance of staying well hydrated should be stressed as well. Again, specific recommendations for how this can be achieved are often needed, especially given adolescents’ busy schedules. Additionally, many schools do not allow water bottles to be carried, and often a school note is needed so patients may be allowed to carry a water bottle at school and also be provided extra bathroom breaks as needed.

Also important is stressing maintenance of daily functioning throughout migraine treatment. By the time adolescents seek medical care, they may already be in a cycle of missing school due to headaches, and some may even be receiving home-schooling. The goals of staying in school and learning to function with headaches should be stressed, often with the help of coping skills, which will be discussed below, as it has been shown that functional disability generally improves before pain [71].

Behavioral Treatments

Psychological treatments are an important aspect of migraine management. Biobehavioral treatments such as relaxation training, biofeedback, and multimodal cognitive behavioral therapy (CBT) have been evaluated in randomized controlled trials and reviewed in meta-analyses in pediatric migraine populations and found to be efficacious [72–75].These treatments have been shown to reduce pain intensity and disability for children and adolescents with headaches and therapeutic gains appear to be maintained [72].

Relaxation training typically includes instruction in techniques such as diaphragmatic breathing, progressive muscle relaxation, and guided imagery. Relaxation training is most effective with children 7 years of age or older [76].Biofeedback is often used in conjunction with relaxation training to provide audio or visual feedback about normally unconscious physiological body responses associated with increased relaxation. Effective biofeedback parameters used with children and adolescents with migraine headache include electromyographic (EMG) activity and peripheral skin temperature [77].Biofeedback techniques can help children and adolescents become more aware of physical responses, better control these responses and generalize physical responses outside of therapy sessions to better cope with pain [76].CBT involves instruction in skills such as biofeedback-assisted relaxation training, activity pacing, distraction, and cognitive strategies for coping with pain. CBT was shown to be effective in a recent study comparing adolescent patients with chronic migraine receiving amitriptyline and CBT with patients receiving amitriptyline and standard headache education [78]. Patients who received CBT plus amitriptyline had greater reductions in days with headache and migraine-related disability compared with patients who received headache education plus amitriptyline [78].Hypnosis and acceptance and commitment therapy (ACT) are also psychological treatments used with children and adolescents with migraine headaches. ACT prioritizes the outcome of improved functioning above headache reduction and has broadly demonstrated efficacy for chronic pain [79]. Both treatments have shown promising benefit but there has been less evidence supporting the use of these therapies in pediatric headache than other well-established behavioral treatments.

The presence of comorbid psychiatric issues such as anxiety, depression, or ADHD can make the treatment of patients with migraine headaches more complex. A recent study found that approximately 30% of a sample of children and adolescents with chronic daily headache had a lifetime psychiatric diagnoses and having a lifetime psychiatric diagnosis was associated with poorer headache-related disability and quality of life [80].As a result, more intensive behavioral treatment for children and adolescents with a psychiatric comorbidity may be needed to focus on emotional and behavioral issues.

Pediatric psychologists can assess pain-related disability and coping difficulties and treat children and adolescents with migraine headaches. Children are often referred to a psychologist or other mental health professional if headaches are severe or impairing functioning. Unfortunately, access to this therapy is sometimes limited, but when available, should be offered to any migraine patients with significant disability requiring prevention, and specifically to patients with chronic migraine.

• How should the patient be treated?

Acute Treatment

The patient reports only minimal response to ibuprofen. However, he is only taking 200 mg and does not take it until well after the headache has started. He should be instructed to take ibuprofen 600 mg (~10 mg/kg) as soon as the headache starts, along with 32 oz of a sports drink, and told that he should repeat this dose in 4 hours if his headache has not completely resolved with the first dose. As his headaches are occurring less than 3 times per week on average, he can do this with every headache. He should be given a note for school allowing him to receive the medication at school, and noting the importance of allowing him to get the medication as soon as he reports a headache. Given that some of his headaches occur on consecutive days, we suspect some may be continuations of a prior headache, so again the importance of obtaining complete pain relief from his acute medication should be stressed. If at his next follow-up visit he reports not always having complete relief with ibuprofen, we would consider trying naproxen instead, and/or adding a triptan, most likely sumatriptan 100 mg given its availability. He would need to understand that he may only use the triptan for 4 to 6 headache days/month. Depending on his response to sumatriptan, it could be used alone or in combination with his NSAID. He also may be instructed to use an NSAID alone for more mild headaches and his NSAID together with sumatriptan for more severe headaches.

Preventive Treatment

PedMIDAS score is a 25, indicating mild disability, however his migraines are frequent, occurring 1–3 times per week and clearly having a significant impact on his functioning. We would therefore recommend starting a prophylactic medication. He notes difficulty remembering to take medications as well as difficulty falling asleep, so amitriptyline would be a good choice for him. For his weight of 50.9 kg, we would start with at 12.5 mg at night and increase by 12.5 mg every 2 weeks to a dose of 50 mg (~1mg/kg/day). He and Mom should be counseled that it will likely take at least a few weeks on his goal dose before they start to see results. He should be counseled also to report to Mom immediately if he has any depressive or suicidal thoughts. Topiramate is another option, especially as it is FDA-approved for migraine prevention in children older than 12 years, although twice daily dosing may be a factor in maintaining compliance. Careful discussion with the patient and family in regards to the potential risks and benefits is important prior to starting any preventative medication.

Biobehavioral Management

The patient should be drinking 8–10 cups of non-caffeinated fluid per day and additional cups on days he plays soccer. He should be given a school note to this effect so he may carry a water bottle at school. He eats well, but the importance of not skipping breakfast should be stressed, and ideas for fitting this in should be given. The importance of a consistent bedtime routine should be stressed, with good sleep hygiene to assist with easier sleep onset. It should be made clear that he should not be using screens within an hour prior to bed. He already exercises frequently and should be commended for being active. Given his report of frequent headaches which are impairing school attendance, functioning at school, and participation in soccer activities, screening for potential co-morbid psychiatric issues and making a referral for further treatment with a pediatric pain psychologist focused on coping with chronic pain is appropriate.

Case Study 2

Initial Presentation and History

A 16-year-old right-handed girl who has been having headaches since she was 10 years old presents for evaluation. She reports unilateral mostly right-sided headaches, which are throbbing and associated with photophobia, phonophobia, osmophobia, nausea, and occasionally vomiting. She has no premonitory or aura symptoms. Her headaches typically occur once a week but she has noted that they tend to be more frequent around the time of her menses and that often these headaches do not fully respond to naproxen, which typically works to break her migraines during other times in the month. Upon further review, she believes these headaches typically start on the day or two prior to her menses, and that this happens almost every month. She often misses school due to these headaches. Her mother would like to know whether the patient should see a gynecologist to potentially be placed on birth control to control her headaches.

Physical Examination

On examination, weight was 61.5 kg (75.8 percentile), height 157.1 cm (18.4 percentile), BMI 24.91 (84 percentile), blood pressure 112/55 mm Hg, and heart rate 90 bpm. Her general physical and neurologic exam results were normal. She had tightness over the left trapezius muscles, otherwise the remainder of headache examination was unremarkable.

• What is the probable diagnosis?

According to the ICHD-IIIβ, the patient meets criteria for episodic migraine without aura. Based on the history, she likely also has menstrually related migraine without aura [5].Officially, however, 3 months of prospective documentation is needed to make this diagnosis. Menstrually related migraine is included in the appendix of the ICHD-IIIβ, meaning there is ongoing debate about how it should be classified. According to the current appendix criteria, headaches should meet criteria for migraine without aura and also have documented and prospectively recorded evidence over at least 3 consecutive cycles with headaches confirmed on day 1+/– 2 (ie, 2 days prior to onset of menstruation or within the first 3 days of menstruation) in at least 2 out of 3 menstrual cycles, with migraines occurring during other times of the month as well [5]. This is distinguished from pure menstrual migraine without aura, in which migraines occur only during days 1+/–2 of menstruation but not during other times of the month [5].While we therefore cannot say that the patient meets ICHD IIIβ criteria for menstrually related migraine due to the lack of prospective documentation, her history suggests this.

Menstrually Related Migraine

An association of migraine with menses is well described in adults, occurring in up to 60% of adult female migraine patients [81].In adults, it has been observed that the migraines associated with the menstrual cycle tend to be more severe [82],associated with more nausea and vomiting [82],longer and less responsive to acute medications [83],and associated with more work-related disability [83]. Recently, analysis of data from the American Migraine Prevalence and Prevention (AMPP) Study found that women with pure menstrual migraine and menstrually associated migraine have on average higher MIDAS scores than those with non-menstrual migraine [81].

Only one study has explored menstrually related migraines in adolescents [84].It was a clinic-based study that found a similar prevalence—50% of adolescent patients who had reached menarch noted an association of migraine with their menses. Overall worse disability was not demonstrated in this study, but individual menstrual attacks were not compared with nonmenstrual attacks [84].No other studies have addressed this population, but it is clear that the pattern of menstrually related migraine exists in adolescents and it is important to recognize this pattern as these patients may require additional focused care in addition to standard migraine management.

• What are treatment options?

In adults, options for more specific management of pure menstrual migraine and menstrually related migraine include intermittent prophylaxis with NSAIDs or triptans or use of hormonal contraceptives. There are no studies addressing any of these treatments in adolescents, so at this point management decisions must be based on evidence extrapolated from adult studies as well as attention to specific concerns in adolescent patients.

Generally, intermittent prophylaxis (using a medication a few days prior to and during the first few days of menses) with various medications has shown efficacy in adult studies. This approach may be more appropriate for patients with pure menstrual migraine, as there is less likelihood of precipitating medication overuse in this population. It can be considered in patients with menstrually related migraine as well if typical daily preventives have not been effective. One small open-label trial using naproxen 550 mg daily prior to and during menses (at differing schedules depending on the month) showed slightly decreased frequency and severity of headaches during that time [85].However, triptans are what are most commonly used.

Triptans

Frovatriptan is the longest-acting triptan and the one used most commonly for intermittent prophylaxis. One double-blind randomized controlled crossover study showed improvements in headache frequency, severity, and duration using frovatriptan 2.5 mg BID for 6 days total starting 2 days prior to menses [86].Frovatriptan 2.5 mg daily showed some efficacy as well but was not as effective as 2.5 mg BID [86].One prospective randomized placebo-controlled trial demonstrated more headache-free cycles using frovatriptan 2.5 mg BID for 6 days total starting 2 days prior to menses, as compared to placebo [87].

Naratriptan, also a longer-acting triptan, was studied in 3 prospective double-blind trials at doses of 1 mg BID used for 5 days total starting 2 days prior to menses, and all 3 showed a decrease in headache frequency as compared to placebo [88,89].Of note no efficacy was shown using 2.5 mg daily [88].

Less commonly used for intermittent prophylaxis are the shorter-acting triptans, but they have shown some efficacy as well. In one prospective study using oral sumatriptan 25 mg TID for 5 days each cycle starting 2 to 3 days before onset of menses, there seemed to be at least some improvement with sumatriptan in most cycles treated [90].Zolmitriptan was studied in one prospective double-blind placebo-controlled study using 2.5 mg BID or 2.5 mg TID for 7 days total with each cycle and was found to be associated with a significant reduction in headache frequency as compared with placebo [91].There has been one prospective trial using eletriptan 20 mg TID for 6 days total starting 2 days prior to menses, which also showed improvement in headache activity in 55% of patients [92].

Hormonal Contraceptives

In general for adult patients, hormonal contraceptives are not considered first-line treatment for menstrually related migraine. However, in patients who do not respond to other modes of treatment, or who plan to use hormonal contraception for contraceptive purposes, published expert opinions have recommended considering extended or continuous hormonal regimens [93,94].

Estrogen withdrawal during the luteal phase of the monthly cycle has long been speculated to be of importance in the pathophysiology of menstrually related migraine [93]and the relationship between hormonal contraceptives and migraine is complicated. Headache is a commonly reported side effect of combined hormonal contraceptives [95]; however, this effect seems to occur mostly during the hormone-free week [96]. It has been shown that headache occurs less frequently in women using an extended cycle regimen (84 or 168 days) as compared to those using a traditional monthly cyclic regimen [97,98].Studies addressing the use of combined hormonal contraceptives for women specifically with menstrually related migraine are limited. One small prospective randomized study showed improvement in menstrually related migraine in patients treated with a low dose (20 mcg ethinyl E[2]) oral hormonal contraceptive in both a 21/7 cycle and a 24/4 cycle, with more improvement in the group using a 24/4 cycle [99].Another showed improvement in menstrually related migraine in all study patients treated with a low-dose hormonal contraceptive (20 mcg ethinyl estradiol) on a 21/7 regimen, but with additional 0.9 mg conjugated equine estrogen during the placebo week [100].There has been one randomized placebo-controlled double-blind trial in patients with menstrually related migraine using an extended 168 hormonal regimen along with frovatriptan vs. placebo for 5 days during the hormone-free interval. Overall daily headache scores were decreased from pre-study cycles, and the increase in headaches during the hormone-free interval was lower in the frovatriptan group [101].A recent study showed that contraceptive-induced amenorrhea can be beneficial for decreasing migraine frequency in patients with menstrual migraine [102].There have been no studies addressing the use of hormonal contraceptives for migraine management in adolescents.

In adolescents, the decision regarding use of hormonal contraceptives is more complicated. There is less of a chance that adolescent patients, especially younger ones, would be planning to use hormones for contraception so their use may be solely for the purpose of migraine management. However, hormonal contraceptives are commonly used in adolescents for management of other menstrual-related disorders, such as menorrhagia, dysmenorrhea, and endometriosis, and extended cycle and continuous regimens have become more popular with adolescent providers in general [103].The general concern with using hormonal contraceptives in adolescents is that they have potential for longer-term use than adult patients, and the effects of using hormonal contraceptives long term are unknown. The major concerns are for potential interference with expected increase in bone mineral density in adolescents, effects on fertility, and risk for cancer and cardiovascular disease [103].Additionally, specifically in migraine patients, is the concern for increased stroke risk. The increased risk for ischemic stroke in patients with migraine, although more specifically with migraine with aura, is well known [104–106]and migraine has recently been shown to be a risk factor for ischemic stroke in adolescents as well [107]. In adults, the use of hormonal contraceptives in patients with migraine with aura is known to increase the risk of ischemic stroke [106],and this has not been studied in adolescents. Given the various unknowns in the use of hormonal contraceptives in patients with menstrually related migraines, we would not recommend this as first-line treatment. However, similarly to adults, in patients who do not respond to other methods of migraine management, or who seek to use hormonal contraceptives for contraception or for other menstrually related disorders, extended or continuous cycle hormonal contraceptives may be a reasonable option, at the lowest possible estrogen dose. However, migraine with aura should be screened for, and its presence should prompt reconsideration of combined hormonal contraceptive use.

• How should this patient be managed?

The patient is having frequent and disabling migraines, so starting a preventive medication would be appropriate. She has migraines throughout the month in addition to during her menses, so a daily prophylactic would be more appropriate than intermittent prophylaxis surrounding her menstrual cycle only. At this point, our recommendation would be to start a daily preventive with either amitriptyline or topiramate. Given that naproxen is not breaking some of her migraines, she should be given a prescription for a triptan. Sumatriptan 100 mg would be an appropriate first choice, and she can be instructed to use it along with her naproxen at the onset of her menstrual migraines. She can use it for other migraines as well but she should be instructed not to use it more than 4 to 6 times per month. She should keep a diary for the next 3 months noting most importantly headache days as well as days of menstruation, so that a more definitive pattern can be confirmed and an official diagnosis based on ICHD-IIIβ criteria can be made. If her migraines do not improve with daily preventives, at that point discussion regarding potential for intermittent prophylaxis or trial of extended cycle hormonal contraception may be considered, although with caution and discussion of risks and benefits.

Corresponding author: Hope O’Brien, MD, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave., MLC 2015 Cincinnati, OH 45229.

Financial disclosures: None.

From the University of North Carolina Medical Center (Dr. Daniels) and Renovion (Dr. Durham), Chapel Hill, NC.

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ABSTRACT

• Objective: To examine common types of medication errors occurring in patients with HIV, with a focus on patient risk, contributing factors, and interventions that can be employed to address the problem of medication errors in this population.

• Methods: Review of the literature.

• Results: The increased complexity and specialization of HIV care, the presence of comorbidities, and the evolving nature of medication management in patients with HIV place these patients at risk for medication errors and adverse drug events. Many studies of hospitalized patients with HIV have reported high rates of medication errors in this population. The consequences of antiretroviral therapy errors can range from minimal harm to life-threatening toxicities and the possibility of resistance and treatment failure. This review discusses the factors contributing to the high rates of error associated with antiretroviral therapy and details strategies to reduce and prevent errors in these patients.

• Conclusion: A comprehensive approach combining multiple interventions can be used to reduce and prevent antiretroviral medication errors in patients with HIV in order to improve the quality of care for this population.

Great progress has been made in the treatment of HIV over the past several decades. With the advancements in treatment options for HIV, considerable reductions in the morbidity and mortality associated with HIV and HIV-related complications have been realized [1,2]. Antiretroviral therapy (ART) has rapidly evolved, offering different mechanisms of action, improved potency, increased tolerability and reduced pill burdens. As a result, HIV infection has transformed from a terminal illness to a manageable chronic disease.

The success of HIV treatment has created a new set of challenges for health care professionals. Patients with successfully treated HIV can expect to live a nearly normal lifespan [3]. With this extended life expectancy, the number of older adults infected with HIV continues to rise, and care for these patients requires a broader and more comprehensive approach. Although HIV-related illnesses such as opportunistic infections have declined, the rate of non–HIV-related comorbidities among patients with HIV has increased [4]. Large cohort studies have shown an association between the risk for HIV-associated non–AIDS-related conditions and CD4 counts [5,6]. HIV-associated non–AIDS-related conditions include cardiovascular disease, kidney disease, liver disease, central nervous system disease, osteoporosis, and non–AIDS-associated malignancies. These conditions occur either more frequently or are more severe in patients with lower CD4 counts or detectable viral loads, but can also arise or persist in virologically suppressed patients with high CD4 counts [4].

The increased complexity and specialization of HIV care, the presence of comorbidities, and the evolving nature of medication management in this population place these patients at risk for experiencing medication errors and adverse drug events. Patients with HIV often receive care by many providers in many different settings. Clinicians caring for patients with HIV must be familiar not only with the treatment of HIV but also with the management and integration of their patients’ primary care needs. In addition, the rates of hospitalization for HIV-infected patients have declined substantially since the mid-1990s [7]. Of the patients with HIV requiring hospitalization, the proportion of hospitalizations due to opportunistic infections has decreased and the proportion of hospitalizations due to other conditions has increased [7]. For many of these patients, the treatment of HIV has retreated to the background as a stable condition, while the management of other acute illness requires more attention.

An estimated 1.5 million adverse drug events occur each year in the United States due to medication errors [8]. Medication errors are common and can occur at any point during the medication use process, including procurement, prescribing, transcribing, preparing or compounding, dispensing, administration, and monitoring. Any time a patient moves from one setting of health care to another, the risk for medication errors is increased. Several reports have highlighted the increased risk for medication errors and adverse effects that can occur during these transitions of care. In fact, up to 70% of patients have an unintentional medication discrepancy at hospital discharge [9]. Errors during hospital admission are common as well, affecting up to two-thirds of patients admitted to hospitals [10,11].

As HIV care becomes more complex, concerns have been raised regarding increases in the number of medication errors in these patients, especially during transitions of care. Most studies of hospitalized patients with HIV have reported error rates of 5% to 30% [12–15]. One study demonstrated that the risk for a medication error at admission for patients with HIV was 3.8 errors per patient, whereas for patients without HIV the rate was 2.8 errors per patient [16]. Because of the potential for the emergence of resistance mutations, adherence to ART is essential for successful treatment and sustained viral suppression. Thus, medication errors of omission could have particularly detrimental effects for the long-term treatment of patients with HIV. Furthermore, as this population ages, polypharmacy becomes common, placing these patients at risk for errors related to dosing and drug interactions [17]. Because medication errors can lead to patient harm and death as well as increased health care costs, elucidating the reasons for errors associated with HIV management and exploring strategies aimed at the reduction and prevention of errors is essential.

The goal of this review is to examine the common types of medication errors occurring in patients with HIV, with a focus on patient risk, contributing factors, and interventions that can be employed to address the problem of medication errors in this population.

Incidence of ART Errors

Several studies have indicated that the incidence of ART errors in hospitalized patients is rising. The rate of ART errors detected at admission among hospitalized patients increased from 2% in 1996 to 12% in 1998 according to one study [13]. Studies conducted from 2004 to 2007 report ART error rates at hospital admission ranging from 17% to 26% [12,15,18]. In more recent studies, high ART error rates ranging from 35% to 55% have been reported [19–23]. Two studies have reported ART error rates occurring at hospital admission to be as high as 70% [24,25].

Various types of ART medication errors can occur. Commonly reported errors include those related to drug interactions, incorrect dosing, incorrect scheduling, and incomplete regimens. Errors occurring at the time of hospital admission appear to be more common than errors occurring at other time points [20,24,26]. A comprehensive systematic review of studies regarding medication errors in hospitalized patients with HIV found that errors at the point of prescribing encompass the majority of errors [27]. One study identified 82 ART errors occurring at admission in 68 hospitalized patients. Of these errors, 37% occurred at the point of prescribing, 27% were attributed to dispensing, and 18% were attributed to inaccuracies in outpatient clinic documentation [24].

Several authors have drawn associations between the rate of errors and the class of antiretroviral prescribed. Protease inhibitors have been the most frequently implicated drug class [13,18,20,27,28]. In an analysis of 145 ART errors in one hospital, 70% of dosing errors involved protease inhibitors and 30% involved nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). In addition, scheduling errors occurred most often with protease inhibitors, and errors due to drug interactions were also most likely to involve protease inhibitors [28]. Conversely, another study did not find an association between protease inhibitors and the risk for error compared to other classes of drugs. In fact, this study showed that the NRTI class was associated with an increased risk of prescribing error compared to protease inhibitors and that the use of co-formulated drugs that were available on the hospital formulary protected against error [20]. These findings highlight the various factors contributing to error among different institutions, especially related to hospital formulary selections and availability of specific drugs.

Fewer studies have evaluated ART errors in outpatient settings. One report evaluated the NRTI medication records from an outpatient electronic medical record system from August 2004 to September 2005. A total of 902 NRTI records for 603 patients were analyzed. The overall error rate was 6% (53/902), with renal dosing errors being most common (75% of errors) [29]. Another evaluation of ART errors among privately insured patients with HIV found that the probability of a patient with HIV receiving an inappropriate drug combination in a given year was higher in 2005 (5.9%) compared to 1999 and 2000 (1.9%). Many of the increased errors seen in 2005 compared to 1999–2000 in this study were attributed to errors related to protease inhibitor boosting [30].

Harms and Consequences of ART Errors

Because of the potential for the emergence of drug resistance, adherence to an ART regimen is essential for successful treatment and sustained viral suppression. ART medication errors causing disrupted therapy, omitted drugs, or suboptimal dosing can lead to the development of viral resistance mutations and ultimately treatment failure placing patients at risk for HIV-related complications such as opportunistic infections as well as non–HIV-related complications [31]. Health care providers should recognize the importance of appropriate uninterrupted therapy for this population and should assist in facilitating this effort. On a community level, patients with elevated plasma HIV RNA levels due to untreated disease or treatment failure have a greater risk of transmitting HIV to others [32]. Effective ART on a population basis will have important public health advantages.

In addition to the potential consequences of ART error relating to treatment failure and resistance, ART errors may also lead to drug toxicities and drug intolerance, increasing the risk of nonadherence, and further exacerbating the aforementioned consequences.

ART errors also carry the same consequences as errors involving other non-ART medications, such as loss of patient trust, civil and criminal legal consequences, professional board discipline, and increased health care costs [33]. One study reported a cost avoidance of $24,000 annually for inpatient and $124,000 annually for outpatient through the use of pharmacists’ interventions to prevent errors [34]. Another study found that patients experiencing an ART error related to protease inhibitor boosting incurred claims costing 21.5% more than patients not experiencing a boosting error [30].

Contributing Factors

Health care professional–associated factors can also contribute to ART errors. The increasing complexity and specialization of HIV care and the rapidly evolving nature of medication management in this population have created an environment in which many providers without extensive experience in the treatment of HIV are responsible for managing HIV in settings beyond the HIV clinic. A survey of non-HIV specialized physicians conducted in 2007 revealed a poor knowledge base of common ART regimens among these physicians [37]. Likewise, HIV providers may be uncomfortable serving a primary care role for patients with HIV due to their own lack of experience and knowledge of primary care [38]. This issue is becoming more relevant, as non-AIDS comorbidities are emerging as the main health concerns for patients with HIV [39]. Health care professionals’ knowledge of HIV care also contributes to ART errors at other points in the medication use process beyond prescribing. Pharmacists lacking experience in identifying appropriate ART regimens may not recognize errors, and, therefore, may not be able to intervene and prevent errors from occurring.

Medication factors contributing to the risk for errors include risks related to the pharmacologic properties of certain drugs as well as drug naming and labeling factors. Certain antiretroviral classes are known to interact with many medications due to inhibition or induction of metabolic pathways responsible for drug metabolism, such as the cytochrome P-450 pathways. In addition, many antiretroviral medications require “boosting” with another drug to increase systemic exposure of the antiretroviral. Boosting is required for most protease inhibitors and for the integrase inhibitor elvitegravir. For some of these medications, the boosting agent is provided in a co-formulated product. However, for others, a separate prescription for the boosting medication is required. These factors contribute to the risks for drug interactions as well as drug and dosing errors.

Errors may also occur due to drug naming and labeling factors. Confusion due to look-alike/sound-alike medications is common, especially with handwritten or verbally transcribed orders. Examples of look-alike/sound-alike medications include lamivudine/lamotrigine, Viramune/Viread/Viracept, and ritonavir/Retrovir. The use of abbreviations can also lead to error. Reports have described errors associated with zidovudine, which is often abbreviated AZT, being confused with azathioprine [40,41]. An evaluation of ART errors reported to a national medication error reporting program found that look-alike/sound-alike medication names contributed to 19% (77/400) of the errors reported during the 48-month time period evaluated [15].

Several antiretroviral medications are co-formulated into single tablets to decrease pill burden and increase adherence. The use of co-formulated products has the potential to either increase or decrease the risk of errors. Prescribing one co-formulated product rather than its individual components simplifies the prescribing process, allowing the prescriber to become familiar with one product and one dosing scheme in place of 2 or more drugs with different dosing recommendations. The risk of inadvertent omission of a drug and the risk of improper dosing is reduced with the use of co-formulated products. On the other hand, when patients are transitioned from one health care setting to another (such as admission to a hospital), these products may require conversion to the individual components of the drug due to formulary availability and/or cost concerns. Studies have shown that formulary conversions from co-formulated products to individual components are frequently associated with ART errors and that the use of co-formulated products in the inpatient setting reduces these errors [20,22,24,26].

Finally, factors related to the health care setting can influence the risk for errors. High patient numbers, time constraints, and workload stresses can all increase the likelihood that an error will occur [36]. Interruptions and distractions occurring at any point in the medication use process can lead to error.

Transitioning from one health care setting to another also places patients at risk for being harmed by medication errors. Up to 70% of patients may have an unintentional medication discrepancy at hospital discharge, and errors occurring at hospital admission have been reported to affect two-thirds of admitted patients [42]. Many of these errors hold the potential to cause harm to the patient, especially if the errors are carried forward throughout the patient’s admission and after discharge. One study found that 22% of ART errors occurring at hospital admission were attributable to outpatient clinic documentation errors [24]. This highlights the need for improved documentation processes and draws attention to the element of communication at transitional points of care. Lack of adequate resources for medication reconciliation is a widely recognized challenge. This includes resources of personnel as well as electronic medical record systems that can facilitate the reconciliation process. The importance of accurately documenting a patient’s medication history and the ability to easily communicate this information to other health care settings cannot be underestimated. Electronic medical record systems should be developed to facilitate and enhance the processes of reconciliation, documentation, and communication.

Interventions to Address ART Errors

The causes of ART errors are multifactorial and should be addressed using comprehensive approaches tailored to the specific health care setting. Several types of interventions aimed at reducing and preventing ART errors have been evaluated in the literature [12,18,26,27]. In general, these interventions have focused on provider education, use of technology and clinical decision support systems, pharmacist-led medication review and intervention, and hospital formulary changes. Other interventions that may lead to a reduction in ART errors include minimizing polypharmacy, improving medication reconciliation processes during transitions of care, and multidisciplinary follow-up clinic visits after hospital discharge.

Because the sources of ART errors are multifactorial, the optimal strategy to prevent and reduce errors is likely to be a comprehensive approach combining several of the aforementioned interventions. One study showed that a combined approach that included updates to the institution’s computerized physician order entry (CPOE) system, education for the pharmacy and ID departments, and daily review of patients’ medications by pharmacists was successful in reducing the percentage of admissions with an ART error from 50% to 34%. In addition, the time to error resolution decreased from 180 hours to 23 hours, and the error resolution rate increased from 32% to 68% [21]. Another study demonstrated benefits using a comprehensive approach including the dissemination of educational pocket cards for physicians, pharmacists and nurses; CPOE alerts; hospital formulary updates to include co-formulated products; and a daily review of medications by an ID-specialized pharmacist for patients receiving ART. These strategies resulted in a reduced ART error rate from 72% to 15% in 7 months [26]. These studies demonstrate the benefit of multifaceted strategies to reduce ART error rates.

Education

Given the complexity of HIV care and overall lack of antiretroviral medication knowledge among non-ID specialized health care professionals, educational programs aimed at increasing the comfort level and familiarity of ART is important [16,37]. Frequent training to update  health care professionals on the newest recommendations for HIV management can help achieve this goal [19,27]. Educational interventions aimed at reducing medication errors have been shown to be transiently effective but may lack sustained effects [43]. Educational programs for health care professionals should be designed to provide frequent brief updates, and are likely to be more successful when combined with other approaches [19,26].

Education directed toward patients, families, and caregivers can also play a pivotal role in error prevention. Patients should be encouraged to use one pharmacy, if possible, to ensure that one complete, accurate, and current profile is maintained. The use of one pharmacy can also assist in the identification of therapeutic duplications and drug interactions. Counseling patients with visual aids, such as charts with pictures of drugs, can also be used as a tool for education. Patients who are familiar with the names and the appearances of their drugs are more likely to recognize errors. In addition, patients should be advised to maintain their own current medication list so that they will be able to provide this information to all of the health care professionals involved in their care [33,44].

Technology and Clinical Decision Support Systems

Overall, the increasing use of technology such as CPOE, decision support systems, and barcoding systems has been shown to decrease the risk of medication error [19,45,46]. Guo et al observed a 35% decrease in ART error rates after the integration of customized order entry sets into an existing CPOE program [19]. Another study reported a 50% decrease in the ART error rate after the introduction of an electronic medical record system [45]. On the other hand, some reports evaluating the role of CPOE systems to reduce medication error rates are conflicting [15,19,23,48]. Differences in system capabilities and programming and differing needs and challenges of institutions may account for the varying results reported in the literature. CPOE systems can serve as valuable tools for assisting in medication prescribing. Confusion due to abbreviations, illegible writing and look-alike/sound-alike drugs should be eliminated or greatly reduced with the use of CPOE. However, the limitations of these systems, which may differ among different systems, should be appreciated. As ART regimens and dosing recommendations change, clinical decision support systems can quickly become out-of-date and require frequent updating. One study identified fields that pre-populated drug names and frequencies within a CPOE system to be the cause of several medication errors [16]. Studies have also identified errors related to disregarded alerts from decision support software [15,16]. “Alert fatigue” is a well-recognized phenomenon that occurs when clinicians are exposed to a large volume of clinical decision support alerts of varying clinical significance. Over time, clinicians begin to become desensitized to the alerts, and they may eventually stop responding to them.

Some limitations of CPOE systems arise from the individual system capabilities. Some systems have the ability to check for appropriate dosing, recommend adjustments in renal dysfunction, and provide alerts for drug interactions, but some systems lack these capabilities. In addition, CPOE systems are often not able to prevent errors of omission, delays in continuation of therapy, and medication scheduling errors [15,45].

Given the limitations of CPOE and clinical decision support technologies, it is unlikely that these interventions alone will be sufficient to fully address the problem of ART errors. These technologies can, however, serve as a powerful tool in the prevention and reduction of ART errors, especially when used in combination with other strategies.

Pharmacist Intervention

Multiple studies have shown that clinical pharmacists are effective at decreasing ART medication errors in the inpatient setting [12,18,23,25,28,45,49,50]. One institution implemented an HIV-specialized pharmacist review strategy that decreased the median time to error correction from 84 hours to 15.5 hours among hospitalized patients [12]. Corrigan et al showed that a review of medications by an HIV-specialized pharmacist 48 hours after hospital admission decreased error rates from 52% to 5% [50]. Another study showed that with the use of an electronic medical record, errors among hospitalized patients with HIV were 9.4 times more likely to be corrected within 24 hours when an HIV-specialized pharmacist was consulted [45].

The majority of studies evaluating the effect of pharmacist interventions have utilized the services of a pharmacist with specialized training in HIV. Few studies have evaluated the impact of interventions by pharmacists without this specialized training. One study retrospectively evaluated and characterized ART errors among hospitalized patients. Medication reconciliation was performed within 24 hours of admission by unit-based pharmacists without specialized training in HIV. Overall, 30.8% of errors were corrected within 24 hours and 14.2% were corrected after 24 hours. However, 54.7% of the errors were not recognized and were never corrected [20]. Just as physicians trained in general medicine lack knowledge of antiretroviral medications, pharmacists without HIV-specialized training may also be less familiar with current ART recommendations [16,37].

Overall, the studies evaluating the impact of pharmacist intervention on reducing ART error rates have shown significant reductions in time to error corrections. The nature of this type of intervention however, lends itself to correction of errors rather than prevention of errors. Indeed, one hospital reported an ART error rate of 29% on the first day of admission compared to 7% on the second day of admission, a decrease that was attributed to retrospective review of medication orders by clinical pharmacists. This study also noted the occurrences of additional errors identified on the second day of admission, highlighting the importance of daily review and follow-up throughout the hospital stay [28].

Hospital Formulary Selections

Several studies have documented an association between hospital formulary options and ART errors [20,22,24,26]. The prescribing of ART medications that are not available on hospital formulary is consistently associated with higher rates of error. Many hospitals minimize the numbers of different medications offered through the maintenance of a formulary. Formularies assist in reducing costs, preserving storage space, and simplifying prescribing. Because some hospitals choose to exclude co-formulated products from the formulary, several ART medications may not be included. In addition, some ART medications may be excluded from formulary due to their infrequent use or higher costs. The extra step of converting a co-formulated product to its individual components increases the risk for errors. In one study, the addition of all co-formulated ART medications to the hospital formulary in combination with several other interventions had a significant effect on reducing the ART error rate [26].

Transitions of Care Interventions

Patients with HIV are at risk for experiencing medication errors and discrepancies any time they transition from one health care setting to another. Hospitalization poses the highest risk as it often disrupts continuity of care and corresponds with a comparatively larger number of medication changes [16,51]. This risk is present on admission, throughout hospitalization, and upon discharge. Perhaps the errors of greatest concern are those that are carried forward after discharge on to the outpatient setting. Medication discrepancies at transitions of care have been associated with increases in adverse events and increased hospital readmission rates [52,53]. One study evaluating adverse events in geriatric patients transitioning from hospital to home found that the most frequently reported adverse events after discharge were related to incorrect drugs or dosages of medication regimens [54]. Tools that can assist in integration and coordination during transitions of care are greatly needed.

One of the most important strategies to prevent and correct medication discrepancies during transitions of care is medication reconciliation. Several studies have demonstrated the efficacy of medication reconciliation in decreasing medication errors [55]. Medication reconciliation is especially important for patients taking many medications. An estimated 14% of patients with HIV older than age 65 take 4 or more medications [56]. This population often requires treatment for other chronic conditions such as hypertension, diabetes, and depression, further increasing the risk for adverse drug events including medication error. Because of the complexities associated with the treatment of HIV and the increased risk for errors, routine medication reconciliation among this population should be a priority.

In addition to medication reconciliation, several studies have evaluated the effects of coordinated pharmacist or multidisciplinary post-discharge follow-up visits for medication therapy management as a strategy to reduce preventable medication-related adverse events [57–59]. Patients receiving clinic-based medication therapy management by a clinical pharmacist after hospital discharge had a lower 60-day hospital readmission rate compared to those who did not have a clinic visit with a pharmacist (18.2% vs. 43.1%) [59]. Another study compared 2 models of post-discharge follow-up, a multidisciplinary team model led by a clinical pharmacist compared to a standard physician-only model. The goal of the multi-disciplinary team model was to complete a thorough medication review, address lifestyle interventions, and address barriers to care. Overall, patients seen by the multidisciplinary team had a 30-day hospital readmission rate of 14.3% compared with a 34.3% readmission rate in the physician-only team [58]. Many different care models have been proposed to improve continuity of care for patients with HIV. The ideal model is not known, and it is likely that several different models would be effective. Optimal models should integrate the patient-physician relationship with multidisciplinary team approaches [60].

Conclusion

The rapidly evolving nature of HIV management and the increase in non–HIV-related comorbidities among this population has created a landscape that places these patients at risk for medication errors. Although ART has improved survival, medication errors place these patients at risk for adverse events and treatment failure. Medication errors are particularly likely to occur during transitions of care. Several interventions to prevent and decrease ART errors have been evaluated including educational strategies, hospital formulary changes, use of technology, and medication review and intervention by clinical pharmacists. However more research is needed to determine optimal strategies to address ART medication errors. Successful approaches have implemented comprehensive methods combining multiple interventions aimed at addressing several distinct sources of error. Promotion of a culture of safety is also an important component of medication error management. Health care professionals should be encouraged to report errors, and lessons learned from errors should be used to guide efforts to prevent future errors. Finally, improved integration of care with a focus on systematic initiatives for medication reconciliation as well as multidisciplinary approaches to transitions of care will be essential for reducing the rate of medication error among patients with HIV.

Corresponding author: Lindsay M. Daniels, PharmD, [email protected].

Financial disclosures: None.

References

1. Egger M, May M, Chene G, et al. Prognosis of HIV-1 infected patients starting highly active, antiretroviral therapy: a collaborative analysis of prospective studies. Lancet 2002;360:119–29.

2. Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998;338:853–60.

3. May MT, Gompels M, Delpech V, et al. Impact on life expectancy of HIV-1 positive individuals of CD4 cell count and viral load response to antiretroviral therapy. AIDS 2014; 28:1193–202.

4. Greene M, Justice AC, Lampiris HW, Valcour V. Management of HIV infection in advanced age. JAMA 2013;309:1397–1405.

5. Baker JV, Peng G, Rapkin J, et al. CD4+ count and risk of non-AIDS diseases following initial treatment of HIV infection. AIDS 2008;22:841–8.

6. Monforte A, Abrams D, Pradier C, et al. HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies. AIDS 2008;22:2143–53.

7. Buchacz K, Baker RK, Moorman AC, et al. Rates of hospitalizations and associated diagnoses in a large multisite cohort of HIV patients in the United States, 1994-2005. AIDS 2008;22:1345–54.

8. Aspden P, Wolcott J, Bootman JL, et al. Preventing medication errors: quality chasm series. Washington DC: National Academies Press; 2007.

9. Kripalani S, Roumie CL, Dalal AK, et al. Effect of a pharmacist intervention on clinically important medication errors after hospital discharge: a randomized trial. Ann Intern Med 2012;157:1–10.

10. Tam VC, Knowles SR, Cornish PL, et al. Frequency, type and clinical importance of medication history errors at admission to hospital: a systematic review. CMAJ 2005;173:510–515.

11. Bell CM, Brener SS, Gunraj N, et al. Association of ICU or hospital admission with unintentional discontinuation of medications for chonic diseases. JAMA 2011;306:840–7.

12. Heelon M, Skiest D, Tereso G, et al. Effect of a clinical pharmacist’s interventions on duration of antiretroviral-related errors in hospitalized patients. Am J Health Syst Pharm 2007;64:2064–8.

13. Purdy BD, Raymond AM, Lesar TS. Antiretroviral prescribing errors in hospitalized patients. Ann Pharmacother 2000;34:833–8.

14. Gray J, Hicks RW, Hutchings C. Antiretroviral medication errors in a national medication error database. AIDS Patient Care STDS 2005;19:803–12.

15. Rastegar DA, Knight AM, Monolakis JS. Antiretroviral medication errors among patients with HIV infection. Clin Infect Dis 2006;43:933–8.

16. Snyder AM, Klinker K, Orrick JJ, et al. An in-depth analysis of medication errors in hospitalized patients with HIV. Ann Pharmacother 2011;45:459–68.

17. Edelman EJ, Gordon KS, Glover J, et al. The next therapeutic challenge in HIV: polypharmacy. Drugs Aging 2013;30:613–28.

18. Carcelero E, Tuset M, Martin M, et al. Evaluation of antiretroviral-related errors and interventions by the clinical pharmacist in hospitalized HIV-infected patients. HIV Medicine 2011;12:494–9.

19. Guo Y, Chung P, Weiss C, et al. Customized order-entry sets can prevent antiretroviral prescribing errors: a novel opportunity for antimicrobial stewardship. P T 2015;40:353–8.

20. Commers T, Swindells S, Sayles H, et al. Antiretroviral medication prescribing errors are common with hospitalization of HIV-infected patients. J Antimicrob Chemother 2014;69:262–7.

21. Sanders J, Pallotta A, Bauer S, et al. Antimicrobial stewardship program to reduce antiretroviral medication errors in hospitalized patients with HIV infection. Infect Control Hosp Epidemiol 2014;35:272–7.

22. Chiampas TD, Kim H, Badowski M. Evaluation of the occurrence and type of antiretroviral and opportunistic infection medication errors within the inpatient setting. Pharm Pract 2015;13:512.

23. Eginger KH, Yarborough LL, Inge LD, et al. Medication errors in HIV-infected hospitalized patients: a pharmacist’s impact. Ann Pharmacother 2013;47:953–60.

24. Pastakia SD, Corbett AH, Raasch RH, et al. Frequency of HIV-related medication errors and associated risk factors in hospitalized patients. Ann Pharmacother 2008;42:491–7.

25. Garey KW, Teichner P. Pharmacist intervention program for hospitalized patients with HIV infection. Am J Health Syst Pharm 2000;57:2283–4.

26. Daniels LM, Raasch RH, Corbett AH. Implementation of targeted interventions to decrease antiretroviral-related errors in hospitalized patients. Am J Health Syst Pharm 2012;69:422–30.

27. Li EH, Foisy MM. Antiretroviral and medication errors in hospitalized HIV-positive patients. Ann Pharmacother 2014;48:998–1010.

28. Yehia BR, Mehta JM, Ciuffetelli D, et al. Antiretroviral medication errors remain high but are quickly corrected among hospitalized HIV-infected adults. Clin Infect Dis 2012;55:593–99.

29. Willig JH, Westfall AO, Allison J, et al. Nucleoside reverse-transcriptase inhibitor dosing errors in an outpatient HIV clinic in the electronic medical record era. Clin Infect Dis 2007;45:658–61.

30. Hellinger FJ, Encinosa WE. The cost and incidence of prescribing errors among privately insured HIV patients. Pharmacoeconomics 2010;28:23–34.

31. Deeks SG, Gange SJ, Kitahata MM, et al. Trends in multidrug treatment failure and subsequent mortality among antiretroviral therapy-experienced patients with HIV infection in North America. Clin Infect Dis 2009;49:1582–90.

32. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011;365:493–505.

33. Wittich CM, Burkle CM, Lanier WL. Medication errors: an overview for clinicians. Mayo Clin Proc 2014;89:1116–25.

34. Merchen BA, Gerzenshtein L, Scarsi KK, et al. Evaluation of HIV-specialized pharmacists’ impact on prescribing errors in hospitalized patients on antiretroviral therapy. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy; 2011 Sep 17-20; Chicago IL. Abstract H2–794.

35. Lesar TS, Briceland L, Stein DS. Factors related to errors in medication prescribing. JAMA 1997;277:312–17.

36. Agu KA, Oqua D, Adeyanju Z, et al. The incidence and types of medication errors in patients receiving antiretroviral therapy in resource constrained settings. PLoS ONE 2014;9:e87338.

37. Arshad S, Rothberg M, Rastegar DA, et al. Survey of physician knowledge regarding antiretroviral medications in hospitalized HIV-infected patients. J Int AIDS Soc 2009;12:1.

38. Fultz SL, Goulet JL, Weissman S, et al. Differences between infectious diseases-certified physicians and general medicine-certified physicians in the level of comfort with providing primary care to patients. Clin Infect Dis 2005;41:738–43.

39. Cheng QJ, Engelage EM, Grogan TR, et al. Who provides primary care? An assessment of HIV patient and provider practices and preferences. J AIDS Clin Res 2014;5:366.

40. Cohen MR, Davis NM. AZT is a dangerous abbreviation. Am Pharm 1992;32:26.

41. Ambrosini MT, Mandler HD, Wood CA. AZT: zidovudine or azathioprine? Lancet 1992;339:935.

42. Sponsler KC, Neal EB, Kripalani S. Improving medication safety during hospital-based transitions of care. Cleve Clin J Med 2015;82:351–60.

43. Peeters MJ, Pinto SL. Assessing the impact of an educational program on decreasing prescribing errors at a university hospital. J Hosp Med 2009;4:97–101.

44. Faragon JJ, Lesar TS. Update on prescribing errors with HAART. AIDS Read 2003;13:268–78.

45. Batra R, Wolbach-Lowes J, Swindells S, et al. Impact of an electronic medical record on the incidence of antiretroviral prescription errors and HIV pharmacist reconciliation on error correction among hospitalized HIV-infected patients. Antivir Ther 2015:2040–58.

46. Keers RN, Williams SD, Cooke J, et al. Impact of interventions designed to reduce medication administration errors in hospitals: a systematic review. Drug Saf 2014;37:317–32.

47. Reckmann MH, Westbrook JI, Koh Y, et al. Does computerized provider order entry reduce prescribing errors for hospital inpatients? A systematic review. J Am Med Inform Assoc 2009;16:613–23.

48. Bozek PS, Perdue BE, Bar-Din M, Weidle PJ. Effect of pharmacist interventions on medication use and cost in hospitalized patients with or without HIV infection. Am J Health Syst Pharm 1998;55:1151–5.

49. De Maat MM, de Boer A, Koks CH, et al. Evaluation of clinical pharmacist interventions on drug interactions in outpatient pharmaceutical HIV care. J Clin Pharm Ther 2004;29:121–30.

50. Corrigan MA, Atkinson KM, Sha BE, Crank CW. Evaluation of pharmacy-implemented medication reconciliation directed at antiretroviral therapy in hospitalized HIV/AIDS patients. Ann Pharmacother 2010;44:222–3.

51. Rao N, Patel V, Grigoriu A, et al. Antiretroviral therapy prescribing in hospitalized HIV clinic patients. HIV Med 2012;13:367–71.

52. Coleman EA, Smith JD, Raha D, Min S. Posthospital medication discrepancies. Arch Intern Med 2005;165:1842–7.

53. Forster AJ, Murff HJ, Peterson JF, et al. The incidence and severity of adverse events affecting patients after discharge from the hospital. Ann Intern Med 2003;138:161–7.

54. Mesteig M, Helbostad JL, Sletvold O, et al. Unwanted incidents during transition of geriatric patients from hospital to home: a prospective observational study. BMC Health Serv Res 2010;10:1.

55. Mueller SK, Sponsler KC, Kripalani S, Schnipper JL. Hospital-based medication reconciliation practices: a systematic review. Arch Intern Med 2012;172:1057–69.

56. Hasse B, Ledergerber B, Furrer H, et al. Morbidity and aging in HIV-infected persons: the Swiss HIV Cohort Study. Clin Infect Dis 2011;53:1130–9.

57. Downes JM, O’Neal KS, Miller MJ, et al. Identifying opportunities to improve medication management in transitions of care. Am J Health Syst Pharm 2015;72:S58–69.

58. Cavanaugh JJ, Lindsey KN, Shilliday BB, Ratner SP. Pharmacist-coordinated multidisciplinary hospital follow-up visits improve patient outcomes. J Manag Care Spec Pharm 2015;21:256–60.

59. Bellone JM, Barner JC, Lopez DA. Postdischarge interventions by pharmacists and impact on hospital readmission rates. J Am Pharm Assoc 2012;52:358–62.

60. Handford CD, Tynan AM, Rackal JM, Glazier RH. Setting and organization of care for persons living with HIV/AIDS. Cochrane Database Syst Rev 2006;19:CD004348.

From the University of North Carolina Medical Center (Dr. Daniels) and Renovion (Dr. Durham), Chapel Hill, NC.

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ABSTRACT

• Objective: To examine common types of medication errors occurring in patients with HIV, with a focus on patient risk, contributing factors, and interventions that can be employed to address the problem of medication errors in this population.

• Methods: Review of the literature.

• Results: The increased complexity and specialization of HIV care, the presence of comorbidities, and the evolving nature of medication management in patients with HIV place these patients at risk for medication errors and adverse drug events. Many studies of hospitalized patients with HIV have reported high rates of medication errors in this population. The consequences of antiretroviral therapy errors can range from minimal harm to life-threatening toxicities and the possibility of resistance and treatment failure. This review discusses the factors contributing to the high rates of error associated with antiretroviral therapy and details strategies to reduce and prevent errors in these patients.

• Conclusion: A comprehensive approach combining multiple interventions can be used to reduce and prevent antiretroviral medication errors in patients with HIV in order to improve the quality of care for this population.

Great progress has been made in the treatment of HIV over the past several decades. With the advancements in treatment options for HIV, considerable reductions in the morbidity and mortality associated with HIV and HIV-related complications have been realized [1,2]. Antiretroviral therapy (ART) has rapidly evolved, offering different mechanisms of action, improved potency, increased tolerability and reduced pill burdens. As a result, HIV infection has transformed from a terminal illness to a manageable chronic disease.

The success of HIV treatment has created a new set of challenges for health care professionals. Patients with successfully treated HIV can expect to live a nearly normal lifespan [3]. With this extended life expectancy, the number of older adults infected with HIV continues to rise, and care for these patients requires a broader and more comprehensive approach. Although HIV-related illnesses such as opportunistic infections have declined, the rate of non–HIV-related comorbidities among patients with HIV has increased [4]. Large cohort studies have shown an association between the risk for HIV-associated non–AIDS-related conditions and CD4 counts [5,6]. HIV-associated non–AIDS-related conditions include cardiovascular disease, kidney disease, liver disease, central nervous system disease, osteoporosis, and non–AIDS-associated malignancies. These conditions occur either more frequently or are more severe in patients with lower CD4 counts or detectable viral loads, but can also arise or persist in virologically suppressed patients with high CD4 counts [4].

The increased complexity and specialization of HIV care, the presence of comorbidities, and the evolving nature of medication management in this population place these patients at risk for experiencing medication errors and adverse drug events. Patients with HIV often receive care by many providers in many different settings. Clinicians caring for patients with HIV must be familiar not only with the treatment of HIV but also with the management and integration of their patients’ primary care needs. In addition, the rates of hospitalization for HIV-infected patients have declined substantially since the mid-1990s [7]. Of the patients with HIV requiring hospitalization, the proportion of hospitalizations due to opportunistic infections has decreased and the proportion of hospitalizations due to other conditions has increased [7]. For many of these patients, the treatment of HIV has retreated to the background as a stable condition, while the management of other acute illness requires more attention.

An estimated 1.5 million adverse drug events occur each year in the United States due to medication errors [8]. Medication errors are common and can occur at any point during the medication use process, including procurement, prescribing, transcribing, preparing or compounding, dispensing, administration, and monitoring. Any time a patient moves from one setting of health care to another, the risk for medication errors is increased. Several reports have highlighted the increased risk for medication errors and adverse effects that can occur during these transitions of care. In fact, up to 70% of patients have an unintentional medication discrepancy at hospital discharge [9]. Errors during hospital admission are common as well, affecting up to two-thirds of patients admitted to hospitals [10,11].

As HIV care becomes more complex, concerns have been raised regarding increases in the number of medication errors in these patients, especially during transitions of care. Most studies of hospitalized patients with HIV have reported error rates of 5% to 30% [12–15]. One study demonstrated that the risk for a medication error at admission for patients with HIV was 3.8 errors per patient, whereas for patients without HIV the rate was 2.8 errors per patient [16]. Because of the potential for the emergence of resistance mutations, adherence to ART is essential for successful treatment and sustained viral suppression. Thus, medication errors of omission could have particularly detrimental effects for the long-term treatment of patients with HIV. Furthermore, as this population ages, polypharmacy becomes common, placing these patients at risk for errors related to dosing and drug interactions [17]. Because medication errors can lead to patient harm and death as well as increased health care costs, elucidating the reasons for errors associated with HIV management and exploring strategies aimed at the reduction and prevention of errors is essential.

The goal of this review is to examine the common types of medication errors occurring in patients with HIV, with a focus on patient risk, contributing factors, and interventions that can be employed to address the problem of medication errors in this population.

Incidence of ART Errors

Several studies have indicated that the incidence of ART errors in hospitalized patients is rising. The rate of ART errors detected at admission among hospitalized patients increased from 2% in 1996 to 12% in 1998 according to one study [13]. Studies conducted from 2004 to 2007 report ART error rates at hospital admission ranging from 17% to 26% [12,15,18]. In more recent studies, high ART error rates ranging from 35% to 55% have been reported [19–23]. Two studies have reported ART error rates occurring at hospital admission to be as high as 70% [24,25].

Various types of ART medication errors can occur. Commonly reported errors include those related to drug interactions, incorrect dosing, incorrect scheduling, and incomplete regimens. Errors occurring at the time of hospital admission appear to be more common than errors occurring at other time points [20,24,26]. A comprehensive systematic review of studies regarding medication errors in hospitalized patients with HIV found that errors at the point of prescribing encompass the majority of errors [27]. One study identified 82 ART errors occurring at admission in 68 hospitalized patients. Of these errors, 37% occurred at the point of prescribing, 27% were attributed to dispensing, and 18% were attributed to inaccuracies in outpatient clinic documentation [24].

Several authors have drawn associations between the rate of errors and the class of antiretroviral prescribed. Protease inhibitors have been the most frequently implicated drug class [13,18,20,27,28]. In an analysis of 145 ART errors in one hospital, 70% of dosing errors involved protease inhibitors and 30% involved nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). In addition, scheduling errors occurred most often with protease inhibitors, and errors due to drug interactions were also most likely to involve protease inhibitors [28]. Conversely, another study did not find an association between protease inhibitors and the risk for error compared to other classes of drugs. In fact, this study showed that the NRTI class was associated with an increased risk of prescribing error compared to protease inhibitors and that the use of co-formulated drugs that were available on the hospital formulary protected against error [20]. These findings highlight the various factors contributing to error among different institutions, especially related to hospital formulary selections and availability of specific drugs.

Fewer studies have evaluated ART errors in outpatient settings. One report evaluated the NRTI medication records from an outpatient electronic medical record system from August 2004 to September 2005. A total of 902 NRTI records for 603 patients were analyzed. The overall error rate was 6% (53/902), with renal dosing errors being most common (75% of errors) [29]. Another evaluation of ART errors among privately insured patients with HIV found that the probability of a patient with HIV receiving an inappropriate drug combination in a given year was higher in 2005 (5.9%) compared to 1999 and 2000 (1.9%). Many of the increased errors seen in 2005 compared to 1999–2000 in this study were attributed to errors related to protease inhibitor boosting [30].

Harms and Consequences of ART Errors

Because of the potential for the emergence of drug resistance, adherence to an ART regimen is essential for successful treatment and sustained viral suppression. ART medication errors causing disrupted therapy, omitted drugs, or suboptimal dosing can lead to the development of viral resistance mutations and ultimately treatment failure placing patients at risk for HIV-related complications such as opportunistic infections as well as non–HIV-related complications [31]. Health care providers should recognize the importance of appropriate uninterrupted therapy for this population and should assist in facilitating this effort. On a community level, patients with elevated plasma HIV RNA levels due to untreated disease or treatment failure have a greater risk of transmitting HIV to others [32]. Effective ART on a population basis will have important public health advantages.

In addition to the potential consequences of ART error relating to treatment failure and resistance, ART errors may also lead to drug toxicities and drug intolerance, increasing the risk of nonadherence, and further exacerbating the aforementioned consequences.

ART errors also carry the same consequences as errors involving other non-ART medications, such as loss of patient trust, civil and criminal legal consequences, professional board discipline, and increased health care costs [33]. One study reported a cost avoidance of $24,000 annually for inpatient and $124,000 annually for outpatient through the use of pharmacists’ interventions to prevent errors [34]. Another study found that patients experiencing an ART error related to protease inhibitor boosting incurred claims costing 21.5% more than patients not experiencing a boosting error [30].

Contributing Factors

Health care professional–associated factors can also contribute to ART errors. The increasing complexity and specialization of HIV care and the rapidly evolving nature of medication management in this population have created an environment in which many providers without extensive experience in the treatment of HIV are responsible for managing HIV in settings beyond the HIV clinic. A survey of non-HIV specialized physicians conducted in 2007 revealed a poor knowledge base of common ART regimens among these physicians [37]. Likewise, HIV providers may be uncomfortable serving a primary care role for patients with HIV due to their own lack of experience and knowledge of primary care [38]. This issue is becoming more relevant, as non-AIDS comorbidities are emerging as the main health concerns for patients with HIV [39]. Health care professionals’ knowledge of HIV care also contributes to ART errors at other points in the medication use process beyond prescribing. Pharmacists lacking experience in identifying appropriate ART regimens may not recognize errors, and, therefore, may not be able to intervene and prevent errors from occurring.

Medication factors contributing to the risk for errors include risks related to the pharmacologic properties of certain drugs as well as drug naming and labeling factors. Certain antiretroviral classes are known to interact with many medications due to inhibition or induction of metabolic pathways responsible for drug metabolism, such as the cytochrome P-450 pathways. In addition, many antiretroviral medications require “boosting” with another drug to increase systemic exposure of the antiretroviral. Boosting is required for most protease inhibitors and for the integrase inhibitor elvitegravir. For some of these medications, the boosting agent is provided in a co-formulated product. However, for others, a separate prescription for the boosting medication is required. These factors contribute to the risks for drug interactions as well as drug and dosing errors.

Errors may also occur due to drug naming and labeling factors. Confusion due to look-alike/sound-alike medications is common, especially with handwritten or verbally transcribed orders. Examples of look-alike/sound-alike medications include lamivudine/lamotrigine, Viramune/Viread/Viracept, and ritonavir/Retrovir. The use of abbreviations can also lead to error. Reports have described errors associated with zidovudine, which is often abbreviated AZT, being confused with azathioprine [40,41]. An evaluation of ART errors reported to a national medication error reporting program found that look-alike/sound-alike medication names contributed to 19% (77/400) of the errors reported during the 48-month time period evaluated [15].

Several antiretroviral medications are co-formulated into single tablets to decrease pill burden and increase adherence. The use of co-formulated products has the potential to either increase or decrease the risk of errors. Prescribing one co-formulated product rather than its individual components simplifies the prescribing process, allowing the prescriber to become familiar with one product and one dosing scheme in place of 2 or more drugs with different dosing recommendations. The risk of inadvertent omission of a drug and the risk of improper dosing is reduced with the use of co-formulated products. On the other hand, when patients are transitioned from one health care setting to another (such as admission to a hospital), these products may require conversion to the individual components of the drug due to formulary availability and/or cost concerns. Studies have shown that formulary conversions from co-formulated products to individual components are frequently associated with ART errors and that the use of co-formulated products in the inpatient setting reduces these errors [20,22,24,26].

Finally, factors related to the health care setting can influence the risk for errors. High patient numbers, time constraints, and workload stresses can all increase the likelihood that an error will occur [36]. Interruptions and distractions occurring at any point in the medication use process can lead to error.

Transitioning from one health care setting to another also places patients at risk for being harmed by medication errors. Up to 70% of patients may have an unintentional medication discrepancy at hospital discharge, and errors occurring at hospital admission have been reported to affect two-thirds of admitted patients [42]. Many of these errors hold the potential to cause harm to the patient, especially if the errors are carried forward throughout the patient’s admission and after discharge. One study found that 22% of ART errors occurring at hospital admission were attributable to outpatient clinic documentation errors [24]. This highlights the need for improved documentation processes and draws attention to the element of communication at transitional points of care. Lack of adequate resources for medication reconciliation is a widely recognized challenge. This includes resources of personnel as well as electronic medical record systems that can facilitate the reconciliation process. The importance of accurately documenting a patient’s medication history and the ability to easily communicate this information to other health care settings cannot be underestimated. Electronic medical record systems should be developed to facilitate and enhance the processes of reconciliation, documentation, and communication.

Interventions to Address ART Errors

The causes of ART errors are multifactorial and should be addressed using comprehensive approaches tailored to the specific health care setting. Several types of interventions aimed at reducing and preventing ART errors have been evaluated in the literature [12,18,26,27]. In general, these interventions have focused on provider education, use of technology and clinical decision support systems, pharmacist-led medication review and intervention, and hospital formulary changes. Other interventions that may lead to a reduction in ART errors include minimizing polypharmacy, improving medication reconciliation processes during transitions of care, and multidisciplinary follow-up clinic visits after hospital discharge.

Because the sources of ART errors are multifactorial, the optimal strategy to prevent and reduce errors is likely to be a comprehensive approach combining several of the aforementioned interventions. One study showed that a combined approach that included updates to the institution’s computerized physician order entry (CPOE) system, education for the pharmacy and ID departments, and daily review of patients’ medications by pharmacists was successful in reducing the percentage of admissions with an ART error from 50% to 34%. In addition, the time to error resolution decreased from 180 hours to 23 hours, and the error resolution rate increased from 32% to 68% [21]. Another study demonstrated benefits using a comprehensive approach including the dissemination of educational pocket cards for physicians, pharmacists and nurses; CPOE alerts; hospital formulary updates to include co-formulated products; and a daily review of medications by an ID-specialized pharmacist for patients receiving ART. These strategies resulted in a reduced ART error rate from 72% to 15% in 7 months [26]. These studies demonstrate the benefit of multifaceted strategies to reduce ART error rates.

Education

Given the complexity of HIV care and overall lack of antiretroviral medication knowledge among non-ID specialized health care professionals, educational programs aimed at increasing the comfort level and familiarity of ART is important [16,37]. Frequent training to update  health care professionals on the newest recommendations for HIV management can help achieve this goal [19,27]. Educational interventions aimed at reducing medication errors have been shown to be transiently effective but may lack sustained effects [43]. Educational programs for health care professionals should be designed to provide frequent brief updates, and are likely to be more successful when combined with other approaches [19,26].

Education directed toward patients, families, and caregivers can also play a pivotal role in error prevention. Patients should be encouraged to use one pharmacy, if possible, to ensure that one complete, accurate, and current profile is maintained. The use of one pharmacy can also assist in the identification of therapeutic duplications and drug interactions. Counseling patients with visual aids, such as charts with pictures of drugs, can also be used as a tool for education. Patients who are familiar with the names and the appearances of their drugs are more likely to recognize errors. In addition, patients should be advised to maintain their own current medication list so that they will be able to provide this information to all of the health care professionals involved in their care [33,44].

Technology and Clinical Decision Support Systems

Overall, the increasing use of technology such as CPOE, decision support systems, and barcoding systems has been shown to decrease the risk of medication error [19,45,46]. Guo et al observed a 35% decrease in ART error rates after the integration of customized order entry sets into an existing CPOE program [19]. Another study reported a 50% decrease in the ART error rate after the introduction of an electronic medical record system [45]. On the other hand, some reports evaluating the role of CPOE systems to reduce medication error rates are conflicting [15,19,23,48]. Differences in system capabilities and programming and differing needs and challenges of institutions may account for the varying results reported in the literature. CPOE systems can serve as valuable tools for assisting in medication prescribing. Confusion due to abbreviations, illegible writing and look-alike/sound-alike drugs should be eliminated or greatly reduced with the use of CPOE. However, the limitations of these systems, which may differ among different systems, should be appreciated. As ART regimens and dosing recommendations change, clinical decision support systems can quickly become out-of-date and require frequent updating. One study identified fields that pre-populated drug names and frequencies within a CPOE system to be the cause of several medication errors [16]. Studies have also identified errors related to disregarded alerts from decision support software [15,16]. “Alert fatigue” is a well-recognized phenomenon that occurs when clinicians are exposed to a large volume of clinical decision support alerts of varying clinical significance. Over time, clinicians begin to become desensitized to the alerts, and they may eventually stop responding to them.

Some limitations of CPOE systems arise from the individual system capabilities. Some systems have the ability to check for appropriate dosing, recommend adjustments in renal dysfunction, and provide alerts for drug interactions, but some systems lack these capabilities. In addition, CPOE systems are often not able to prevent errors of omission, delays in continuation of therapy, and medication scheduling errors [15,45].

Given the limitations of CPOE and clinical decision support technologies, it is unlikely that these interventions alone will be sufficient to fully address the problem of ART errors. These technologies can, however, serve as a powerful tool in the prevention and reduction of ART errors, especially when used in combination with other strategies.

Pharmacist Intervention

Multiple studies have shown that clinical pharmacists are effective at decreasing ART medication errors in the inpatient setting [12,18,23,25,28,45,49,50]. One institution implemented an HIV-specialized pharmacist review strategy that decreased the median time to error correction from 84 hours to 15.5 hours among hospitalized patients [12]. Corrigan et al showed that a review of medications by an HIV-specialized pharmacist 48 hours after hospital admission decreased error rates from 52% to 5% [50]. Another study showed that with the use of an electronic medical record, errors among hospitalized patients with HIV were 9.4 times more likely to be corrected within 24 hours when an HIV-specialized pharmacist was consulted [45].

The majority of studies evaluating the effect of pharmacist interventions have utilized the services of a pharmacist with specialized training in HIV. Few studies have evaluated the impact of interventions by pharmacists without this specialized training. One study retrospectively evaluated and characterized ART errors among hospitalized patients. Medication reconciliation was performed within 24 hours of admission by unit-based pharmacists without specialized training in HIV. Overall, 30.8% of errors were corrected within 24 hours and 14.2% were corrected after 24 hours. However, 54.7% of the errors were not recognized and were never corrected [20]. Just as physicians trained in general medicine lack knowledge of antiretroviral medications, pharmacists without HIV-specialized training may also be less familiar with current ART recommendations [16,37].

Overall, the studies evaluating the impact of pharmacist intervention on reducing ART error rates have shown significant reductions in time to error corrections. The nature of this type of intervention however, lends itself to correction of errors rather than prevention of errors. Indeed, one hospital reported an ART error rate of 29% on the first day of admission compared to 7% on the second day of admission, a decrease that was attributed to retrospective review of medication orders by clinical pharmacists. This study also noted the occurrences of additional errors identified on the second day of admission, highlighting the importance of daily review and follow-up throughout the hospital stay [28].

Hospital Formulary Selections

Several studies have documented an association between hospital formulary options and ART errors [20,22,24,26]. The prescribing of ART medications that are not available on hospital formulary is consistently associated with higher rates of error. Many hospitals minimize the numbers of different medications offered through the maintenance of a formulary. Formularies assist in reducing costs, preserving storage space, and simplifying prescribing. Because some hospitals choose to exclude co-formulated products from the formulary, several ART medications may not be included. In addition, some ART medications may be excluded from formulary due to their infrequent use or higher costs. The extra step of converting a co-formulated product to its individual components increases the risk for errors. In one study, the addition of all co-formulated ART medications to the hospital formulary in combination with several other interventions had a significant effect on reducing the ART error rate [26].

Transitions of Care Interventions

Patients with HIV are at risk for experiencing medication errors and discrepancies any time they transition from one health care setting to another. Hospitalization poses the highest risk as it often disrupts continuity of care and corresponds with a comparatively larger number of medication changes [16,51]. This risk is present on admission, throughout hospitalization, and upon discharge. Perhaps the errors of greatest concern are those that are carried forward after discharge on to the outpatient setting. Medication discrepancies at transitions of care have been associated with increases in adverse events and increased hospital readmission rates [52,53]. One study evaluating adverse events in geriatric patients transitioning from hospital to home found that the most frequently reported adverse events after discharge were related to incorrect drugs or dosages of medication regimens [54]. Tools that can assist in integration and coordination during transitions of care are greatly needed.

One of the most important strategies to prevent and correct medication discrepancies during transitions of care is medication reconciliation. Several studies have demonstrated the efficacy of medication reconciliation in decreasing medication errors [55]. Medication reconciliation is especially important for patients taking many medications. An estimated 14% of patients with HIV older than age 65 take 4 or more medications [56]. This population often requires treatment for other chronic conditions such as hypertension, diabetes, and depression, further increasing the risk for adverse drug events including medication error. Because of the complexities associated with the treatment of HIV and the increased risk for errors, routine medication reconciliation among this population should be a priority.

In addition to medication reconciliation, several studies have evaluated the effects of coordinated pharmacist or multidisciplinary post-discharge follow-up visits for medication therapy management as a strategy to reduce preventable medication-related adverse events [57–59]. Patients receiving clinic-based medication therapy management by a clinical pharmacist after hospital discharge had a lower 60-day hospital readmission rate compared to those who did not have a clinic visit with a pharmacist (18.2% vs. 43.1%) [59]. Another study compared 2 models of post-discharge follow-up, a multidisciplinary team model led by a clinical pharmacist compared to a standard physician-only model. The goal of the multi-disciplinary team model was to complete a thorough medication review, address lifestyle interventions, and address barriers to care. Overall, patients seen by the multidisciplinary team had a 30-day hospital readmission rate of 14.3% compared with a 34.3% readmission rate in the physician-only team [58]. Many different care models have been proposed to improve continuity of care for patients with HIV. The ideal model is not known, and it is likely that several different models would be effective. Optimal models should integrate the patient-physician relationship with multidisciplinary team approaches [60].

Conclusion

The rapidly evolving nature of HIV management and the increase in non–HIV-related comorbidities among this population has created a landscape that places these patients at risk for medication errors. Although ART has improved survival, medication errors place these patients at risk for adverse events and treatment failure. Medication errors are particularly likely to occur during transitions of care. Several interventions to prevent and decrease ART errors have been evaluated including educational strategies, hospital formulary changes, use of technology, and medication review and intervention by clinical pharmacists. However more research is needed to determine optimal strategies to address ART medication errors. Successful approaches have implemented comprehensive methods combining multiple interventions aimed at addressing several distinct sources of error. Promotion of a culture of safety is also an important component of medication error management. Health care professionals should be encouraged to report errors, and lessons learned from errors should be used to guide efforts to prevent future errors. Finally, improved integration of care with a focus on systematic initiatives for medication reconciliation as well as multidisciplinary approaches to transitions of care will be essential for reducing the rate of medication error among patients with HIV.

Corresponding author: Lindsay M. Daniels, PharmD, [email protected].

Financial disclosures: None.

References

1. Egger M, May M, Chene G, et al. Prognosis of HIV-1 infected patients starting highly active, antiretroviral therapy: a collaborative analysis of prospective studies. Lancet 2002;360:119–29.

2. Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998;338:853–60.

3. May MT, Gompels M, Delpech V, et al. Impact on life expectancy of HIV-1 positive individuals of CD4 cell count and viral load response to antiretroviral therapy. AIDS 2014; 28:1193–202.

4. Greene M, Justice AC, Lampiris HW, Valcour V. Management of HIV infection in advanced age. JAMA 2013;309:1397–1405.

5. Baker JV, Peng G, Rapkin J, et al. CD4+ count and risk of non-AIDS diseases following initial treatment of HIV infection. AIDS 2008;22:841–8.

6. Monforte A, Abrams D, Pradier C, et al. HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies. AIDS 2008;22:2143–53.

7. Buchacz K, Baker RK, Moorman AC, et al. Rates of hospitalizations and associated diagnoses in a large multisite cohort of HIV patients in the United States, 1994-2005. AIDS 2008;22:1345–54.

8. Aspden P, Wolcott J, Bootman JL, et al. Preventing medication errors: quality chasm series. Washington DC: National Academies Press; 2007.

9. Kripalani S, Roumie CL, Dalal AK, et al. Effect of a pharmacist intervention on clinically important medication errors after hospital discharge: a randomized trial. Ann Intern Med 2012;157:1–10.

10. Tam VC, Knowles SR, Cornish PL, et al. Frequency, type and clinical importance of medication history errors at admission to hospital: a systematic review. CMAJ 2005;173:510–515.

11. Bell CM, Brener SS, Gunraj N, et al. Association of ICU or hospital admission with unintentional discontinuation of medications for chonic diseases. JAMA 2011;306:840–7.

12. Heelon M, Skiest D, Tereso G, et al. Effect of a clinical pharmacist’s interventions on duration of antiretroviral-related errors in hospitalized patients. Am J Health Syst Pharm 2007;64:2064–8.

13. Purdy BD, Raymond AM, Lesar TS. Antiretroviral prescribing errors in hospitalized patients. Ann Pharmacother 2000;34:833–8.

14. Gray J, Hicks RW, Hutchings C. Antiretroviral medication errors in a national medication error database. AIDS Patient Care STDS 2005;19:803–12.

15. Rastegar DA, Knight AM, Monolakis JS. Antiretroviral medication errors among patients with HIV infection. Clin Infect Dis 2006;43:933–8.

16. Snyder AM, Klinker K, Orrick JJ, et al. An in-depth analysis of medication errors in hospitalized patients with HIV. Ann Pharmacother 2011;45:459–68.

17. Edelman EJ, Gordon KS, Glover J, et al. The next therapeutic challenge in HIV: polypharmacy. Drugs Aging 2013;30:613–28.

18. Carcelero E, Tuset M, Martin M, et al. Evaluation of antiretroviral-related errors and interventions by the clinical pharmacist in hospitalized HIV-infected patients. HIV Medicine 2011;12:494–9.

19. Guo Y, Chung P, Weiss C, et al. Customized order-entry sets can prevent antiretroviral prescribing errors: a novel opportunity for antimicrobial stewardship. P T 2015;40:353–8.

20. Commers T, Swindells S, Sayles H, et al. Antiretroviral medication prescribing errors are common with hospitalization of HIV-infected patients. J Antimicrob Chemother 2014;69:262–7.

21. Sanders J, Pallotta A, Bauer S, et al. Antimicrobial stewardship program to reduce antiretroviral medication errors in hospitalized patients with HIV infection. Infect Control Hosp Epidemiol 2014;35:272–7.

22. Chiampas TD, Kim H, Badowski M. Evaluation of the occurrence and type of antiretroviral and opportunistic infection medication errors within the inpatient setting. Pharm Pract 2015;13:512.

23. Eginger KH, Yarborough LL, Inge LD, et al. Medication errors in HIV-infected hospitalized patients: a pharmacist’s impact. Ann Pharmacother 2013;47:953–60.

24. Pastakia SD, Corbett AH, Raasch RH, et al. Frequency of HIV-related medication errors and associated risk factors in hospitalized patients. Ann Pharmacother 2008;42:491–7.

25. Garey KW, Teichner P. Pharmacist intervention program for hospitalized patients with HIV infection. Am J Health Syst Pharm 2000;57:2283–4.

26. Daniels LM, Raasch RH, Corbett AH. Implementation of targeted interventions to decrease antiretroviral-related errors in hospitalized patients. Am J Health Syst Pharm 2012;69:422–30.

27. Li EH, Foisy MM. Antiretroviral and medication errors in hospitalized HIV-positive patients. Ann Pharmacother 2014;48:998–1010.

28. Yehia BR, Mehta JM, Ciuffetelli D, et al. Antiretroviral medication errors remain high but are quickly corrected among hospitalized HIV-infected adults. Clin Infect Dis 2012;55:593–99.

29. Willig JH, Westfall AO, Allison J, et al. Nucleoside reverse-transcriptase inhibitor dosing errors in an outpatient HIV clinic in the electronic medical record era. Clin Infect Dis 2007;45:658–61.

30. Hellinger FJ, Encinosa WE. The cost and incidence of prescribing errors among privately insured HIV patients. Pharmacoeconomics 2010;28:23–34.

31. Deeks SG, Gange SJ, Kitahata MM, et al. Trends in multidrug treatment failure and subsequent mortality among antiretroviral therapy-experienced patients with HIV infection in North America. Clin Infect Dis 2009;49:1582–90.

32. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011;365:493–505.

33. Wittich CM, Burkle CM, Lanier WL. Medication errors: an overview for clinicians. Mayo Clin Proc 2014;89:1116–25.

34. Merchen BA, Gerzenshtein L, Scarsi KK, et al. Evaluation of HIV-specialized pharmacists’ impact on prescribing errors in hospitalized patients on antiretroviral therapy. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy; 2011 Sep 17-20; Chicago IL. Abstract H2–794.

35. Lesar TS, Briceland L, Stein DS. Factors related to errors in medication prescribing. JAMA 1997;277:312–17.

36. Agu KA, Oqua D, Adeyanju Z, et al. The incidence and types of medication errors in patients receiving antiretroviral therapy in resource constrained settings. PLoS ONE 2014;9:e87338.

37. Arshad S, Rothberg M, Rastegar DA, et al. Survey of physician knowledge regarding antiretroviral medications in hospitalized HIV-infected patients. J Int AIDS Soc 2009;12:1.

38. Fultz SL, Goulet JL, Weissman S, et al. Differences between infectious diseases-certified physicians and general medicine-certified physicians in the level of comfort with providing primary care to patients. Clin Infect Dis 2005;41:738–43.

39. Cheng QJ, Engelage EM, Grogan TR, et al. Who provides primary care? An assessment of HIV patient and provider practices and preferences. J AIDS Clin Res 2014;5:366.

40. Cohen MR, Davis NM. AZT is a dangerous abbreviation. Am Pharm 1992;32:26.

41. Ambrosini MT, Mandler HD, Wood CA. AZT: zidovudine or azathioprine? Lancet 1992;339:935.

42. Sponsler KC, Neal EB, Kripalani S. Improving medication safety during hospital-based transitions of care. Cleve Clin J Med 2015;82:351–60.

43. Peeters MJ, Pinto SL. Assessing the impact of an educational program on decreasing prescribing errors at a university hospital. J Hosp Med 2009;4:97–101.

44. Faragon JJ, Lesar TS. Update on prescribing errors with HAART. AIDS Read 2003;13:268–78.

45. Batra R, Wolbach-Lowes J, Swindells S, et al. Impact of an electronic medical record on the incidence of antiretroviral prescription errors and HIV pharmacist reconciliation on error correction among hospitalized HIV-infected patients. Antivir Ther 2015:2040–58.

46. Keers RN, Williams SD, Cooke J, et al. Impact of interventions designed to reduce medication administration errors in hospitals: a systematic review. Drug Saf 2014;37:317–32.

47. Reckmann MH, Westbrook JI, Koh Y, et al. Does computerized provider order entry reduce prescribing errors for hospital inpatients? A systematic review. J Am Med Inform Assoc 2009;16:613–23.

48. Bozek PS, Perdue BE, Bar-Din M, Weidle PJ. Effect of pharmacist interventions on medication use and cost in hospitalized patients with or without HIV infection. Am J Health Syst Pharm 1998;55:1151–5.

49. De Maat MM, de Boer A, Koks CH, et al. Evaluation of clinical pharmacist interventions on drug interactions in outpatient pharmaceutical HIV care. J Clin Pharm Ther 2004;29:121–30.

50. Corrigan MA, Atkinson KM, Sha BE, Crank CW. Evaluation of pharmacy-implemented medication reconciliation directed at antiretroviral therapy in hospitalized HIV/AIDS patients. Ann Pharmacother 2010;44:222–3.

51. Rao N, Patel V, Grigoriu A, et al. Antiretroviral therapy prescribing in hospitalized HIV clinic patients. HIV Med 2012;13:367–71.

52. Coleman EA, Smith JD, Raha D, Min S. Posthospital medication discrepancies. Arch Intern Med 2005;165:1842–7.

53. Forster AJ, Murff HJ, Peterson JF, et al. The incidence and severity of adverse events affecting patients after discharge from the hospital. Ann Intern Med 2003;138:161–7.

54. Mesteig M, Helbostad JL, Sletvold O, et al. Unwanted incidents during transition of geriatric patients from hospital to home: a prospective observational study. BMC Health Serv Res 2010;10:1.

55. Mueller SK, Sponsler KC, Kripalani S, Schnipper JL. Hospital-based medication reconciliation practices: a systematic review. Arch Intern Med 2012;172:1057–69.

56. Hasse B, Ledergerber B, Furrer H, et al. Morbidity and aging in HIV-infected persons: the Swiss HIV Cohort Study. Clin Infect Dis 2011;53:1130–9.

57. Downes JM, O’Neal KS, Miller MJ, et al. Identifying opportunities to improve medication management in transitions of care. Am J Health Syst Pharm 2015;72:S58–69.

58. Cavanaugh JJ, Lindsey KN, Shilliday BB, Ratner SP. Pharmacist-coordinated multidisciplinary hospital follow-up visits improve patient outcomes. J Manag Care Spec Pharm 2015;21:256–60.

59. Bellone JM, Barner JC, Lopez DA. Postdischarge interventions by pharmacists and impact on hospital readmission rates. J Am Pharm Assoc 2012;52:358–62.

60. Handford CD, Tynan AM, Rackal JM, Glazier RH. Setting and organization of care for persons living with HIV/AIDS. Cochrane Database Syst Rev 2006;19:CD004348.

From the University of North Carolina Medical Center (Dr. Daniels) and Renovion (Dr. Durham), Chapel Hill, NC.

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ABSTRACT

• Objective: To examine common types of medication errors occurring in patients with HIV, with a focus on patient risk, contributing factors, and interventions that can be employed to address the problem of medication errors in this population.

• Methods: Review of the literature.

• Results: The increased complexity and specialization of HIV care, the presence of comorbidities, and the evolving nature of medication management in patients with HIV place these patients at risk for medication errors and adverse drug events. Many studies of hospitalized patients with HIV have reported high rates of medication errors in this population. The consequences of antiretroviral therapy errors can range from minimal harm to life-threatening toxicities and the possibility of resistance and treatment failure. This review discusses the factors contributing to the high rates of error associated with antiretroviral therapy and details strategies to reduce and prevent errors in these patients.

• Conclusion: A comprehensive approach combining multiple interventions can be used to reduce and prevent antiretroviral medication errors in patients with HIV in order to improve the quality of care for this population.

Great progress has been made in the treatment of HIV over the past several decades. With the advancements in treatment options for HIV, considerable reductions in the morbidity and mortality associated with HIV and HIV-related complications have been realized [1,2]. Antiretroviral therapy (ART) has rapidly evolved, offering different mechanisms of action, improved potency, increased tolerability and reduced pill burdens. As a result, HIV infection has transformed from a terminal illness to a manageable chronic disease.

The success of HIV treatment has created a new set of challenges for health care professionals. Patients with successfully treated HIV can expect to live a nearly normal lifespan [3]. With this extended life expectancy, the number of older adults infected with HIV continues to rise, and care for these patients requires a broader and more comprehensive approach. Although HIV-related illnesses such as opportunistic infections have declined, the rate of non–HIV-related comorbidities among patients with HIV has increased [4]. Large cohort studies have shown an association between the risk for HIV-associated non–AIDS-related conditions and CD4 counts [5,6]. HIV-associated non–AIDS-related conditions include cardiovascular disease, kidney disease, liver disease, central nervous system disease, osteoporosis, and non–AIDS-associated malignancies. These conditions occur either more frequently or are more severe in patients with lower CD4 counts or detectable viral loads, but can also arise or persist in virologically suppressed patients with high CD4 counts [4].

The increased complexity and specialization of HIV care, the presence of comorbidities, and the evolving nature of medication management in this population place these patients at risk for experiencing medication errors and adverse drug events. Patients with HIV often receive care by many providers in many different settings. Clinicians caring for patients with HIV must be familiar not only with the treatment of HIV but also with the management and integration of their patients’ primary care needs. In addition, the rates of hospitalization for HIV-infected patients have declined substantially since the mid-1990s [7]. Of the patients with HIV requiring hospitalization, the proportion of hospitalizations due to opportunistic infections has decreased and the proportion of hospitalizations due to other conditions has increased [7]. For many of these patients, the treatment of HIV has retreated to the background as a stable condition, while the management of other acute illness requires more attention.

An estimated 1.5 million adverse drug events occur each year in the United States due to medication errors [8]. Medication errors are common and can occur at any point during the medication use process, including procurement, prescribing, transcribing, preparing or compounding, dispensing, administration, and monitoring. Any time a patient moves from one setting of health care to another, the risk for medication errors is increased. Several reports have highlighted the increased risk for medication errors and adverse effects that can occur during these transitions of care. In fact, up to 70% of patients have an unintentional medication discrepancy at hospital discharge [9]. Errors during hospital admission are common as well, affecting up to two-thirds of patients admitted to hospitals [10,11].

As HIV care becomes more complex, concerns have been raised regarding increases in the number of medication errors in these patients, especially during transitions of care. Most studies of hospitalized patients with HIV have reported error rates of 5% to 30% [12–15]. One study demonstrated that the risk for a medication error at admission for patients with HIV was 3.8 errors per patient, whereas for patients without HIV the rate was 2.8 errors per patient [16]. Because of the potential for the emergence of resistance mutations, adherence to ART is essential for successful treatment and sustained viral suppression. Thus, medication errors of omission could have particularly detrimental effects for the long-term treatment of patients with HIV. Furthermore, as this population ages, polypharmacy becomes common, placing these patients at risk for errors related to dosing and drug interactions [17]. Because medication errors can lead to patient harm and death as well as increased health care costs, elucidating the reasons for errors associated with HIV management and exploring strategies aimed at the reduction and prevention of errors is essential.

The goal of this review is to examine the common types of medication errors occurring in patients with HIV, with a focus on patient risk, contributing factors, and interventions that can be employed to address the problem of medication errors in this population.

Incidence of ART Errors

Several studies have indicated that the incidence of ART errors in hospitalized patients is rising. The rate of ART errors detected at admission among hospitalized patients increased from 2% in 1996 to 12% in 1998 according to one study [13]. Studies conducted from 2004 to 2007 report ART error rates at hospital admission ranging from 17% to 26% [12,15,18]. In more recent studies, high ART error rates ranging from 35% to 55% have been reported [19–23]. Two studies have reported ART error rates occurring at hospital admission to be as high as 70% [24,25].

Various types of ART medication errors can occur. Commonly reported errors include those related to drug interactions, incorrect dosing, incorrect scheduling, and incomplete regimens. Errors occurring at the time of hospital admission appear to be more common than errors occurring at other time points [20,24,26]. A comprehensive systematic review of studies regarding medication errors in hospitalized patients with HIV found that errors at the point of prescribing encompass the majority of errors [27]. One study identified 82 ART errors occurring at admission in 68 hospitalized patients. Of these errors, 37% occurred at the point of prescribing, 27% were attributed to dispensing, and 18% were attributed to inaccuracies in outpatient clinic documentation [24].

Several authors have drawn associations between the rate of errors and the class of antiretroviral prescribed. Protease inhibitors have been the most frequently implicated drug class [13,18,20,27,28]. In an analysis of 145 ART errors in one hospital, 70% of dosing errors involved protease inhibitors and 30% involved nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). In addition, scheduling errors occurred most often with protease inhibitors, and errors due to drug interactions were also most likely to involve protease inhibitors [28]. Conversely, another study did not find an association between protease inhibitors and the risk for error compared to other classes of drugs. In fact, this study showed that the NRTI class was associated with an increased risk of prescribing error compared to protease inhibitors and that the use of co-formulated drugs that were available on the hospital formulary protected against error [20]. These findings highlight the various factors contributing to error among different institutions, especially related to hospital formulary selections and availability of specific drugs.

Fewer studies have evaluated ART errors in outpatient settings. One report evaluated the NRTI medication records from an outpatient electronic medical record system from August 2004 to September 2005. A total of 902 NRTI records for 603 patients were analyzed. The overall error rate was 6% (53/902), with renal dosing errors being most common (75% of errors) [29]. Another evaluation of ART errors among privately insured patients with HIV found that the probability of a patient with HIV receiving an inappropriate drug combination in a given year was higher in 2005 (5.9%) compared to 1999 and 2000 (1.9%). Many of the increased errors seen in 2005 compared to 1999–2000 in this study were attributed to errors related to protease inhibitor boosting [30].

Harms and Consequences of ART Errors

Because of the potential for the emergence of drug resistance, adherence to an ART regimen is essential for successful treatment and sustained viral suppression. ART medication errors causing disrupted therapy, omitted drugs, or suboptimal dosing can lead to the development of viral resistance mutations and ultimately treatment failure placing patients at risk for HIV-related complications such as opportunistic infections as well as non–HIV-related complications [31]. Health care providers should recognize the importance of appropriate uninterrupted therapy for this population and should assist in facilitating this effort. On a community level, patients with elevated plasma HIV RNA levels due to untreated disease or treatment failure have a greater risk of transmitting HIV to others [32]. Effective ART on a population basis will have important public health advantages.

In addition to the potential consequences of ART error relating to treatment failure and resistance, ART errors may also lead to drug toxicities and drug intolerance, increasing the risk of nonadherence, and further exacerbating the aforementioned consequences.

ART errors also carry the same consequences as errors involving other non-ART medications, such as loss of patient trust, civil and criminal legal consequences, professional board discipline, and increased health care costs [33]. One study reported a cost avoidance of $24,000 annually for inpatient and $124,000 annually for outpatient through the use of pharmacists’ interventions to prevent errors [34]. Another study found that patients experiencing an ART error related to protease inhibitor boosting incurred claims costing 21.5% more than patients not experiencing a boosting error [30].

Contributing Factors

Health care professional–associated factors can also contribute to ART errors. The increasing complexity and specialization of HIV care and the rapidly evolving nature of medication management in this population have created an environment in which many providers without extensive experience in the treatment of HIV are responsible for managing HIV in settings beyond the HIV clinic. A survey of non-HIV specialized physicians conducted in 2007 revealed a poor knowledge base of common ART regimens among these physicians [37]. Likewise, HIV providers may be uncomfortable serving a primary care role for patients with HIV due to their own lack of experience and knowledge of primary care [38]. This issue is becoming more relevant, as non-AIDS comorbidities are emerging as the main health concerns for patients with HIV [39]. Health care professionals’ knowledge of HIV care also contributes to ART errors at other points in the medication use process beyond prescribing. Pharmacists lacking experience in identifying appropriate ART regimens may not recognize errors, and, therefore, may not be able to intervene and prevent errors from occurring.

Medication factors contributing to the risk for errors include risks related to the pharmacologic properties of certain drugs as well as drug naming and labeling factors. Certain antiretroviral classes are known to interact with many medications due to inhibition or induction of metabolic pathways responsible for drug metabolism, such as the cytochrome P-450 pathways. In addition, many antiretroviral medications require “boosting” with another drug to increase systemic exposure of the antiretroviral. Boosting is required for most protease inhibitors and for the integrase inhibitor elvitegravir. For some of these medications, the boosting agent is provided in a co-formulated product. However, for others, a separate prescription for the boosting medication is required. These factors contribute to the risks for drug interactions as well as drug and dosing errors.

Errors may also occur due to drug naming and labeling factors. Confusion due to look-alike/sound-alike medications is common, especially with handwritten or verbally transcribed orders. Examples of look-alike/sound-alike medications include lamivudine/lamotrigine, Viramune/Viread/Viracept, and ritonavir/Retrovir. The use of abbreviations can also lead to error. Reports have described errors associated with zidovudine, which is often abbreviated AZT, being confused with azathioprine [40,41]. An evaluation of ART errors reported to a national medication error reporting program found that look-alike/sound-alike medication names contributed to 19% (77/400) of the errors reported during the 48-month time period evaluated [15].

Several antiretroviral medications are co-formulated into single tablets to decrease pill burden and increase adherence. The use of co-formulated products has the potential to either increase or decrease the risk of errors. Prescribing one co-formulated product rather than its individual components simplifies the prescribing process, allowing the prescriber to become familiar with one product and one dosing scheme in place of 2 or more drugs with different dosing recommendations. The risk of inadvertent omission of a drug and the risk of improper dosing is reduced with the use of co-formulated products. On the other hand, when patients are transitioned from one health care setting to another (such as admission to a hospital), these products may require conversion to the individual components of the drug due to formulary availability and/or cost concerns. Studies have shown that formulary conversions from co-formulated products to individual components are frequently associated with ART errors and that the use of co-formulated products in the inpatient setting reduces these errors [20,22,24,26].

Finally, factors related to the health care setting can influence the risk for errors. High patient numbers, time constraints, and workload stresses can all increase the likelihood that an error will occur [36]. Interruptions and distractions occurring at any point in the medication use process can lead to error.

Transitioning from one health care setting to another also places patients at risk for being harmed by medication errors. Up to 70% of patients may have an unintentional medication discrepancy at hospital discharge, and errors occurring at hospital admission have been reported to affect two-thirds of admitted patients [42]. Many of these errors hold the potential to cause harm to the patient, especially if the errors are carried forward throughout the patient’s admission and after discharge. One study found that 22% of ART errors occurring at hospital admission were attributable to outpatient clinic documentation errors [24]. This highlights the need for improved documentation processes and draws attention to the element of communication at transitional points of care. Lack of adequate resources for medication reconciliation is a widely recognized challenge. This includes resources of personnel as well as electronic medical record systems that can facilitate the reconciliation process. The importance of accurately documenting a patient’s medication history and the ability to easily communicate this information to other health care settings cannot be underestimated. Electronic medical record systems should be developed to facilitate and enhance the processes of reconciliation, documentation, and communication.

Interventions to Address ART Errors

The causes of ART errors are multifactorial and should be addressed using comprehensive approaches tailored to the specific health care setting. Several types of interventions aimed at reducing and preventing ART errors have been evaluated in the literature [12,18,26,27]. In general, these interventions have focused on provider education, use of technology and clinical decision support systems, pharmacist-led medication review and intervention, and hospital formulary changes. Other interventions that may lead to a reduction in ART errors include minimizing polypharmacy, improving medication reconciliation processes during transitions of care, and multidisciplinary follow-up clinic visits after hospital discharge.

Because the sources of ART errors are multifactorial, the optimal strategy to prevent and reduce errors is likely to be a comprehensive approach combining several of the aforementioned interventions. One study showed that a combined approach that included updates to the institution’s computerized physician order entry (CPOE) system, education for the pharmacy and ID departments, and daily review of patients’ medications by pharmacists was successful in reducing the percentage of admissions with an ART error from 50% to 34%. In addition, the time to error resolution decreased from 180 hours to 23 hours, and the error resolution rate increased from 32% to 68% [21]. Another study demonstrated benefits using a comprehensive approach including the dissemination of educational pocket cards for physicians, pharmacists and nurses; CPOE alerts; hospital formulary updates to include co-formulated products; and a daily review of medications by an ID-specialized pharmacist for patients receiving ART. These strategies resulted in a reduced ART error rate from 72% to 15% in 7 months [26]. These studies demonstrate the benefit of multifaceted strategies to reduce ART error rates.

Education

Given the complexity of HIV care and overall lack of antiretroviral medication knowledge among non-ID specialized health care professionals, educational programs aimed at increasing the comfort level and familiarity of ART is important [16,37]. Frequent training to update  health care professionals on the newest recommendations for HIV management can help achieve this goal [19,27]. Educational interventions aimed at reducing medication errors have been shown to be transiently effective but may lack sustained effects [43]. Educational programs for health care professionals should be designed to provide frequent brief updates, and are likely to be more successful when combined with other approaches [19,26].

Education directed toward patients, families, and caregivers can also play a pivotal role in error prevention. Patients should be encouraged to use one pharmacy, if possible, to ensure that one complete, accurate, and current profile is maintained. The use of one pharmacy can also assist in the identification of therapeutic duplications and drug interactions. Counseling patients with visual aids, such as charts with pictures of drugs, can also be used as a tool for education. Patients who are familiar with the names and the appearances of their drugs are more likely to recognize errors. In addition, patients should be advised to maintain their own current medication list so that they will be able to provide this information to all of the health care professionals involved in their care [33,44].

Technology and Clinical Decision Support Systems

Overall, the increasing use of technology such as CPOE, decision support systems, and barcoding systems has been shown to decrease the risk of medication error [19,45,46]. Guo et al observed a 35% decrease in ART error rates after the integration of customized order entry sets into an existing CPOE program [19]. Another study reported a 50% decrease in the ART error rate after the introduction of an electronic medical record system [45]. On the other hand, some reports evaluating the role of CPOE systems to reduce medication error rates are conflicting [15,19,23,48]. Differences in system capabilities and programming and differing needs and challenges of institutions may account for the varying results reported in the literature. CPOE systems can serve as valuable tools for assisting in medication prescribing. Confusion due to abbreviations, illegible writing and look-alike/sound-alike drugs should be eliminated or greatly reduced with the use of CPOE. However, the limitations of these systems, which may differ among different systems, should be appreciated. As ART regimens and dosing recommendations change, clinical decision support systems can quickly become out-of-date and require frequent updating. One study identified fields that pre-populated drug names and frequencies within a CPOE system to be the cause of several medication errors [16]. Studies have also identified errors related to disregarded alerts from decision support software [15,16]. “Alert fatigue” is a well-recognized phenomenon that occurs when clinicians are exposed to a large volume of clinical decision support alerts of varying clinical significance. Over time, clinicians begin to become desensitized to the alerts, and they may eventually stop responding to them.

Some limitations of CPOE systems arise from the individual system capabilities. Some systems have the ability to check for appropriate dosing, recommend adjustments in renal dysfunction, and provide alerts for drug interactions, but some systems lack these capabilities. In addition, CPOE systems are often not able to prevent errors of omission, delays in continuation of therapy, and medication scheduling errors [15,45].

Given the limitations of CPOE and clinical decision support technologies, it is unlikely that these interventions alone will be sufficient to fully address the problem of ART errors. These technologies can, however, serve as a powerful tool in the prevention and reduction of ART errors, especially when used in combination with other strategies.

Pharmacist Intervention

Multiple studies have shown that clinical pharmacists are effective at decreasing ART medication errors in the inpatient setting [12,18,23,25,28,45,49,50]. One institution implemented an HIV-specialized pharmacist review strategy that decreased the median time to error correction from 84 hours to 15.5 hours among hospitalized patients [12]. Corrigan et al showed that a review of medications by an HIV-specialized pharmacist 48 hours after hospital admission decreased error rates from 52% to 5% [50]. Another study showed that with the use of an electronic medical record, errors among hospitalized patients with HIV were 9.4 times more likely to be corrected within 24 hours when an HIV-specialized pharmacist was consulted [45].

The majority of studies evaluating the effect of pharmacist interventions have utilized the services of a pharmacist with specialized training in HIV. Few studies have evaluated the impact of interventions by pharmacists without this specialized training. One study retrospectively evaluated and characterized ART errors among hospitalized patients. Medication reconciliation was performed within 24 hours of admission by unit-based pharmacists without specialized training in HIV. Overall, 30.8% of errors were corrected within 24 hours and 14.2% were corrected after 24 hours. However, 54.7% of the errors were not recognized and were never corrected [20]. Just as physicians trained in general medicine lack knowledge of antiretroviral medications, pharmacists without HIV-specialized training may also be less familiar with current ART recommendations [16,37].

Overall, the studies evaluating the impact of pharmacist intervention on reducing ART error rates have shown significant reductions in time to error corrections. The nature of this type of intervention however, lends itself to correction of errors rather than prevention of errors. Indeed, one hospital reported an ART error rate of 29% on the first day of admission compared to 7% on the second day of admission, a decrease that was attributed to retrospective review of medication orders by clinical pharmacists. This study also noted the occurrences of additional errors identified on the second day of admission, highlighting the importance of daily review and follow-up throughout the hospital stay [28].

Hospital Formulary Selections

Several studies have documented an association between hospital formulary options and ART errors [20,22,24,26]. The prescribing of ART medications that are not available on hospital formulary is consistently associated with higher rates of error. Many hospitals minimize the numbers of different medications offered through the maintenance of a formulary. Formularies assist in reducing costs, preserving storage space, and simplifying prescribing. Because some hospitals choose to exclude co-formulated products from the formulary, several ART medications may not be included. In addition, some ART medications may be excluded from formulary due to their infrequent use or higher costs. The extra step of converting a co-formulated product to its individual components increases the risk for errors. In one study, the addition of all co-formulated ART medications to the hospital formulary in combination with several other interventions had a significant effect on reducing the ART error rate [26].

Transitions of Care Interventions

Patients with HIV are at risk for experiencing medication errors and discrepancies any time they transition from one health care setting to another. Hospitalization poses the highest risk as it often disrupts continuity of care and corresponds with a comparatively larger number of medication changes [16,51]. This risk is present on admission, throughout hospitalization, and upon discharge. Perhaps the errors of greatest concern are those that are carried forward after discharge on to the outpatient setting. Medication discrepancies at transitions of care have been associated with increases in adverse events and increased hospital readmission rates [52,53]. One study evaluating adverse events in geriatric patients transitioning from hospital to home found that the most frequently reported adverse events after discharge were related to incorrect drugs or dosages of medication regimens [54]. Tools that can assist in integration and coordination during transitions of care are greatly needed.

One of the most important strategies to prevent and correct medication discrepancies during transitions of care is medication reconciliation. Several studies have demonstrated the efficacy of medication reconciliation in decreasing medication errors [55]. Medication reconciliation is especially important for patients taking many medications. An estimated 14% of patients with HIV older than age 65 take 4 or more medications [56]. This population often requires treatment for other chronic conditions such as hypertension, diabetes, and depression, further increasing the risk for adverse drug events including medication error. Because of the complexities associated with the treatment of HIV and the increased risk for errors, routine medication reconciliation among this population should be a priority.

In addition to medication reconciliation, several studies have evaluated the effects of coordinated pharmacist or multidisciplinary post-discharge follow-up visits for medication therapy management as a strategy to reduce preventable medication-related adverse events [57–59]. Patients receiving clinic-based medication therapy management by a clinical pharmacist after hospital discharge had a lower 60-day hospital readmission rate compared to those who did not have a clinic visit with a pharmacist (18.2% vs. 43.1%) [59]. Another study compared 2 models of post-discharge follow-up, a multidisciplinary team model led by a clinical pharmacist compared to a standard physician-only model. The goal of the multi-disciplinary team model was to complete a thorough medication review, address lifestyle interventions, and address barriers to care. Overall, patients seen by the multidisciplinary team had a 30-day hospital readmission rate of 14.3% compared with a 34.3% readmission rate in the physician-only team [58]. Many different care models have been proposed to improve continuity of care for patients with HIV. The ideal model is not known, and it is likely that several different models would be effective. Optimal models should integrate the patient-physician relationship with multidisciplinary team approaches [60].

Conclusion

The rapidly evolving nature of HIV management and the increase in non–HIV-related comorbidities among this population has created a landscape that places these patients at risk for medication errors. Although ART has improved survival, medication errors place these patients at risk for adverse events and treatment failure. Medication errors are particularly likely to occur during transitions of care. Several interventions to prevent and decrease ART errors have been evaluated including educational strategies, hospital formulary changes, use of technology, and medication review and intervention by clinical pharmacists. However more research is needed to determine optimal strategies to address ART medication errors. Successful approaches have implemented comprehensive methods combining multiple interventions aimed at addressing several distinct sources of error. Promotion of a culture of safety is also an important component of medication error management. Health care professionals should be encouraged to report errors, and lessons learned from errors should be used to guide efforts to prevent future errors. Finally, improved integration of care with a focus on systematic initiatives for medication reconciliation as well as multidisciplinary approaches to transitions of care will be essential for reducing the rate of medication error among patients with HIV.

Corresponding author: Lindsay M. Daniels, PharmD, [email protected].

Financial disclosures: None.

References

1. Egger M, May M, Chene G, et al. Prognosis of HIV-1 infected patients starting highly active, antiretroviral therapy: a collaborative analysis of prospective studies. Lancet 2002;360:119–29.

2. Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998;338:853–60.

3. May MT, Gompels M, Delpech V, et al. Impact on life expectancy of HIV-1 positive individuals of CD4 cell count and viral load response to antiretroviral therapy. AIDS 2014; 28:1193–202.

4. Greene M, Justice AC, Lampiris HW, Valcour V. Management of HIV infection in advanced age. JAMA 2013;309:1397–1405.

5. Baker JV, Peng G, Rapkin J, et al. CD4+ count and risk of non-AIDS diseases following initial treatment of HIV infection. AIDS 2008;22:841–8.

6. Monforte A, Abrams D, Pradier C, et al. HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies. AIDS 2008;22:2143–53.

7. Buchacz K, Baker RK, Moorman AC, et al. Rates of hospitalizations and associated diagnoses in a large multisite cohort of HIV patients in the United States, 1994-2005. AIDS 2008;22:1345–54.

8. Aspden P, Wolcott J, Bootman JL, et al. Preventing medication errors: quality chasm series. Washington DC: National Academies Press; 2007.

9. Kripalani S, Roumie CL, Dalal AK, et al. Effect of a pharmacist intervention on clinically important medication errors after hospital discharge: a randomized trial. Ann Intern Med 2012;157:1–10.

10. Tam VC, Knowles SR, Cornish PL, et al. Frequency, type and clinical importance of medication history errors at admission to hospital: a systematic review. CMAJ 2005;173:510–515.

11. Bell CM, Brener SS, Gunraj N, et al. Association of ICU or hospital admission with unintentional discontinuation of medications for chonic diseases. JAMA 2011;306:840–7.

12. Heelon M, Skiest D, Tereso G, et al. Effect of a clinical pharmacist’s interventions on duration of antiretroviral-related errors in hospitalized patients. Am J Health Syst Pharm 2007;64:2064–8.

13. Purdy BD, Raymond AM, Lesar TS. Antiretroviral prescribing errors in hospitalized patients. Ann Pharmacother 2000;34:833–8.

14. Gray J, Hicks RW, Hutchings C. Antiretroviral medication errors in a national medication error database. AIDS Patient Care STDS 2005;19:803–12.

15. Rastegar DA, Knight AM, Monolakis JS. Antiretroviral medication errors among patients with HIV infection. Clin Infect Dis 2006;43:933–8.

16. Snyder AM, Klinker K, Orrick JJ, et al. An in-depth analysis of medication errors in hospitalized patients with HIV. Ann Pharmacother 2011;45:459–68.

17. Edelman EJ, Gordon KS, Glover J, et al. The next therapeutic challenge in HIV: polypharmacy. Drugs Aging 2013;30:613–28.

18. Carcelero E, Tuset M, Martin M, et al. Evaluation of antiretroviral-related errors and interventions by the clinical pharmacist in hospitalized HIV-infected patients. HIV Medicine 2011;12:494–9.

19. Guo Y, Chung P, Weiss C, et al. Customized order-entry sets can prevent antiretroviral prescribing errors: a novel opportunity for antimicrobial stewardship. P T 2015;40:353–8.

20. Commers T, Swindells S, Sayles H, et al. Antiretroviral medication prescribing errors are common with hospitalization of HIV-infected patients. J Antimicrob Chemother 2014;69:262–7.

21. Sanders J, Pallotta A, Bauer S, et al. Antimicrobial stewardship program to reduce antiretroviral medication errors in hospitalized patients with HIV infection. Infect Control Hosp Epidemiol 2014;35:272–7.

22. Chiampas TD, Kim H, Badowski M. Evaluation of the occurrence and type of antiretroviral and opportunistic infection medication errors within the inpatient setting. Pharm Pract 2015;13:512.

23. Eginger KH, Yarborough LL, Inge LD, et al. Medication errors in HIV-infected hospitalized patients: a pharmacist’s impact. Ann Pharmacother 2013;47:953–60.

24. Pastakia SD, Corbett AH, Raasch RH, et al. Frequency of HIV-related medication errors and associated risk factors in hospitalized patients. Ann Pharmacother 2008;42:491–7.

25. Garey KW, Teichner P. Pharmacist intervention program for hospitalized patients with HIV infection. Am J Health Syst Pharm 2000;57:2283–4.

26. Daniels LM, Raasch RH, Corbett AH. Implementation of targeted interventions to decrease antiretroviral-related errors in hospitalized patients. Am J Health Syst Pharm 2012;69:422–30.

27. Li EH, Foisy MM. Antiretroviral and medication errors in hospitalized HIV-positive patients. Ann Pharmacother 2014;48:998–1010.

28. Yehia BR, Mehta JM, Ciuffetelli D, et al. Antiretroviral medication errors remain high but are quickly corrected among hospitalized HIV-infected adults. Clin Infect Dis 2012;55:593–99.

29. Willig JH, Westfall AO, Allison J, et al. Nucleoside reverse-transcriptase inhibitor dosing errors in an outpatient HIV clinic in the electronic medical record era. Clin Infect Dis 2007;45:658–61.

30. Hellinger FJ, Encinosa WE. The cost and incidence of prescribing errors among privately insured HIV patients. Pharmacoeconomics 2010;28:23–34.

31. Deeks SG, Gange SJ, Kitahata MM, et al. Trends in multidrug treatment failure and subsequent mortality among antiretroviral therapy-experienced patients with HIV infection in North America. Clin Infect Dis 2009;49:1582–90.

32. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011;365:493–505.

33. Wittich CM, Burkle CM, Lanier WL. Medication errors: an overview for clinicians. Mayo Clin Proc 2014;89:1116–25.

34. Merchen BA, Gerzenshtein L, Scarsi KK, et al. Evaluation of HIV-specialized pharmacists’ impact on prescribing errors in hospitalized patients on antiretroviral therapy. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy; 2011 Sep 17-20; Chicago IL. Abstract H2–794.

35. Lesar TS, Briceland L, Stein DS. Factors related to errors in medication prescribing. JAMA 1997;277:312–17.

36. Agu KA, Oqua D, Adeyanju Z, et al. The incidence and types of medication errors in patients receiving antiretroviral therapy in resource constrained settings. PLoS ONE 2014;9:e87338.

37. Arshad S, Rothberg M, Rastegar DA, et al. Survey of physician knowledge regarding antiretroviral medications in hospitalized HIV-infected patients. J Int AIDS Soc 2009;12:1.

38. Fultz SL, Goulet JL, Weissman S, et al. Differences between infectious diseases-certified physicians and general medicine-certified physicians in the level of comfort with providing primary care to patients. Clin Infect Dis 2005;41:738–43.

39. Cheng QJ, Engelage EM, Grogan TR, et al. Who provides primary care? An assessment of HIV patient and provider practices and preferences. J AIDS Clin Res 2014;5:366.

40. Cohen MR, Davis NM. AZT is a dangerous abbreviation. Am Pharm 1992;32:26.

41. Ambrosini MT, Mandler HD, Wood CA. AZT: zidovudine or azathioprine? Lancet 1992;339:935.

42. Sponsler KC, Neal EB, Kripalani S. Improving medication safety during hospital-based transitions of care. Cleve Clin J Med 2015;82:351–60.

43. Peeters MJ, Pinto SL. Assessing the impact of an educational program on decreasing prescribing errors at a university hospital. J Hosp Med 2009;4:97–101.

44. Faragon JJ, Lesar TS. Update on prescribing errors with HAART. AIDS Read 2003;13:268–78.

45. Batra R, Wolbach-Lowes J, Swindells S, et al. Impact of an electronic medical record on the incidence of antiretroviral prescription errors and HIV pharmacist reconciliation on error correction among hospitalized HIV-infected patients. Antivir Ther 2015:2040–58.

46. Keers RN, Williams SD, Cooke J, et al. Impact of interventions designed to reduce medication administration errors in hospitals: a systematic review. Drug Saf 2014;37:317–32.

47. Reckmann MH, Westbrook JI, Koh Y, et al. Does computerized provider order entry reduce prescribing errors for hospital inpatients? A systematic review. J Am Med Inform Assoc 2009;16:613–23.

48. Bozek PS, Perdue BE, Bar-Din M, Weidle PJ. Effect of pharmacist interventions on medication use and cost in hospitalized patients with or without HIV infection. Am J Health Syst Pharm 1998;55:1151–5.

49. De Maat MM, de Boer A, Koks CH, et al. Evaluation of clinical pharmacist interventions on drug interactions in outpatient pharmaceutical HIV care. J Clin Pharm Ther 2004;29:121–30.

50. Corrigan MA, Atkinson KM, Sha BE, Crank CW. Evaluation of pharmacy-implemented medication reconciliation directed at antiretroviral therapy in hospitalized HIV/AIDS patients. Ann Pharmacother 2010;44:222–3.

51. Rao N, Patel V, Grigoriu A, et al. Antiretroviral therapy prescribing in hospitalized HIV clinic patients. HIV Med 2012;13:367–71.

52. Coleman EA, Smith JD, Raha D, Min S. Posthospital medication discrepancies. Arch Intern Med 2005;165:1842–7.

53. Forster AJ, Murff HJ, Peterson JF, et al. The incidence and severity of adverse events affecting patients after discharge from the hospital. Ann Intern Med 2003;138:161–7.

54. Mesteig M, Helbostad JL, Sletvold O, et al. Unwanted incidents during transition of geriatric patients from hospital to home: a prospective observational study. BMC Health Serv Res 2010;10:1.

55. Mueller SK, Sponsler KC, Kripalani S, Schnipper JL. Hospital-based medication reconciliation practices: a systematic review. Arch Intern Med 2012;172:1057–69.

56. Hasse B, Ledergerber B, Furrer H, et al. Morbidity and aging in HIV-infected persons: the Swiss HIV Cohort Study. Clin Infect Dis 2011;53:1130–9.

57. Downes JM, O’Neal KS, Miller MJ, et al. Identifying opportunities to improve medication management in transitions of care. Am J Health Syst Pharm 2015;72:S58–69.

58. Cavanaugh JJ, Lindsey KN, Shilliday BB, Ratner SP. Pharmacist-coordinated multidisciplinary hospital follow-up visits improve patient outcomes. J Manag Care Spec Pharm 2015;21:256–60.

59. Bellone JM, Barner JC, Lopez DA. Postdischarge interventions by pharmacists and impact on hospital readmission rates. J Am Pharm Assoc 2012;52:358–62.

60. Handford CD, Tynan AM, Rackal JM, Glazier RH. Setting and organization of care for persons living with HIV/AIDS. Cochrane Database Syst Rev 2006;19:CD004348.

Study Overview

Objective. To examine the cross-sectional relationships between standing time, obesity, and metabolic syndrome.

Design. Cross-sectional study.

Setting and participants. Participants were patients aged 20–79 years old attending Cooper Clinic in Dallas for a preventive medicine visit who enrolled in the Cooper Center Longitudinal Study, an ongoing prospective investigation established in 1970 to explore the effects of physical activity on morbidity and mortality [1]. Included in the analysis were those enrolled starting in 2010, when questions pertaining to standing patterns began to be included in the medical history. Patients who did not have complete information or who had a history of myocardial infarction, stroke, or cancer were excluded.

Measures. Obesity was directly measured using body mass index (≥ 30), waist circumference (men: ≥ 102 cm; women: ≥ 88 cm), and body fat percentage (men: ≥ 25%; women ≥ 30%) and was adjusted for history of diabetes and hypertension. Metabolic syndrome, a clustering of risk factors that increase the risk for heart disease, stroke, and diabetes, was assessed. Participants’ standing patterns were ascertained from responses to survey questions derived from the Canada Fitness Survey Questionnaire (“For those activities that you do most days of the week, such as work, school, and housework, how much time do you spend standing: Almost all of the time, ¾ of the time, ½ of the time, ¼ of the time, almost none of the time?”). Leisure-time physical activity was determined based on responses to survey questions, and answers were used to categorize participants as either meeting or not meeting the Physical Activity Guidelines for Americans.

Results. The study sample consisted of 7075 participants, who were primarily white and college educated. Over two-thirds were men and the mean age was 50.0 ± 10.1 years. Multivariable analysis showed that in men, increased standing was significantly associated with a lower likelihood of elevated body fat percentage. Specifically, standing a quarter of the time was linked to a 32% reduced likelihood of obesity (body fat percentage), standing half the time was associated with a 59% reduced likelihood of obesity, but standing more than three-quarters of the time was not associated with a lower risk of obesity. In women, standing a quarter, half, and three-quarters of the time was associated with 35%, 47%, and 57% respective reductions in the likelihood of abdominal obesity (waist circumference). No relationship between standing and metabolic syndrome was found among women or men.

The study also examined whether physical activity in conjunction with standing provided additional reduction risk for obesity. The study showed that 150 minutes of moderate activity and/or 75 minutes of vigorous activity per week added to standing time was associated with significant reduction in the probability of obesity and metabolic syndrome in both women and men.

Conclusion. Standing a quarter of the time per day or more is associated with reduced odds of obesity. The inverse relationship of standing to obesity and metabolic syndrome is more robust when combined with health-promoting leisure-time physical activity.

Commentary

Obesity is considered one of the main risk factors for cardiovascular diseases worldwide. Obesity-related conditions include heart disease, stroke, type 2 diabetes, and certain types of cancer, some of the leading causes of preventable death. The effects of obesity among Americans add more than $147 billion in medical costs to the U.S. economy annually [2].

Obesity is a national epidemic, with more than 78.9 million obese adults in the United States [2]. Studies have shown that Americans are currently less active as compared to past decades [3]. This decline in physical activity combined with other factors, such as the ubiquity of low-cost high-energy foods and beverages, has likely contributed to the high rate of obesity.

This cross-sectional study aimed to assess the relationship between standing time, obesity, and metabolic syndrome alongside and independent of leisure-time physical activity. The researchers found that standing for at least one quarter of the day is linked to lower odds of obesity, which was directly assessed through 3 measures: BMI, body fat percentage, and waist circumference. The apparent benefit of standing is an important finding in light of obesity being such an important public health concern.

The large sample size is a strength of this study in terms of statistical power; however, there are important limitations that must be acknowledged. First, given the cross-sectional design, no causal inferences can be made. Moreover, while obesity and metabolic syndrome were objectively measured, standing and physical activity were based on self-report, which may lead to over- or underestimation of these behaviors. In addition, due to the survey measure used in the study, it is unclear whether study participants were standing still or standing and moving. More information in this regard would be helpful. Longitudinal research is encouraged in order to provide better evidence of these relationships and their effects.

In addition, cultural aspects were not assessed in this study. Racial and ethnic differences may influence the relationship between the variables of physical activity and obesity reduction.

Applications for Clinical Practice

Obesity is a complex but preventable health problem commonly associated with sedentary lifestyle. Physical activity is recommended as a component of weight management for prevention of weight gain and for weight loss [4]. Whether standing more often will aid in reducing obesity cannot be determined from this study.

—Paloma Cesar de Sales, BS, RN, MS

Study Overview

Objective. To examine the cross-sectional relationships between standing time, obesity, and metabolic syndrome.

Design. Cross-sectional study.

Setting and participants. Participants were patients aged 20–79 years old attending Cooper Clinic in Dallas for a preventive medicine visit who enrolled in the Cooper Center Longitudinal Study, an ongoing prospective investigation established in 1970 to explore the effects of physical activity on morbidity and mortality [1]. Included in the analysis were those enrolled starting in 2010, when questions pertaining to standing patterns began to be included in the medical history. Patients who did not have complete information or who had a history of myocardial infarction, stroke, or cancer were excluded.

Measures. Obesity was directly measured using body mass index (≥ 30), waist circumference (men: ≥ 102 cm; women: ≥ 88 cm), and body fat percentage (men: ≥ 25%; women ≥ 30%) and was adjusted for history of diabetes and hypertension. Metabolic syndrome, a clustering of risk factors that increase the risk for heart disease, stroke, and diabetes, was assessed. Participants’ standing patterns were ascertained from responses to survey questions derived from the Canada Fitness Survey Questionnaire (“For those activities that you do most days of the week, such as work, school, and housework, how much time do you spend standing: Almost all of the time, ¾ of the time, ½ of the time, ¼ of the time, almost none of the time?”). Leisure-time physical activity was determined based on responses to survey questions, and answers were used to categorize participants as either meeting or not meeting the Physical Activity Guidelines for Americans.

Results. The study sample consisted of 7075 participants, who were primarily white and college educated. Over two-thirds were men and the mean age was 50.0 ± 10.1 years. Multivariable analysis showed that in men, increased standing was significantly associated with a lower likelihood of elevated body fat percentage. Specifically, standing a quarter of the time was linked to a 32% reduced likelihood of obesity (body fat percentage), standing half the time was associated with a 59% reduced likelihood of obesity, but standing more than three-quarters of the time was not associated with a lower risk of obesity. In women, standing a quarter, half, and three-quarters of the time was associated with 35%, 47%, and 57% respective reductions in the likelihood of abdominal obesity (waist circumference). No relationship between standing and metabolic syndrome was found among women or men.

The study also examined whether physical activity in conjunction with standing provided additional reduction risk for obesity. The study showed that 150 minutes of moderate activity and/or 75 minutes of vigorous activity per week added to standing time was associated with significant reduction in the probability of obesity and metabolic syndrome in both women and men.

Conclusion. Standing a quarter of the time per day or more is associated with reduced odds of obesity. The inverse relationship of standing to obesity and metabolic syndrome is more robust when combined with health-promoting leisure-time physical activity.

Commentary

Obesity is considered one of the main risk factors for cardiovascular diseases worldwide. Obesity-related conditions include heart disease, stroke, type 2 diabetes, and certain types of cancer, some of the leading causes of preventable death. The effects of obesity among Americans add more than $147 billion in medical costs to the U.S. economy annually [2].

Obesity is a national epidemic, with more than 78.9 million obese adults in the United States [2]. Studies have shown that Americans are currently less active as compared to past decades [3]. This decline in physical activity combined with other factors, such as the ubiquity of low-cost high-energy foods and beverages, has likely contributed to the high rate of obesity.

This cross-sectional study aimed to assess the relationship between standing time, obesity, and metabolic syndrome alongside and independent of leisure-time physical activity. The researchers found that standing for at least one quarter of the day is linked to lower odds of obesity, which was directly assessed through 3 measures: BMI, body fat percentage, and waist circumference. The apparent benefit of standing is an important finding in light of obesity being such an important public health concern.

The large sample size is a strength of this study in terms of statistical power; however, there are important limitations that must be acknowledged. First, given the cross-sectional design, no causal inferences can be made. Moreover, while obesity and metabolic syndrome were objectively measured, standing and physical activity were based on self-report, which may lead to over- or underestimation of these behaviors. In addition, due to the survey measure used in the study, it is unclear whether study participants were standing still or standing and moving. More information in this regard would be helpful. Longitudinal research is encouraged in order to provide better evidence of these relationships and their effects.

In addition, cultural aspects were not assessed in this study. Racial and ethnic differences may influence the relationship between the variables of physical activity and obesity reduction.

Applications for Clinical Practice

Obesity is a complex but preventable health problem commonly associated with sedentary lifestyle. Physical activity is recommended as a component of weight management for prevention of weight gain and for weight loss [4]. Whether standing more often will aid in reducing obesity cannot be determined from this study.

—Paloma Cesar de Sales, BS, RN, MS

Study Overview

Objective. To examine the cross-sectional relationships between standing time, obesity, and metabolic syndrome.

Design. Cross-sectional study.

Setting and participants. Participants were patients aged 20–79 years old attending Cooper Clinic in Dallas for a preventive medicine visit who enrolled in the Cooper Center Longitudinal Study, an ongoing prospective investigation established in 1970 to explore the effects of physical activity on morbidity and mortality [1]. Included in the analysis were those enrolled starting in 2010, when questions pertaining to standing patterns began to be included in the medical history. Patients who did not have complete information or who had a history of myocardial infarction, stroke, or cancer were excluded.

Measures. Obesity was directly measured using body mass index (≥ 30), waist circumference (men: ≥ 102 cm; women: ≥ 88 cm), and body fat percentage (men: ≥ 25%; women ≥ 30%) and was adjusted for history of diabetes and hypertension. Metabolic syndrome, a clustering of risk factors that increase the risk for heart disease, stroke, and diabetes, was assessed. Participants’ standing patterns were ascertained from responses to survey questions derived from the Canada Fitness Survey Questionnaire (“For those activities that you do most days of the week, such as work, school, and housework, how much time do you spend standing: Almost all of the time, ¾ of the time, ½ of the time, ¼ of the time, almost none of the time?”). Leisure-time physical activity was determined based on responses to survey questions, and answers were used to categorize participants as either meeting or not meeting the Physical Activity Guidelines for Americans.

Results. The study sample consisted of 7075 participants, who were primarily white and college educated. Over two-thirds were men and the mean age was 50.0 ± 10.1 years. Multivariable analysis showed that in men, increased standing was significantly associated with a lower likelihood of elevated body fat percentage. Specifically, standing a quarter of the time was linked to a 32% reduced likelihood of obesity (body fat percentage), standing half the time was associated with a 59% reduced likelihood of obesity, but standing more than three-quarters of the time was not associated with a lower risk of obesity. In women, standing a quarter, half, and three-quarters of the time was associated with 35%, 47%, and 57% respective reductions in the likelihood of abdominal obesity (waist circumference). No relationship between standing and metabolic syndrome was found among women or men.

The study also examined whether physical activity in conjunction with standing provided additional reduction risk for obesity. The study showed that 150 minutes of moderate activity and/or 75 minutes of vigorous activity per week added to standing time was associated with significant reduction in the probability of obesity and metabolic syndrome in both women and men.

Conclusion. Standing a quarter of the time per day or more is associated with reduced odds of obesity. The inverse relationship of standing to obesity and metabolic syndrome is more robust when combined with health-promoting leisure-time physical activity.

Commentary

Obesity is considered one of the main risk factors for cardiovascular diseases worldwide. Obesity-related conditions include heart disease, stroke, type 2 diabetes, and certain types of cancer, some of the leading causes of preventable death. The effects of obesity among Americans add more than $147 billion in medical costs to the U.S. economy annually [2].

Obesity is a national epidemic, with more than 78.9 million obese adults in the United States [2]. Studies have shown that Americans are currently less active as compared to past decades [3]. This decline in physical activity combined with other factors, such as the ubiquity of low-cost high-energy foods and beverages, has likely contributed to the high rate of obesity.

This cross-sectional study aimed to assess the relationship between standing time, obesity, and metabolic syndrome alongside and independent of leisure-time physical activity. The researchers found that standing for at least one quarter of the day is linked to lower odds of obesity, which was directly assessed through 3 measures: BMI, body fat percentage, and waist circumference. The apparent benefit of standing is an important finding in light of obesity being such an important public health concern.

The large sample size is a strength of this study in terms of statistical power; however, there are important limitations that must be acknowledged. First, given the cross-sectional design, no causal inferences can be made. Moreover, while obesity and metabolic syndrome were objectively measured, standing and physical activity were based on self-report, which may lead to over- or underestimation of these behaviors. In addition, due to the survey measure used in the study, it is unclear whether study participants were standing still or standing and moving. More information in this regard would be helpful. Longitudinal research is encouraged in order to provide better evidence of these relationships and their effects.

In addition, cultural aspects were not assessed in this study. Racial and ethnic differences may influence the relationship between the variables of physical activity and obesity reduction.

Applications for Clinical Practice

Obesity is a complex but preventable health problem commonly associated with sedentary lifestyle. Physical activity is recommended as a component of weight management for prevention of weight gain and for weight loss [4]. Whether standing more often will aid in reducing obesity cannot be determined from this study.

—Paloma Cesar de Sales, BS, RN, MS

HIV budding from a

cultured lymphocyte

Image courtesy of the CDC

Patients with HIV-associated Hodgkin lymphoma may not be getting potentially curative treatment, according to a study published in the journal AIDS.

The study showed that 16% of HIV-positive patients did not receive treatment for their lymphoma, compared to 9% of Hodgkin lymphoma patients who were HIV-negative.

“Hodgkin lymphoma is generally believed to be highly curable,” said study author Adam Olszewski, MD, of Brown University in Providence, Rhode Island.

“We have an expectation to cure over 90% of early stage patients and even 70% to 80% of quite advanced cases.”

It hasn’t been clear whether HIV-positive patients with Hodgkin lymphoma survive the cancer as well as people who are HIV-negative. While some small studies, particularly in Europe, have shown that HIV status makes no difference to survival, observations in the US population suggest that being HIV-positive makes survival less likely.

The new study, which is the largest of its kind to date, may reconcile that conflict. It suggests that, in the US, the reason people with HIV seem to fare worse with the cancer is because they are less likely to be treated for it.

The study included 2090 cases of HIV-associated Hodgkin lymphoma recorded in the National Cancer Data Base between 2004 and 2012, as well as 41,846 cases of Hodgkin lymphoma in patients who were HIV-negative.

The unadjusted 5-year overall survival was 66% for HIV-positive patients and 80% for the HIV-negative population.

Among the HIV-positive patients, 81% received chemotherapy (12% in combination with radiation), 13% received any radiation therapy, and 16% received no treatment for their lymphoma. The corresponding numbers for HIV-negative patients were 87%, 31%, and 9%, respectively (P<0.00001 for all comparisons).

The researchers assessed patient- and disease-related factors associated with the risk of not receiving chemotherapy in the HIV-positive population.

And they found the risk was significantly higher for patients who were older than 40, male, “nonwhite” (black, Hispanic, or Asian/”other”), did not have health insurance, lived in areas with the lowest median income, and had early stage Hodgkin lymphoma or an undetermined histology.

Dr Olszewski said the lack of treatment among HIV-positive patients could be due to a lingering assumption that they won’t tolerate the treatment well. Or some patients may be declining treatment, either for HIV (thereby making them seem more vulnerable) or for the lymphoma itself.

He noted, however, that lymphoma treatment can be effective for and tolerated by HIV-positive patients, especially when the lymphoma subtype is known.

Among the patients who received chemotherapy in this study, there was no significant difference in the hazard of death between HIV-positive and HIV-negative patients who had one of the defined classical histologic subtypes: nodular sclerosis, mixed cellularity, lymphocyte-rich, or lymphocyte-depleted Hodgkin lymphoma. However, mortality was significantly higher for HIV-positive patients with an undetermined histologic subtype.

HIV budding from a

cultured lymphocyte

Image courtesy of the CDC

Patients with HIV-associated Hodgkin lymphoma may not be getting potentially curative treatment, according to a study published in the journal AIDS.

The study showed that 16% of HIV-positive patients did not receive treatment for their lymphoma, compared to 9% of Hodgkin lymphoma patients who were HIV-negative.

“Hodgkin lymphoma is generally believed to be highly curable,” said study author Adam Olszewski, MD, of Brown University in Providence, Rhode Island.

“We have an expectation to cure over 90% of early stage patients and even 70% to 80% of quite advanced cases.”

It hasn’t been clear whether HIV-positive patients with Hodgkin lymphoma survive the cancer as well as people who are HIV-negative. While some small studies, particularly in Europe, have shown that HIV status makes no difference to survival, observations in the US population suggest that being HIV-positive makes survival less likely.

The new study, which is the largest of its kind to date, may reconcile that conflict. It suggests that, in the US, the reason people with HIV seem to fare worse with the cancer is because they are less likely to be treated for it.

The study included 2090 cases of HIV-associated Hodgkin lymphoma recorded in the National Cancer Data Base between 2004 and 2012, as well as 41,846 cases of Hodgkin lymphoma in patients who were HIV-negative.

The unadjusted 5-year overall survival was 66% for HIV-positive patients and 80% for the HIV-negative population.

Among the HIV-positive patients, 81% received chemotherapy (12% in combination with radiation), 13% received any radiation therapy, and 16% received no treatment for their lymphoma. The corresponding numbers for HIV-negative patients were 87%, 31%, and 9%, respectively (P<0.00001 for all comparisons).

The researchers assessed patient- and disease-related factors associated with the risk of not receiving chemotherapy in the HIV-positive population.

And they found the risk was significantly higher for patients who were older than 40, male, “nonwhite” (black, Hispanic, or Asian/”other”), did not have health insurance, lived in areas with the lowest median income, and had early stage Hodgkin lymphoma or an undetermined histology.

Dr Olszewski said the lack of treatment among HIV-positive patients could be due to a lingering assumption that they won’t tolerate the treatment well. Or some patients may be declining treatment, either for HIV (thereby making them seem more vulnerable) or for the lymphoma itself.

He noted, however, that lymphoma treatment can be effective for and tolerated by HIV-positive patients, especially when the lymphoma subtype is known.

Among the patients who received chemotherapy in this study, there was no significant difference in the hazard of death between HIV-positive and HIV-negative patients who had one of the defined classical histologic subtypes: nodular sclerosis, mixed cellularity, lymphocyte-rich, or lymphocyte-depleted Hodgkin lymphoma. However, mortality was significantly higher for HIV-positive patients with an undetermined histologic subtype.

HIV budding from a

cultured lymphocyte

Image courtesy of the CDC

Patients with HIV-associated Hodgkin lymphoma may not be getting potentially curative treatment, according to a study published in the journal AIDS.

The study showed that 16% of HIV-positive patients did not receive treatment for their lymphoma, compared to 9% of Hodgkin lymphoma patients who were HIV-negative.

“Hodgkin lymphoma is generally believed to be highly curable,” said study author Adam Olszewski, MD, of Brown University in Providence, Rhode Island.

“We have an expectation to cure over 90% of early stage patients and even 70% to 80% of quite advanced cases.”

It hasn’t been clear whether HIV-positive patients with Hodgkin lymphoma survive the cancer as well as people who are HIV-negative. While some small studies, particularly in Europe, have shown that HIV status makes no difference to survival, observations in the US population suggest that being HIV-positive makes survival less likely.

The new study, which is the largest of its kind to date, may reconcile that conflict. It suggests that, in the US, the reason people with HIV seem to fare worse with the cancer is because they are less likely to be treated for it.

The study included 2090 cases of HIV-associated Hodgkin lymphoma recorded in the National Cancer Data Base between 2004 and 2012, as well as 41,846 cases of Hodgkin lymphoma in patients who were HIV-negative.

The unadjusted 5-year overall survival was 66% for HIV-positive patients and 80% for the HIV-negative population.

Among the HIV-positive patients, 81% received chemotherapy (12% in combination with radiation), 13% received any radiation therapy, and 16% received no treatment for their lymphoma. The corresponding numbers for HIV-negative patients were 87%, 31%, and 9%, respectively (P<0.00001 for all comparisons).

The researchers assessed patient- and disease-related factors associated with the risk of not receiving chemotherapy in the HIV-positive population.

And they found the risk was significantly higher for patients who were older than 40, male, “nonwhite” (black, Hispanic, or Asian/”other”), did not have health insurance, lived in areas with the lowest median income, and had early stage Hodgkin lymphoma or an undetermined histology.

Dr Olszewski said the lack of treatment among HIV-positive patients could be due to a lingering assumption that they won’t tolerate the treatment well. Or some patients may be declining treatment, either for HIV (thereby making them seem more vulnerable) or for the lymphoma itself.

He noted, however, that lymphoma treatment can be effective for and tolerated by HIV-positive patients, especially when the lymphoma subtype is known.

Among the patients who received chemotherapy in this study, there was no significant difference in the hazard of death between HIV-positive and HIV-negative patients who had one of the defined classical histologic subtypes: nodular sclerosis, mixed cellularity, lymphocyte-rich, or lymphocyte-depleted Hodgkin lymphoma. However, mortality was significantly higher for HIV-positive patients with an undetermined histologic subtype.

Vial of cangrelor

Photo courtesy of

The Medicines Company

The watchdog group Public Citizen is alleging that ethics violations were made during the CHAMPION PHOENIX trial, in which researchers compared cangrelor and clopidogrel as thromboprophylaxis for patients undergoing coronary stent procedures.

Public Citizen said the trial “needlessly threatened” the lives of subjects assigned to the control group, and trial participants may not have been informed about the potential risks of enrollment.

Public Citizen sent a letter to the Office of Research Oversight (ORO) at the US Department of Veterans Affairs (VA) asserting that the CHAMPION PHOENIX trial unnecessarily increased the risk of death, heart attack, and other adverse cardiac events for subjects placed in the control group.

The trial was conducted at 153 institutions around the world, including 3 VA facilities: the Dallas VA Medical Center, the Jesse Brown VA Medical Center in Chicago, and the VA Boston Healthcare System. The study involved more than 11,000 subjects, 84 of whom were patients at the 3 VA medical centers.

The primary goal of the trial was to determine whether cangrelor is more effective than clopidogrel at preventing death, heart attacks, and other serious cardiac complications in patients undergoing coronary artery stent procedures.

Public Citizen said the increased risk to subjects in the control group resulted from failure to ensure they were treated with clopidogrel prior to their coronary stent procedures.

An analysis by a senior medical reviewer at the US Food and Drug Administration revealed that failure to administer the necessary antiplatelet treatment occurred in 89% of subjects enrolled at the 3 VA facilities, compared with 30% of subjects enrolled at non-VA facilities.

“The seriously flawed trial protocol paved the way for inappropriate and shocking delays in antiplatelet therapy for subjects enrolled in the control group at all trial institutions,” said Michael Carome, MD, director of Public Citizen’s Health Research Group.

“Inexplicably, the rate of such delays was extraordinarily high at the VA trial sites, making participation in the trial even more hazardous for subjects randomized to the control group at those sites compared with other sites.”

Public Citizen’s complaint contends that the trial’s research protocol was unethical because it failed to require that control group subjects receive lifesaving antiplatelet medications as soon as possible prior to undergoing coronary artery stent procedures.

Prior research conducted by the same research team, expert clinical practice guidelines, and other data available to the researchers established that withholding clopidogrel until after the coronary stent procedures constitutes substandard care.

Indeed, one of the two lead researchers for the trial stated publicly before the trial’s initiation, “If you ask the experts, they will all tell you to give antiplatelet therapy upfront before the PCI [coronary stent] procedure.”

Public Citizen is calling on the ORO to investigate why the institutional review boards responsible for reviewing human research at the 3 VA medical facilities approved the trial given a design that was unethical and failed to minimize the risks to the control group subjects.

The complaint also urges the ORO to investigate whether proper consent of the subjects was obtained in light of the risks, as required by the VA’s human subjects protection rules.

Public Citizen said another issue that requires further inquiry—but falls outside the scope of the ORO’s jurisdiction—is whether inappropriate delays in antiplatelet therapy were more widespread at VA healthcare facilities for patients who did not participate in the trial.

In a separate letter, Public Citizen urged the VA’s Office of Inspector General to launch an investigation to find out.

Vial of cangrelor

Photo courtesy of

The Medicines Company

The watchdog group Public Citizen is alleging that ethics violations were made during the CHAMPION PHOENIX trial, in which researchers compared cangrelor and clopidogrel as thromboprophylaxis for patients undergoing coronary stent procedures.

Public Citizen said the trial “needlessly threatened” the lives of subjects assigned to the control group, and trial participants may not have been informed about the potential risks of enrollment.

Public Citizen sent a letter to the Office of Research Oversight (ORO) at the US Department of Veterans Affairs (VA) asserting that the CHAMPION PHOENIX trial unnecessarily increased the risk of death, heart attack, and other adverse cardiac events for subjects placed in the control group.

The trial was conducted at 153 institutions around the world, including 3 VA facilities: the Dallas VA Medical Center, the Jesse Brown VA Medical Center in Chicago, and the VA Boston Healthcare System. The study involved more than 11,000 subjects, 84 of whom were patients at the 3 VA medical centers.

The primary goal of the trial was to determine whether cangrelor is more effective than clopidogrel at preventing death, heart attacks, and other serious cardiac complications in patients undergoing coronary artery stent procedures.

Public Citizen said the increased risk to subjects in the control group resulted from failure to ensure they were treated with clopidogrel prior to their coronary stent procedures.

An analysis by a senior medical reviewer at the US Food and Drug Administration revealed that failure to administer the necessary antiplatelet treatment occurred in 89% of subjects enrolled at the 3 VA facilities, compared with 30% of subjects enrolled at non-VA facilities.

“The seriously flawed trial protocol paved the way for inappropriate and shocking delays in antiplatelet therapy for subjects enrolled in the control group at all trial institutions,” said Michael Carome, MD, director of Public Citizen’s Health Research Group.

“Inexplicably, the rate of such delays was extraordinarily high at the VA trial sites, making participation in the trial even more hazardous for subjects randomized to the control group at those sites compared with other sites.”

Public Citizen’s complaint contends that the trial’s research protocol was unethical because it failed to require that control group subjects receive lifesaving antiplatelet medications as soon as possible prior to undergoing coronary artery stent procedures.

Prior research conducted by the same research team, expert clinical practice guidelines, and other data available to the researchers established that withholding clopidogrel until after the coronary stent procedures constitutes substandard care.

Indeed, one of the two lead researchers for the trial stated publicly before the trial’s initiation, “If you ask the experts, they will all tell you to give antiplatelet therapy upfront before the PCI [coronary stent] procedure.”

Public Citizen is calling on the ORO to investigate why the institutional review boards responsible for reviewing human research at the 3 VA medical facilities approved the trial given a design that was unethical and failed to minimize the risks to the control group subjects.

The complaint also urges the ORO to investigate whether proper consent of the subjects was obtained in light of the risks, as required by the VA’s human subjects protection rules.

Public Citizen said another issue that requires further inquiry—but falls outside the scope of the ORO’s jurisdiction—is whether inappropriate delays in antiplatelet therapy were more widespread at VA healthcare facilities for patients who did not participate in the trial.

In a separate letter, Public Citizen urged the VA’s Office of Inspector General to launch an investigation to find out.

Vial of cangrelor

Photo courtesy of

The Medicines Company

The watchdog group Public Citizen is alleging that ethics violations were made during the CHAMPION PHOENIX trial, in which researchers compared cangrelor and clopidogrel as thromboprophylaxis for patients undergoing coronary stent procedures.

Public Citizen said the trial “needlessly threatened” the lives of subjects assigned to the control group, and trial participants may not have been informed about the potential risks of enrollment.

Public Citizen sent a letter to the Office of Research Oversight (ORO) at the US Department of Veterans Affairs (VA) asserting that the CHAMPION PHOENIX trial unnecessarily increased the risk of death, heart attack, and other adverse cardiac events for subjects placed in the control group.

The trial was conducted at 153 institutions around the world, including 3 VA facilities: the Dallas VA Medical Center, the Jesse Brown VA Medical Center in Chicago, and the VA Boston Healthcare System. The study involved more than 11,000 subjects, 84 of whom were patients at the 3 VA medical centers.

The primary goal of the trial was to determine whether cangrelor is more effective than clopidogrel at preventing death, heart attacks, and other serious cardiac complications in patients undergoing coronary artery stent procedures.

Public Citizen said the increased risk to subjects in the control group resulted from failure to ensure they were treated with clopidogrel prior to their coronary stent procedures.

An analysis by a senior medical reviewer at the US Food and Drug Administration revealed that failure to administer the necessary antiplatelet treatment occurred in 89% of subjects enrolled at the 3 VA facilities, compared with 30% of subjects enrolled at non-VA facilities.

“The seriously flawed trial protocol paved the way for inappropriate and shocking delays in antiplatelet therapy for subjects enrolled in the control group at all trial institutions,” said Michael Carome, MD, director of Public Citizen’s Health Research Group.

“Inexplicably, the rate of such delays was extraordinarily high at the VA trial sites, making participation in the trial even more hazardous for subjects randomized to the control group at those sites compared with other sites.”

Public Citizen’s complaint contends that the trial’s research protocol was unethical because it failed to require that control group subjects receive lifesaving antiplatelet medications as soon as possible prior to undergoing coronary artery stent procedures.

Prior research conducted by the same research team, expert clinical practice guidelines, and other data available to the researchers established that withholding clopidogrel until after the coronary stent procedures constitutes substandard care.

Indeed, one of the two lead researchers for the trial stated publicly before the trial’s initiation, “If you ask the experts, they will all tell you to give antiplatelet therapy upfront before the PCI [coronary stent] procedure.”

Public Citizen is calling on the ORO to investigate why the institutional review boards responsible for reviewing human research at the 3 VA medical facilities approved the trial given a design that was unethical and failed to minimize the risks to the control group subjects.

The complaint also urges the ORO to investigate whether proper consent of the subjects was obtained in light of the risks, as required by the VA’s human subjects protection rules.

Public Citizen said another issue that requires further inquiry—but falls outside the scope of the ORO’s jurisdiction—is whether inappropriate delays in antiplatelet therapy were more widespread at VA healthcare facilities for patients who did not participate in the trial.

In a separate letter, Public Citizen urged the VA’s Office of Inspector General to launch an investigation to find out.

The development of concomitant allergic reactions to multiple drugs is uncommon. Dermatitis induced by topical or inhaled corticosteroids (eg, budesonide) is rare,¹ and allergic reactions associated with oral nystatin, a macrolide antifungal drug, also are unusual.² We present the case of concomitant sensitization to inhaled budesonide and oral nystatin presenting as allergic contact stomatitis and systemic allergic contact dermatitis. Concomitant allergic reactions to these treatments are rare and may result in diagnostic challenges for the physician.

Case Report

A 66-year-old woman presented to the Allergy Department for evaluation of painful erosions on the oral mucosa that had developed 72 hours after she started treatment with inhaled budesonide (400 mcg every 12 hours) prescribed by her general practitioner for a nonproductive cough. Budesonide inhalation was discontinued due to suspected oral candidiasis and treatment with oral nystatin (500,000 IU every 8 hours) was started, but the erosions did not resolve. After 2 days of treatment with oral nystatin, the patient presented with erythematous macules on the abdomen and thighs as well as a larger erythematous and edematous lesion with papules and vesicles on the hypothenar eminence of the right hand. Nystatin was discontinued and the lesions turned desquamative and healed spontaneously 7 days later. The oral lesions resolved after 15 days with no further treatment.

Patch testing was conducted using a commercially standard series of contact allergens, all of which showed negative results at 48 and 96 hours except for budesonide and triamcinolone, which led to the diagnosis of allergic contact stomatitis from the inhaled budesonide. Patch testing with other corticosteroids was negative. Challenge tests with alternative corticosteroids (ie, oral methylprednisolone, parenteral betamethasone, topical mometasone furoate, inhaled fluticasone) were negative.

In order to rule out involvement of oral nystatin, a single-blind, placebo-controlled oral challenge test was performed. Eight hours after taking oral nystatin (500,000 IU), erythematous macules developed on the patient’s abdomen along with an erythematous, 3×4-cm lesion with papules on the hypothenar eminence of the right hand that was similar in appearance to the original presentation. The lesion on the hand was biopsied and histologic examination revealed spongiosis, edema of the superficial dermis, perivascular lymphocytic infiltrates, and extravasated erythrocytes with no vasculitis. Further patch testing subsequently was conducted with antifungal and antibiotic macrolides in different vehicles (ie, petrolatum, water, polyethylene glycol), as well as with excipients of the oral nystatin formulation that had been tested (Figure). Patch testing was positive with nystatin 10% in petrolatum and nystatin 30,000 IU and 90,000 IU in polyethylene glycol. Testing also were conducted in 7 healthy volunteers to rule out an irritant reaction and showed negative results. Finally, challenge tests conducted in our patient with another antifungal macrolide (parenteral amphotericin B) and antibiotic macrolides (oral clarithromycin, erythromycin, and azithromycin) were negative.

Patch and challenge test results along with the histologic findings led to diagnosis of concomitant systemic allergic contact dermatitis from oral nystatin.

Comment

Our patient presented with 2 unusual delayed hypersensitivity reactions that occurred in the same medical episode: allergic contact stomatitis from inhaled budesonide and systemic allergic contact dermatitis from oral nystatin. It is noteworthy that, despite the poor intestinal absorption of nystatin, systemic contact dermatitis to this drug has been previously described.³ Patch testing with macrolides proved useful for diagnosis in our patient, and based on the results we concluded that polyethylene glycol seemed to be the optimal vehicle for patch testing macrolide drugs versus water or petrolatum, as has been previously suggested.⁴

When a diagnosis of drug allergy is established, it is important to rule out cross-reactivity with other similar drugs by assessing if they produce the same reaction despite differences in chemical structure. Possible cross-reactivity of nystatin with other macrolides (validated on patch testing) has been reported but the tolerability was not evaluated.⁵ Our patient showed good tolerability to other macrolide drugs, both antibiotics and antifungals. Therefore, nystatin does not seem to cross-react with other structurally related drugs belonging to the macrolide group based on our results.

Corticosteroid allergies are more common than those associated with macrolides, especially contact dermatitis. Nonhalogenated corticosteroids (eg, hydrocortisone, budesonide) are most frequently associated with allergic reactions,⁶ and patch testing remains the diagnostic method of choice for the detection of delayed hypersensitivity to corticosteroids. In Europe, standard series include budesonide and tixocortol pivalate, and in the United States they include hydrocortisone 17–butyrate, triamcinolone acetonide, and clobetasol 17–propionate.⁶

To assess cross-reactivity among topical corticosteroids, patch testing with other steroids should be performed. In 1989, Coopman et al⁷ established a classification system for corticosteroids based on molecular structure, thus dividing them into 4 empirical groups: group A, hydrocortisone type; group B, acetonide type; group C, betamethasone type; and group D, ester type. The investigators hypothesized that allergic contact reactions occurred more frequently with corticosteroids belonging to the same group, while cross-reactions were uncommon between groups; however, cross-reactivity is known to occur among corticosteroids belonging to different groups in standard clinical practice, which conflicts with this claim.

Due to distinctively different behaviors among certain compounds in group D, Matura et al⁸ proposed subdividing the ester steroids into 2 groups: group D1, containing C16 methyl substitution and halogenation on the B ring, and group D2, comprising the labile ester steroids that lack both substitutions. A modified classification system including these subdivided groups is presented in the Table.⁸

In recent years, new corticosteroid drugs such as deflazacort, fluticasone propionate, and mometasone furoate have been developed, but classification of these agents has been difficult due to differences in their chemical structure, although mometasone furoate and fluticasone propionate have been included in group D1.⁹ Futhermore, the structural differences of these new steroids may mean less cross-reactivity with other steroids, which would facilitate their use in patients who are allergic to classic steroids. However, cross-reactivity between mometasone furoate and corticosteroids belonging to group B has already been described,¹⁰ which may restrict its use in patients who are allergic to other corticosteroids.

The classification of corticosteroids can provide useful information about cross-reactivity, which may help physicians in choosing an alternative drug in patients with an allergy to topical corticosteroids, but this advice about cross-reactivity does not seem to apply to systemic allergic dermatitis or immediate-type reactions to corticosteroids.¹¹ Therefore, in these types of reactions, an individualized evaluation of the sensitization profile is needed, performing wider studies with alternative corticosteroids by skin tests with late readings and challenge tests.

It is important to emphasize that hypersensitivity to corticosteroids should always be considered in the differential diagnosis along with oral candidiasis when oropharyngeal symptoms appear during inhaled corticosteroid along with oral candidiasis. We recommend that all drugs involved in a presumed allergic reaction must be systematically evaluated because an unexpected concomitant sensitization to multiple drugs could be present.

The development of concomitant allergic reactions to multiple drugs is uncommon. Dermatitis induced by topical or inhaled corticosteroids (eg, budesonide) is rare,¹ and allergic reactions associated with oral nystatin, a macrolide antifungal drug, also are unusual.² We present the case of concomitant sensitization to inhaled budesonide and oral nystatin presenting as allergic contact stomatitis and systemic allergic contact dermatitis. Concomitant allergic reactions to these treatments are rare and may result in diagnostic challenges for the physician.

Case Report

A 66-year-old woman presented to the Allergy Department for evaluation of painful erosions on the oral mucosa that had developed 72 hours after she started treatment with inhaled budesonide (400 mcg every 12 hours) prescribed by her general practitioner for a nonproductive cough. Budesonide inhalation was discontinued due to suspected oral candidiasis and treatment with oral nystatin (500,000 IU every 8 hours) was started, but the erosions did not resolve. After 2 days of treatment with oral nystatin, the patient presented with erythematous macules on the abdomen and thighs as well as a larger erythematous and edematous lesion with papules and vesicles on the hypothenar eminence of the right hand. Nystatin was discontinued and the lesions turned desquamative and healed spontaneously 7 days later. The oral lesions resolved after 15 days with no further treatment.

Patch testing was conducted using a commercially standard series of contact allergens, all of which showed negative results at 48 and 96 hours except for budesonide and triamcinolone, which led to the diagnosis of allergic contact stomatitis from the inhaled budesonide. Patch testing with other corticosteroids was negative. Challenge tests with alternative corticosteroids (ie, oral methylprednisolone, parenteral betamethasone, topical mometasone furoate, inhaled fluticasone) were negative.

In order to rule out involvement of oral nystatin, a single-blind, placebo-controlled oral challenge test was performed. Eight hours after taking oral nystatin (500,000 IU), erythematous macules developed on the patient’s abdomen along with an erythematous, 3×4-cm lesion with papules on the hypothenar eminence of the right hand that was similar in appearance to the original presentation. The lesion on the hand was biopsied and histologic examination revealed spongiosis, edema of the superficial dermis, perivascular lymphocytic infiltrates, and extravasated erythrocytes with no vasculitis. Further patch testing subsequently was conducted with antifungal and antibiotic macrolides in different vehicles (ie, petrolatum, water, polyethylene glycol), as well as with excipients of the oral nystatin formulation that had been tested (Figure). Patch testing was positive with nystatin 10% in petrolatum and nystatin 30,000 IU and 90,000 IU in polyethylene glycol. Testing also were conducted in 7 healthy volunteers to rule out an irritant reaction and showed negative results. Finally, challenge tests conducted in our patient with another antifungal macrolide (parenteral amphotericin B) and antibiotic macrolides (oral clarithromycin, erythromycin, and azithromycin) were negative.

Patch and challenge test results along with the histologic findings led to diagnosis of concomitant systemic allergic contact dermatitis from oral nystatin.

Comment

Our patient presented with 2 unusual delayed hypersensitivity reactions that occurred in the same medical episode: allergic contact stomatitis from inhaled budesonide and systemic allergic contact dermatitis from oral nystatin. It is noteworthy that, despite the poor intestinal absorption of nystatin, systemic contact dermatitis to this drug has been previously described.³ Patch testing with macrolides proved useful for diagnosis in our patient, and based on the results we concluded that polyethylene glycol seemed to be the optimal vehicle for patch testing macrolide drugs versus water or petrolatum, as has been previously suggested.⁴

When a diagnosis of drug allergy is established, it is important to rule out cross-reactivity with other similar drugs by assessing if they produce the same reaction despite differences in chemical structure. Possible cross-reactivity of nystatin with other macrolides (validated on patch testing) has been reported but the tolerability was not evaluated.⁵ Our patient showed good tolerability to other macrolide drugs, both antibiotics and antifungals. Therefore, nystatin does not seem to cross-react with other structurally related drugs belonging to the macrolide group based on our results.

Corticosteroid allergies are more common than those associated with macrolides, especially contact dermatitis. Nonhalogenated corticosteroids (eg, hydrocortisone, budesonide) are most frequently associated with allergic reactions,⁶ and patch testing remains the diagnostic method of choice for the detection of delayed hypersensitivity to corticosteroids. In Europe, standard series include budesonide and tixocortol pivalate, and in the United States they include hydrocortisone 17–butyrate, triamcinolone acetonide, and clobetasol 17–propionate.⁶

To assess cross-reactivity among topical corticosteroids, patch testing with other steroids should be performed. In 1989, Coopman et al⁷ established a classification system for corticosteroids based on molecular structure, thus dividing them into 4 empirical groups: group A, hydrocortisone type; group B, acetonide type; group C, betamethasone type; and group D, ester type. The investigators hypothesized that allergic contact reactions occurred more frequently with corticosteroids belonging to the same group, while cross-reactions were uncommon between groups; however, cross-reactivity is known to occur among corticosteroids belonging to different groups in standard clinical practice, which conflicts with this claim.

Due to distinctively different behaviors among certain compounds in group D, Matura et al⁸ proposed subdividing the ester steroids into 2 groups: group D1, containing C16 methyl substitution and halogenation on the B ring, and group D2, comprising the labile ester steroids that lack both substitutions. A modified classification system including these subdivided groups is presented in the Table.⁸

In recent years, new corticosteroid drugs such as deflazacort, fluticasone propionate, and mometasone furoate have been developed, but classification of these agents has been difficult due to differences in their chemical structure, although mometasone furoate and fluticasone propionate have been included in group D1.⁹ Futhermore, the structural differences of these new steroids may mean less cross-reactivity with other steroids, which would facilitate their use in patients who are allergic to classic steroids. However, cross-reactivity between mometasone furoate and corticosteroids belonging to group B has already been described,¹⁰ which may restrict its use in patients who are allergic to other corticosteroids.

The classification of corticosteroids can provide useful information about cross-reactivity, which may help physicians in choosing an alternative drug in patients with an allergy to topical corticosteroids, but this advice about cross-reactivity does not seem to apply to systemic allergic dermatitis or immediate-type reactions to corticosteroids.¹¹ Therefore, in these types of reactions, an individualized evaluation of the sensitization profile is needed, performing wider studies with alternative corticosteroids by skin tests with late readings and challenge tests.

It is important to emphasize that hypersensitivity to corticosteroids should always be considered in the differential diagnosis along with oral candidiasis when oropharyngeal symptoms appear during inhaled corticosteroid along with oral candidiasis. We recommend that all drugs involved in a presumed allergic reaction must be systematically evaluated because an unexpected concomitant sensitization to multiple drugs could be present.

The development of concomitant allergic reactions to multiple drugs is uncommon. Dermatitis induced by topical or inhaled corticosteroids (eg, budesonide) is rare,¹ and allergic reactions associated with oral nystatin, a macrolide antifungal drug, also are unusual.² We present the case of concomitant sensitization to inhaled budesonide and oral nystatin presenting as allergic contact stomatitis and systemic allergic contact dermatitis. Concomitant allergic reactions to these treatments are rare and may result in diagnostic challenges for the physician.

Case Report

A 66-year-old woman presented to the Allergy Department for evaluation of painful erosions on the oral mucosa that had developed 72 hours after she started treatment with inhaled budesonide (400 mcg every 12 hours) prescribed by her general practitioner for a nonproductive cough. Budesonide inhalation was discontinued due to suspected oral candidiasis and treatment with oral nystatin (500,000 IU every 8 hours) was started, but the erosions did not resolve. After 2 days of treatment with oral nystatin, the patient presented with erythematous macules on the abdomen and thighs as well as a larger erythematous and edematous lesion with papules and vesicles on the hypothenar eminence of the right hand. Nystatin was discontinued and the lesions turned desquamative and healed spontaneously 7 days later. The oral lesions resolved after 15 days with no further treatment.

Patch testing was conducted using a commercially standard series of contact allergens, all of which showed negative results at 48 and 96 hours except for budesonide and triamcinolone, which led to the diagnosis of allergic contact stomatitis from the inhaled budesonide. Patch testing with other corticosteroids was negative. Challenge tests with alternative corticosteroids (ie, oral methylprednisolone, parenteral betamethasone, topical mometasone furoate, inhaled fluticasone) were negative.

In order to rule out involvement of oral nystatin, a single-blind, placebo-controlled oral challenge test was performed. Eight hours after taking oral nystatin (500,000 IU), erythematous macules developed on the patient’s abdomen along with an erythematous, 3×4-cm lesion with papules on the hypothenar eminence of the right hand that was similar in appearance to the original presentation. The lesion on the hand was biopsied and histologic examination revealed spongiosis, edema of the superficial dermis, perivascular lymphocytic infiltrates, and extravasated erythrocytes with no vasculitis. Further patch testing subsequently was conducted with antifungal and antibiotic macrolides in different vehicles (ie, petrolatum, water, polyethylene glycol), as well as with excipients of the oral nystatin formulation that had been tested (Figure). Patch testing was positive with nystatin 10% in petrolatum and nystatin 30,000 IU and 90,000 IU in polyethylene glycol. Testing also were conducted in 7 healthy volunteers to rule out an irritant reaction and showed negative results. Finally, challenge tests conducted in our patient with another antifungal macrolide (parenteral amphotericin B) and antibiotic macrolides (oral clarithromycin, erythromycin, and azithromycin) were negative.

Patch and challenge test results along with the histologic findings led to diagnosis of concomitant systemic allergic contact dermatitis from oral nystatin.

Comment

Our patient presented with 2 unusual delayed hypersensitivity reactions that occurred in the same medical episode: allergic contact stomatitis from inhaled budesonide and systemic allergic contact dermatitis from oral nystatin. It is noteworthy that, despite the poor intestinal absorption of nystatin, systemic contact dermatitis to this drug has been previously described.³ Patch testing with macrolides proved useful for diagnosis in our patient, and based on the results we concluded that polyethylene glycol seemed to be the optimal vehicle for patch testing macrolide drugs versus water or petrolatum, as has been previously suggested.⁴

When a diagnosis of drug allergy is established, it is important to rule out cross-reactivity with other similar drugs by assessing if they produce the same reaction despite differences in chemical structure. Possible cross-reactivity of nystatin with other macrolides (validated on patch testing) has been reported but the tolerability was not evaluated.⁵ Our patient showed good tolerability to other macrolide drugs, both antibiotics and antifungals. Therefore, nystatin does not seem to cross-react with other structurally related drugs belonging to the macrolide group based on our results.

Corticosteroid allergies are more common than those associated with macrolides, especially contact dermatitis. Nonhalogenated corticosteroids (eg, hydrocortisone, budesonide) are most frequently associated with allergic reactions,⁶ and patch testing remains the diagnostic method of choice for the detection of delayed hypersensitivity to corticosteroids. In Europe, standard series include budesonide and tixocortol pivalate, and in the United States they include hydrocortisone 17–butyrate, triamcinolone acetonide, and clobetasol 17–propionate.⁶

To assess cross-reactivity among topical corticosteroids, patch testing with other steroids should be performed. In 1989, Coopman et al⁷ established a classification system for corticosteroids based on molecular structure, thus dividing them into 4 empirical groups: group A, hydrocortisone type; group B, acetonide type; group C, betamethasone type; and group D, ester type. The investigators hypothesized that allergic contact reactions occurred more frequently with corticosteroids belonging to the same group, while cross-reactions were uncommon between groups; however, cross-reactivity is known to occur among corticosteroids belonging to different groups in standard clinical practice, which conflicts with this claim.

Due to distinctively different behaviors among certain compounds in group D, Matura et al⁸ proposed subdividing the ester steroids into 2 groups: group D1, containing C16 methyl substitution and halogenation on the B ring, and group D2, comprising the labile ester steroids that lack both substitutions. A modified classification system including these subdivided groups is presented in the Table.⁸

In recent years, new corticosteroid drugs such as deflazacort, fluticasone propionate, and mometasone furoate have been developed, but classification of these agents has been difficult due to differences in their chemical structure, although mometasone furoate and fluticasone propionate have been included in group D1.⁹ Futhermore, the structural differences of these new steroids may mean less cross-reactivity with other steroids, which would facilitate their use in patients who are allergic to classic steroids. However, cross-reactivity between mometasone furoate and corticosteroids belonging to group B has already been described,¹⁰ which may restrict its use in patients who are allergic to other corticosteroids.

The classification of corticosteroids can provide useful information about cross-reactivity, which may help physicians in choosing an alternative drug in patients with an allergy to topical corticosteroids, but this advice about cross-reactivity does not seem to apply to systemic allergic dermatitis or immediate-type reactions to corticosteroids.¹¹ Therefore, in these types of reactions, an individualized evaluation of the sensitization profile is needed, performing wider studies with alternative corticosteroids by skin tests with late readings and challenge tests.

It is important to emphasize that hypersensitivity to corticosteroids should always be considered in the differential diagnosis along with oral candidiasis when oropharyngeal symptoms appear during inhaled corticosteroid along with oral candidiasis. We recommend that all drugs involved in a presumed allergic reaction must be systematically evaluated because an unexpected concomitant sensitization to multiple drugs could be present.